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Chemistry of Lipids and Eicosanoids

Q.1- Which out of the  following alcohols  is used for waxes

a) Cholesterol                                                                   

b) Glycerol

c)  Cetyl Alcohol                                                               

d) Sphingol                                        

Q.2- Choose the Dienoic fatty acid out of the following-

a) Oleic acid                                                                       

b) Linoleic acid

c) Linolenic acid                                                                

d) Stearic acid                                   

Q.3- Which of the following lipids is abundantly present in the white matter of brain?

a) Galactocerebroside                                                  

b) Glucocerebroside

c) Triglycerides                                                                 

d) Gangliosides                                

Q.4- Which out of the following is not a Glycerophospholipid?

a) Cardiolipin                                                                     

b) Plasmalogen

c) Lecithin                                                                           

d) Sphingomyelin                            

Q.5- Which out of the following enzymes is defective in Gaucher’s disease?

a) β- Glucocerebrosidase                                            

b) Hexosaminidase A

c) Sphingomyelinase                                                     

d) β- Galactocerebosidase          

Q.6- Choose the Glycerophospholipid that acts as a precursor for second messenger-

a) Phosphatidyl choline                                                

b) Phosphatidyl Inositol

c) Phosphatidyl Serine                                                  

d) Phosphatidyl Ethanolamine  

Q.7- Cholesterol is transported from extra hepatic tissues to liver by which of the following lipoproteins?

a) Chylomicrons                                                                               

b) VLDL

c) LDL                                                                                   

d) HDL                                                  

8) All are non-essential fatty acids except-              

a)Palmitic acid                                                  

b) Linolenic

c) Oleic acid                                                                       

d) Stearic acid                                   

9) Which out of the following fatty acids is a precursor of prostaglandins?

a) Linoleic acid                                                                  

b) Arachidonic acid

c) Eicosapentaenoic acid                                              

d) Linolenic acid                               

10) Which of the following is an animal sterol?

a)Ergo sterol,                                                                    

b) Stigma sterol,

c) Sitosterol                                                                       

d) Cholesterol                                  

11) Which out of the following is a fatty acid with 16 carbon atoms and one double bond?

a) Palmitoleic acid                                                           

b) Stearic acid

c) Erucic acid                                                                      

d) Elaidic acid                                    

12) Which out of the following is an ώ 6 fatty acid?

a) α Linolenic acid                                                           

b) Elaidic acid

c) Oleic acid                                                                       

d) Arachidonic acid                         

13) A  polar derivative of cholesterol is

a) Bile salt                                                                           

b) Oestrogen

c) Vitamin D                                                                       

d) Progesterone                                              

14) Which type of lipid is a receptor for cholera toxin in the intestine?

a) GM2 Ganglioside                                                       

b) GM1Ganglioside

c) Sphingomyelin                                                            

d) Galactocerebroside                  

15) Acetyl number is a measure of-                                                        

a) Degree of unsaturation of a fat                           

b) Degree of rancidity of a fat

c) Measure of volatile fatty acids in a fat                               

d) Measure of number of –OH groups in a fat

16) All are conditions of hypercholesterolemia except-

a) Anemia,                                                                         

b) Diabetes Mellitus,

c) Hypothyroidism                                                          

d) Nephrotic syndrome                

17) Which out of the following is an inter mediate both for the synthesis of phospholipids and Triacylglycerols?

a) Diacyl glycerol                                                              

b) Cholesterol

c) Choline                                                                           

d) Inositol                                           

18) Which   fatty acid would have the least melting point out of the following-?

a) Stearic acid                                                                   

b) Arachidonic acid

c) Timnodonic acid                                                          

d) Palmitic acid                                 

19) A 3 year child was brought with hepatosplenomegaly and mental retardation. Biopsy reveals accumulation of sphingomyelin. What is the nature of the disease?

a)Gaucher’s                                                                      

b) Niemann Pick’s

c) Krabbe’s                                                                        

d Tay Sach’s                                       

20) Which of the following is not a source of glycerol?

a) Diet                                                                                  

b) Adipolysis

c) Glycolysis                                                                       

d) Glycogenolysis                            

Answer Key

1)- c, 2)-b, 3)-a, 4)-d, 5)-a, 6)-b, 7)-d, 8)-b, 9)-b,10)-d,11)-a,12)-d,13)-a,14)-b,15)-d,16)-a, 17)-a, 18)-c, 19)-b, 20)-d.

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Q.1- Which out of the following lipid is a charged lipid?

a) Phospholipid                                                                

b) Cholesterol

b) Triacyl glycerol                                                            

d) Glucocerebroside      

Q.2- Choose the ω9 fatty acid out of the following-

a) Oleic acid                                                                       

b) Linoleic acid

c) Linolenic acid                                                                

d) Stearic acid                                   

Q.3- Choose the incorrect statement about fatty acids out of the following-      

a) The melting point of fatty acids decreases with the increasing degree of unsaturation

b) The membrane lipids contain mostly unsaturated fatty acids

c) Lipids in tissues that are subject to cooling are more unsaturated

d) Naturally occurring unsaturated long-chain fatty acids are nearly all of the Trans configuration.

Q.4- Which out of the following is a Glycerophospholipid?

a) Cardiolipin                                                                     

b) Galactosyl ceramide

c) GM2                                                                                

d) Sphingomyelin                            

Q.5- Which out of the following enzymes is defective in Niemann Pick’s disease?

a) β- Glucocerebrosidase                                            

b) Hexosaminidase A

c) Sphingomyelinase                                                     

d) β- Galactocerebosidase          

Q.6- Choose a lipid that acts as a precursor for Glycerophospholipids

a) Cholesterol                                                   

b) Sphingosine

c) N-Acetyl Neuraminic acid                                                       

d) Phosphatidic acid                       

Q.7- Dietary triacylglycerols are transported from liver to extra hepatic tissues by which of the following lipoproteins?

a) Chylomicrons                                                                               

b) VLDL

c) LDL                                                                                   

d) HDL                                                  

Q.8) All except one are fatty acids with 18 carbon atoms –

a)Oleic acid                                                                        

b) Linolenic

c) Palmitic acid                                                                  

d) Stearic acid                                   

Q.9) For which out of the following compounds cholesterol serves as a precursor?

a) Bile pigments                                                                               

b) Bile salts

c) Vitamin K                                                                       

d) Triacyl glycerol                            

Q.10) Glycerol is required for the formation of all of the following compounds except-

a) Glucose                                                                          

b) Triacyl glycerol

c) Phospholipids                                                              

d) Glycolipids                                    

Q.11) Which out of the following is a fatty acid with 18 carbon atoms and one double bond in the trans  configuration?

a) Palmitoleic acid                                                           

b) Oleic acid

c) Erucic acid                                                                      

d) Elaidic acid                                    

Q. 12) Which out of the following is a hydroxy fatty acid?

a) α Linolenic acid                                                           

b) Linoleic acid

c) Palmitic acid                                                                  

d) Cerebronic acid                          

Q. 13)Which of the following enzymes is present in the snake venom ?

a) Phospholipase A1                                                      

b) PhospholipaseA2

c) Phospholipase B                                                         

d) Phospholipase D        

Q. 14) Which type of lipid is negatively charged at physiological pH?

a) GM2 Ganglioside                                                       

b) Glucocerebroside

c) Sphingomyelin                                                            

d) Galactocerebroside                  

Q. 15) The Iodine number of Linolenic acid is-                                                                                  

a) 1                                                                                        

b) 6

c) 4                                                                                        

d) 3                                                       

Q. 16) Which of the following is not a derived lipid?

a) Arachidonic acid                                                         

b) Diacyl glycerol

c) HDL                                                                                  

d) Vitamin D                                      

Q. 17) Which out of the following is not an essential fatty acid

a) Arachidic acid                                                               

b) Arachidonic acid

c) Linoleic acid                                                                  

d) Linolenic acid                                               

Q. 18) – The number of mgms of KOH required to neutralize the free and combined fatty acids in one gram of a given fat is called-

a) Acid number                                                                

b) Polenske number

c) Saponification number                                            

d) Iodine number                           

Q. 19) – Choose out of the following, a fatty acid with 20 carbon atoms and four double bonds-

a) Timnodonic acid                                                         

b) Arachidonic acid

c) Clupanodonic acid                                                      

d) Nervonic acid                              

Q. 20) Glycerol is not present in-

a) Cerebrosides                                                                               

b) Platelet activating factor

c) Lecithin                                                                           

d) Plasmalogen   

 Answer key                       

1)-a, 2)-a, 3)-d, 4)-a, 5)- b, 6)- d, 7)- b, 8)- c, 9)- b, 10)- d, 11)- d, 12)- d, 13)- b, 14)- a, 15)- b, 16)- c, 17)- a, 18)- c, 19)- b, 20)-a.

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Q.1- Which out of the following is a storage form of lipid?

a) Phospholipid                                                                

b) Glycolipid

c) Triacyl glycerol                                                             

d) Sulfolipid                                       

Q.2- Choose the monounsaturated fatty acid out of the following-

a) Oleic acid                                                                       

b) Linoleic acid

c) Linolenic acid                                                                

d) Stearic acid                                   

Q.3- Choose the correct statement about fatty acids out of the following-          

a) The melting point of fatty acids increases with the increasing degree of unsaturation

b) The membrane lipids contain mostly unsaturated fatty acids

c) Lipids in tissues that are subject to cooling are more saturated

d) Naturally occurring unsaturated long-chain fatty acids are nearly all of the Trans configuration.

Q.4- Which out of the following is a Sphingophospholipid?

a) Cardiolipin                                                                     

b) Plasmalogen

c) Lecithin                                                                           

d) Sphingomyelin                            

Q.5- Which out of the following enzymes is defective in Gaucher’s disease?

a) β- Glucocerebrosidase                                            

b) Hexosaminidase A

c) Sphingomyelinase                                                     

d) β- Galactocerebosidase          

Q.6- Choose the Glycerophospholipid that acts as a lipotropic agent-

a) Phosphatidyl choline                                                

b) Phosphatidyl Inositol

c) Phosphatidyl Serine                                                  

d)Cardiolipin     

Q.7- Dietary triacylglycerols are transported from intestine to hepatic and extra hepatic tissues by which of the following lipoproteins?

a) Chylomicrons                                                                               

b) VLDL

c) LDL                                                                                   

d) HDL                                                  

Q.8) All are non -essential fatty acids except-             

a)Oleic acid                                                                        

b) Linolenic

c) Palmitic acid                                                                  

d) Stearic acid                                   

Q.9) For which out of the following compounds cholesterol does not serve as a precursor?

a) Bile pigments                                                                               

b) Bile salts

c) Vitamin D                                                                       

d) Sex hormones                            

Q.10) Glycerol is required for the formation of all of the following compounds except-

a) Glucose                                                                          

b) Triacyl glycerol

c) Phospholipids                                                              

d) Glycolipids                    

Q.11) Which out of the following is a fatty acid with 18 carbon atoms and one double bond in the cis configuration?

a) Palmitoleic acid                                                           

b) Oleic acid

c) Erucic acid                                                                      

d) Elaidic acid                                    

Q. 12) Which out of the following is an ώ 6 fatty acid?

a) α Linolenic acid                                                           

b) Linoleic acid

c) Palmitic acid                                                                  

d) Cerebronic acid                          

Q. 13) The normal level of serum Total cholesterol is———–?

a) 150-220 mg/dl                                                             

b) 100-200 mg/dl

c) 1.5-2.5g/dl                                                                     

d) 20-40 mg/dl                                  

Q. 14) Which type of lipid is left undegraded in Niemann Pick’s disease?

a) GM2 Ganglioside                                                       

b) GM1Ganglioside

c) Sphingomyelin                                                            

d) Galactocerebroside                  

Q. 15) The Iodine number of cholesterol is-                                                                                       

a) 1                                                                                        

b) 2

c) 4                                                                                        

d) 3                                                       

Q. 16) What are the components of a Galactocerebroside?                     

a) Sphingosine+ fatty acid+ Galactose                                   

b) Glycerol +Fatty acids +Phosphoric acid+ Galactose

c) Glycerol +Fatty acids +Phosphoric acid +Nitrogenous base+ Galactose

d) Sphingosine+ fatty acids +Phosphoric acid+ Galactose                                              

Q. 17) Which phospholipid out of the following is a component of inner mitochondrial membrane?

a) Cardiolipin                                                                     

b) Lecithin

c) Plasmalogen                                                                 

d) Cephalin                                        

Q. 18)- The significance of estimating L: S ratio of amniotic fluid in a pregnant female lies in evaluating-

a) Fetal heart rate                                           

b) Fetal lung maturity

c) Fetal head size                                                            

d) Expected date of delivery      

Q. 19) – Choose out of the following, a fatty acid with 20 carbon atoms and four double bonds-

a) Timnodonic acid                                                         

b) Arachidonic acid

c) Clupanodonic acid                                                     

d) Nervonic acid                              

Q. 20) Glycerol is present in-

a) Cerebrosides                                                                               

b) Gangliosides

c) Sphingomyelin                                                            

d) Plasmalogen                

Key to Answers

1)- c, 2)-a,3)-b,4)-d,5)-a,6)-a,7)-a,8)-b,9)-a,10)-d,11)-b,12)-b,13)-b,14)-c,15)-b,16)-a,17)-a,18)-b,19)-b,20)-d

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Q.1- What are ω6 and ω3 fatty acid ? Give examples in support of your answer and discuss their biological significance.

Q.2- Explain the terms-

a) Saponification

b)  Rancidity

c) Lipid Peroxidation

Q.3- Give example of each of the following

a)  Cyclic fatty acid

b) Branched chain fatty acid

c) Trans fatty acid

d) Pentaenoic acid

e) Saturated fatty acid with 20 carbon atoms

Q.4- What is the relationship of melting point with the degree of unsaturation of fatty acids? What is its biological significance?

Q.5- What are essential fatty acids, discuss the functions and the clinical consequences of their deficiencies?

Q.6- Discuss the structure, functions and clinical significance of cholesterol.

Q.7- Give a brief account of the chemistry and functions of phospholipids.

Q.8- Differentiate between Cerebrosides and Gangliosides, in reference to chemistry, functions and clinical significance of each of them.

Q.9- Give a brief account of biochemical defect, clinical symptoms, laboratory diagnosis and treatment of the following diseases-

a) Tay- sach’s disease

b) Gaucher disease

c) Niemann Pick’s disease

Q.10- What is the clinical significance of Lecithin/ Sphingomyelin (L/S) ratio?

Q.11- Discuss in brief about the sources, functions and significance of glycerol.

Q.12- Draw a well labeled diagram of a liposome, discuss its structure and functions.

Q.13- Enumerate the derived lipids and give a detailed account of any two of them.

Q.14- Why do saturated fatty acids have a higher boiling point than the unsaturated fatty acids with the same number of carbon atoms?

Q.15- Give a brief account of esterification of cholesterol by Acyl transferases, differentiate between the activities of each of them.

Q.16- What are phospholipases? Mention the site of action and the biological significance of each of them.

Q.17-Give the components and the biological function of each of the following

a) Triglycerides

b) Phosphatidyl Choline

c) Sphingomyelin

d) GM1- Ganglioside

Q.18- Give an account of lipid storage diseases in a tabular manner, mentioning the biochemical defect and clinical manifestations.

Q.19- Write the significance of-

a) Acid number

b) Acetyl number

c) Saponification number

d) Iodine number.

Q.20- Give a brief account of the steps of Prostaglandin synthesis, mention the role of COX inhibitors.

Q.21- What is the biological and clinical significance of prostaglandins?

Q.22- What is the biochemical basis of low dose Aspirin in antithrombotic prophylaxis?

Q.23-Discuss the synthesis of biologically important Leukotrienes and Lipoxins from Arachidonic acid

Q.24-What is the relationship of COX inhibition and gastric ulceration?

Q.25-What is the role played by Prostaglandins in pregnancy?

Q.26-What is the drawback of usage of prostaglandins as conventional drugs ?

Q.27-What is the reason of Aspirin induced asthma?

Q.28- Differentiate between prostacyclin and Thromboxane.

Q.29- What is the clinical significance of Leukotrienes ?

Q.30- What is SRSA ? Explain briefly.

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Q.1- What are Eicosanoids? Discuss in brief about the chemistry and biological importance of Eicosanoids.

Answer- Prostaglandins and related compounds are collectively known as Eicosanoids. Most are produced from Arachidonic acid, a 20-carbon polyunsaturated fatty acid  (5,8,11,14-eicosatetraenoic acid).(Figure-1)

Figure-1- showing the structure of Arachidonic acid

Dihomo-gamma-linolenic acid (DGLA) and eicosapentaenoic acid (EPA, timnodonic acid) also serve as eicosanoid precursors.

Eicosanoids are basically classified in to two main groups-

a)      Prostanoids

b)     Leukotrienes and Lipoxins.

Prostanoids are further sub classified in to three groups-

1)     Prostaglandins(PGs)

2)     Prostacyclins(PGIs)

3)     Thromboxanes (TXs)

 a) Prostanoids- All prostanoids are considered to be derivatives of a cyclic saturated fatty acid called Prostanoic acid.

1) Chemistry of Prostaglandins- According to structure PGs can be divided into  four major groups.-  PG-E, PG-F, PG-A and PG-B groups. Besides these PG-C and PG-D groups have also been recognized (Figure-2).

PG- G and PG-H considered as Primary PGs, are intermediates in the synthesis of other prostaglandins. Difference in the four main groups is due to the difference in the structure of cyclpentane ring.

Figure-2 –showing the structure of different prostaglandins. R1 and R2 represent the side chain which is same in all members of a series.

Depending upon the number of double bonds in the side chain they are denoted by a subscript- PGE-1, PGE-2, PGE-3 etc.

Series-1 contain one double bond at 13-14 position (Trans)

Series-2 have two double bonds at 13-14 (trans) and 5-6 (Cis)

Series-3 – have three double bonds at13-14 (trans) , 5-6 (Cis) and 17-18 (Cis) positions

2) Chemistry of Prostacyclins- contain another ring between 6 th and 9th carbon atoms (Figure-3).

There are three series of Prostacyclins same as PGs i.e. PI-1,PI-2 and PI-3 etc.

 

Figure-3- showing the structure of Prostacyclin

3) Chemistry of Thromboxanes-  Thromboxanes have a six membered Oxane ring (Figure-4).  

There are three series for Thromboxanes.

Figure-4- showing the structure of Thromboxanes

Series- 2 Prostanoids are the most important Prostanoids in the biological system.

b) Leukotrienes and Lipoxins- Unlike the prostaglandins and the thromboxanes, which are products of the cyclooxygenase pathway, leukotrienes and lipoxins are products of the 5- and 15- lipoxygenase pathways, respectively. The name “leukotrienes” refers to the leukocyte origin of these molecules, and to the conjugated double bonds in their structure.

The lipoxins are derived from the 15-lipoxygenase pathway and have a fully conjugated tetraene structure.

Leukotrienes of series-1 are denoted by subscript 3 and there are different types of leukotrienes varying from A to E which are represented by LT-A 3, LT-B3 etc.

Series -2 is represented by suffix-4- LT-A4, LTB-4 and seies-3 is represented by suffix-5, LT-A5, LT-B5, LT-C5 s etc.

Biological importance- Eicosanoids are not stored within cells; rather they are synthesized as required in response to hormonal signals. They are considered “local hormones. They are not transported to distal sites within the body.” They function close to the site of synthesis (autocrine, paracrine), where they are rapidly deactivated before they enter circulation as inactive metabolites.

They have various roles in inflammation, fever, regulation of blood pressure, blood clotting, immune system modulation, control of reproductive processes, tissue growth, and regulation of the sleep/wake cycle. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. The lipoxins are anti-inflammatory eicosanoids synthesized through lipoxygenase interactions.

Q.2- Give a brief account of the synthesis of Prostanoids. Highlight the clinical significance if any of this pathway.

Answer-

Synthesis of Prostanoids- The principal precursor of prostanoids is Arachidonic acid. Additionally, biologically significant prostanoids are derived from dihomo-γ-linolenic acid (DGLA) which is produced in the reaction pathway leading to arachidonic acid from Linoleic acid (see Figure-5 below) ; and also from Eicosa pentaenoic acid which is produced from dietary Alpha Linolenic acid.

Figure-5 showing the formation of Arachidonic acid from dietary Linoleic acid and synthesis of Eicosa pentaenoic acid from Alpha Linolenic acid

Series -1 Eicosanoids are synthesized from dihomo-γ-linolenic acid (DGLA)

Series-2 from Arachidonic acid and

Series-3 are synthesized from Eicosa pentaenoic acid.

The major source of arachidonic acid is through its release from cellular stores. Within the cell, it resides predominantly at the C–2 position of membrane phospholipids and is released from there upon the activation of PLA2 (Phospholipase A2)

Steps of synthesis of Prostanoids- This pathway is also called Cyclo-oxygenase pathway or cyclic pathway.

The prostanoid signaling cascade begins with an external stimulus, most often the binding of a ligand to a cell surface receptor that activates one or more phospholipase A2. The latter are enzymes that release Arachidonic acid from its esterified form in membrane phospholipids such as phosphatidylethanolamine and phosphatidyl Inositol.

Figure-6 – showing the release of Arachidonic acid from Membrane phospholipid

Arachidonate is converted to PGH2 by one of the isoforms of PGH synthase (PGHS-1 or -2), enzymes localized to the endoplasmic reticulum membrane and the nuclear envelope.

PGH2 is in turn metabolized to the prostanoid lipid signals (PGD2, PGE2, PGF2α, PGH2, PGI2, or TXA2) by one of the secondary enzymes that are named for the individual prostanoid produced. The type of prostanoid produced is determined by which downstream enzyme is present; usually one downstream enzyme predominates in a given cell. For example, the prominent secondary enzyme in platelets is thromboxane synthase, whereas vascular endothelial cells feature prostacyclin (PGI) synthase.

Conversion of Arachidonate to PGH2 is a key regulatory step in prostanoid biosynthesis. (Figure )

Each PGHS isoform catalyzes two separate reactions.

The first reaction (Arachidonate to PGG2) involves insertion of two molecules of oxygen and cyclization of the fatty acid backbone. This step is catalyzed by the cyclo-oxygenase activity of PGHS-1 or -2; it is these cyclo-oxygenase activities (also called COX-1 and COX-2) that are inhibited by nonsteroidal antiinflammatory drugs (NSAIDs).

The second step (PGG2 to PGH2) involves the reduction of the hydro peroxide on C15 to an alcohol and is catalyzed by the peroxidase activity of PGHS-1 or -2.

Clinical significance

Although both PGHS isoforms have cyclooxygenase and peroxidase activities and are structurally similar proteins, they have very distinct pathophysiological functions.

  • Many cells, including platelets and gastric mucosal cells, have moderate levels of the “basal” isoform, PGHS-1. Functions attributed to PGHS-1 include regulating hemostasis and vascular tone, renal function, and maintaining gastric mucosal integrity.
  • A smaller number of cells, such as macrophages, vascular endothelial cells, and fibroblasts, dramatically upregulate levels of the “inducible” isoform, PGHS-2, in response to cytokines or mitogens. PGHS-2 has been implicated in cell proliferation, inflammation, carcinogenesis, and parturition.
  • Many cyclooxygenase inhibitors have been developed and their structures are quite varied substrate for binding to the cyclooxygenase site on the enzyme. Aspirin was one of the earliest NSAIDs discovered and is now widely used as an analgesic and antiinflammatory agent. More recently, aspirin has emerged as a very useful antithrombotic agent because of its action against platelet cyclooxygenase activity. Aspirin brings about inhibition of the enzyme by covalent modification making the transition irreversible.
  • Flurbiprofen and indomethacin are able to inhibit both PGHS-1 and -2, although they do not covalently modify either protein. Ibuprofen forms only transient complexes with both PGHS isoforms.

 

Figure -7– showing the steps of formation of Eicosanoids

  • The recently developed coxibs (such as celecoxib and rofecoxib) derive their exquisitely selective inhibition of PGHS-2 cyclooxygenase from their ability to  bring about noncovalent modification of PGHS-2 and not of PGHS-1. This selectivity has made the coxibs very useful for antiinflammatory and antiproliferative therapy with reduced gastrointestinal side effects, but it also makes them ineffective as antiplatelet agents and consequently can increase cardiovascular risks.

Low-dose aspirin is often used in antithrombotic prophylaxis

Thromboxane produced by platelet COX-1 in concert with a downstream enzyme is prothrombotic, so aspirin and other NSAIDs cause platelet dysfunction and increase bleeding time. Aspirin is unusual in that it causes covalent, irreversible inhibition of the COX protein, whereas other NSAIDs have noncovalent, reversible actions. Thus, platelets, because they cannot synthesize more COX protein, are irreversibly affected by aspirin but only temporarily affected by other NSAIDs. Due to this reason only Low-dose aspirin is often used in antithrombotic prophylaxis as in the prevention of stroke, I.H.D.etc.

Figure-8- showing the activities of COX-1 and COX-2 enzymes

The prothrombotic and vasoconstrictive actions of COX-1-derived Thromboxane in the vasculature are opposed by an antithrombotic and vasodilative  prostaglandin, prostacyclin, that originates from COX-2 in vascular endothelial cells. The COX-2 selective coxibs thus tend to decrease prostacyclin levels in the vasculature without reducing the thromboxane levels. This tendency is thought to explain the small but significant increase in cardiovascular risk that recently led to withdrawal of two coxibs from theU.S. market. Moreover COX protein, are irreversibly affected by aspirin but only temporarily affected by other NSAIDs.

 Q.3- How are prostaglandins catabolized in the body?

Answer-All Arachidonic acid derivatives are quickly, in less than a few minutes, inactivated in the body by several complex reactions. “Switching off” of prostaglandin activity is partly achieved by a remarkable property of cyclooxygenase—that of self-catalyzed destruction; ie, it is a “suicide enzyme.” Furthermore, the inactivation of prostaglandins by 15-hydroxyprostaglandin dehydrogenase is rapid.(OH group preset at 15 th position  is changed to a keto group).Blocking the action of this enzyme with Sulfasalazine or indomethacin can prolong the half-life of prostaglandins in the body. After the action of this enzyme the resultant fatty acids are completely oxidized by beta oxidation.

Q.4- Discus the synthesis of clinically relevant Leukotrienes and Lipoxins from Arachidonic acid .

Answer-

The leukotrienes are identified as LTs. They are a family of conjugated trienes formed from eicosanoic acids in leukocytes, mastocytoma cells, platelets, and macrophages by the lipoxygenase pathway in response to both immunologic and nonimmunologic stimuli.

Three different lipoxygenases (dioxygenases) insert oxygen into the 5, 12, and 15 positions of arachidonic acid, giving rise to hydroperoxides (HPETE).

Only 5-lipoxygenase forms leukotrienes.(Figure-9)

Lipoxins are a family of conjugated tetraenes also arising in leukocytes. They are formed by the combined action of more than one lipoxygenase.

Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate PLA2 which hydrolyzes arachidonic acid from membrane phospholipids. The enzyme 5-lipoxygenase (5-LOX) in association with the protein, 5-LOX activating protein (FLAP), catalyzes the conversion of arachidonic acid, first to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). LTA4 is synthesized by the action of dehydrase on 5HPETE.

LTA4 is unstable and is converted to LTB4 in neutrophils and monocytes harboring LTA4 hydrolase. In mast cells and eosinophils, which harbor LTC4 synthase, LTA4 is converted to LTC4. The leukotrienes LTC4, LTD4, LTE4 and LTF4 are known as the peptidoleukotrienes or the cysteinyl leukotrienes because of the presence of amino acids.

The peptidoleukotrienes, LTC4, LTD4 and LTE4 are components of slow-reacting substance of anaphylaxis (SRSA).

The subscript 4 in each molecule refers to the number of carbon-carbon double bonds present.

Lipoxins-Three pathways exist for the synthesis of the lipoxins. The “classic” pathway involves 5-LOX activity in leukocytes followed by 12-LOX action in platelets. The action of 15-LOX in epithelial cell (such as in the airway) followed by 5-LOX action in leukocytes is the second major lipoxin synthesis pathway. The action of aspirin on COX-2 in epithelial, or endothelial cells as wells as in monocytes results in the eventual production of the 15 epi-lipoxins (also referred to as aspirin triggered lipoxins, ATLs  

Figure-9- Showing the steps of formation of  Leukotrienes and lipoxins

Clinical significance-Slow-reacting substance of anaphylaxis (SRS-A) is a mixture of leukotrienes C4, D4, and E4. This mixture of leukotrienes is a potent constrictor of the bronchial airway musculature. These leukotrienes together with leukotriene B4 also cause vascular permeability and attraction and activation of leukocytes and are important regulators in many diseases involving inflammatory or immediate hypersensitivity reactions, such as asthma. Leukotrienes are vasoactive, and 5-lipoxygenase has been found in arterial walls.

Q. 5- Discuss the  mechanism of action  and  the details of biological activities associated with Eicosanoids.

Answer-Each of the eicosanoids function via interactions with cell-surface receptors that are members of the G-protein coupled receptor (GPCR) family. There are at least 9 characterized prostaglandin receptors. Receptors that bind the prostaglandin D family of lipids are called the PGD receptors and those that bind E family prostaglandins are called the PGE receptors. The PGD receptors are coupled to the production of cAMP and activation of PKA. The PGE receptors couple to the activation of PLCγ (Phospholipase C) and as a consequence the production of Diacylglycerol (DAG) and  Inositol triphosphate (IP3) from membrane phospholipids. The receptor for prostacyclin (PGI2) is called the PC receptor and it couples to production of cAMP. There are 2 receptors that bind LTB4 called BLT1 and BLT2. The peptidoleukotrienes (cysteinyl leukotrienes) bind to receptors called CysLT1 and CysLT2. The thromboxane receptor is coupled to the activation of PLCγ. Thus  majority of the prostaglandins act by increasing the c AMP level in the cell. Prostaglandins may also bind to nuclear receptors and alter gene transcription.

The major biological activities associated with Eicosanoids are as follows-

Eicosanoid Site of synthesis  Biological Activities
Prostaglandins Almost all cells of the body
PGD2 mast cells Inhibits platelet and leukocyte aggregation, decreases T-cell proliferation, lymphocyte migration  and secretion of IL-1α and IL-2; induces vasodilation and production of cAMP
PGE2 kidney, spleen, heart Increases vasodilation and cAMP production, enhancement of the effects of bradykinin and histamine, induction of uterine contractions and of platelet aggregation, maintaining the open passageway of the fetal ductus arteriosus; decreases T-cell proliferation , lymphocyte migration and secretion of IL-1α and IL-2
PGF2α kidney, spleen, heart Increases vasoconstriction, Bronchoconstriction and smooth muscle contraction
PGH2   Precursor to thromboxanes A2, induction of platelet aggregation and vasoconstriction
PGI2 heart, vascular endothelial cells Inhibits platelet and leukocyte aggregation, decreases T-cell proliferation and lymphocyte migration and secretion of IL-1α and IL-2; induces vasodilation and production of cAMP
Thromboxanes  
TXA2 platelets Induces platelet aggregation, vasoconstriction, lymphocyte proliferation and Bronchoconstriction
TXB2 platelets Vasoconstriction
Leukotrienes  
LTB4 monocytes, basophils, neutrophils, eosinophils, mast cells, epithelial cells powerful inducer of leukocyte chemotaxis and aggregation, vascular permeability, T-cell proliferation and secretion of INF-γ, IL-1 and IL-2

LTC4

monocytes and alveolar macrophages, basophils, eosinophils, mast cells, epithelial cells component of SRS-A, microvascular vasoconstrictor, vascular permeability and bronchoconstriction and secretion of INF-γ, recruitment of leukocytes to sites of inflammation, enhance mucus secretions in gut and airway

LTD4

monocytes and alveolar macrophages, eosinophils, mast cells, epithelial cells

same as LTC4

LTE4

mast cells and basophils

same as LTC4

Lipoxins

 

LXA4 platelets, endothelial cells, mucosal epithelial cells and other leukocytes via inteactions with PMNs Reduce PMN and eosinophil infiltration to sites of inflammation, stimulate nonphlogistic (non-inflammatory-inducing) monocyte recruitment, stimulate macrophage phagocytosis of apoptotic PMNs, block IL-8 (chemokine) expression, block TNF-α release and actions, stimulate TGF-β action
LXB4 platelets, endothelial cells, mucosal epithelial cells and other leukocytes via inteactions with PMNs same as for LXA4

 

Q . 6- Discuss the physiological functions of Prostaglandins in various tissues

Answer-  The functions of Prostaglandin are incompletely understood.

Known actions include-

S. N. Tissue Physiological function
1) Inflammatory Response i) Fever- PGs induce fever by stimulating the thermoregulatory center in the brain. There is increased body temperature as a result of it.ii) Pain- PGs sensitize pain receptors to stimulation, as a result increase pain perception.iii) Swelling-There is vasodilatation and increased capillary permeability induced by PGS which is responsible for swelling of the inflammed tissue.

iv Erythema, wheal and Flare is also induced by PGs like PGE and PGD2.

v) PGD2 is considered an important mediator of anaphylaxis

 

2) Intestinal smooth muscles PGE and PGF produce contraction of the longitudinal smooth muscles producing diarrhea, cramps and reflux of bile.
3) Bronchial smooth Muscles PGFs contract and PGE s relax  bronchial smooth muscles.PGE1 and PGE2 are therapeutically used as bronchodilators
4) Vascular Smooth Muscles PGEs and PGI2 cause vasodilatation. PGF2 α and Thromboxane A2 cause vasoconstriction. Systemic blood pressure falls in response to PGEs and PGAs
5) Uterine Muscles PGE1, PGE1 and PGF2α cause uterine contractions.PGE2 has been used for the induction of labor at or near term. In higher dosage PGEs are used as abortificients in first and second trimester of pregnancy. They are also responsible for causing dysmenorrhea.
6) Platelets PGE1 and PGI2 cause inhibition of platelet aggregation, while TXA2 promotes platelet aggregation. PGE1 has been used for harvesting and storage of blood platelets for therapeutic transfusion.
7) Kidney PGEs cause in renal plasma flow, GFR, diuresis, Natriuresis. and kaliuresis is also induced by the action of PGE2
8) Gastrointestinal Secretions PGE1and E2 inhibit gastric secretions and are required for maintaining the integrity of gastric mucosa. The effect is opposite on the pancreatic and intestinal secretions. There is increase in the volume, enzyme and electrolyte content of the pancreatic and intestinal secretions in response to PGE1. Watery diarrhea results in response to administration of PGE1.
9) Endocrine glands i) PGEs have insulin like effects, They inhibit lipolysis and the effects on carbohydrate metabolism are same as insulinii) PTH(Parathormone) like effects are also seen on bone metabolism by PGs. They mobilize calcium from bones producing hypercalcemia.iii)Thyrotropin like effects-are seen on thyroid gland.

iv)Steroidogenic effects are seen on the adrenal tissues

10) Immunological Response PGEs secreted by macrophages may modulate or decrease the functions of T and B lymphocytes .

 

Q.7- What is the relationship of COX inhibition and Gastric ulceration?

Answer-

Prostaglandins play a critical role in maintaining gastro duodenal mucosal integrity and repair. The gastric mucosa contains abundant levels of prostaglandins that regulate the release of mucosal bicarbonate and mucus, inhibit parietal cell secretion, and are important in maintaining mucosal blood flow and epithelial cell restitution.  It therefore follows that interruption of prostaglandin synthesis can impair mucosal defense and repair, thus facilitating mucosal injury via a systemic mechanism.  

Humans, and most other mammals have two genes for cyclooxygenase. The products of the genes, COX-1 and COX-2, are structurally quite similar, with only subtle differences. The catalyze the same reactions, although COX-2 works with a wider range of substrates. COX-1 is constitutively expressed in nearly all tissues. In contrast, COX-2 is inducible, especially by inflammatory stimuli. Some evidence suggests that COX-1 is responsible for generating the prostaglandins required for protection of the gastrointestinal tract, while COX-2 is responsible for the increased prostaglandin synthesis associated with inflammation, fever, and pain responses.

Indomethacin, a high affinity inhibitor of COX (and in some individuals, aspirin, and to a lesser extent ibuprofen) induces ulceration; some anti-ulcer drugs appear to function by increasing prostaglandin synthesis. The recently developed coxibs (such as celecoxib and rofecoxib)  cause selective inhibition of COX-2 and not of COX-1. This selectivity has made the coxibs very useful for antiinflammatory and antiproliferative therapy with reduced gastrointestinal side effects.

In view of their central role in maintaining mucosal integrity and repair, stable prostaglandin analogues have been developed for the treatment of peptic ulcers. Primary prevention of NSAID-induced ulceration can be accomplished by misoprostol, which is a Prostaglandin Analogue.

Q. 8- What is the role played by prostaglandins in pregnancy ?

Answer- Prostaglandins are required for normal implantation of the fertilized oocyte. In addition, prostaglandins are involved in initiation of labor. Prostaglandins are used for labor induction (and for induction of  abortions); COX-inhibitors (probably via COX-2) delay onset of labor. COX-2 seems to be required for ovulation.

Q.9- Why are COX inhibitors used as antipyretic agents ?

Answer- Prostaglandins appear to form a major part of the signaling pathway in fever induction. COX inhibitors are thought to exert their anti-pyretic actions by interrupting this pathway. Prostaglandins appear to be involved in some pain pathways; inhibition of COX (probably COX-2) is thus analgesic.

Q. 10-What is the role of COX inhibitors in cancers and Alzheimer’s disease?

Answer- Colon cancer is a major life-threatening cancer. Aspirin has been shown to have an apparent protective effect against colon cancer; some evidence suggests that inhibition of colon tumor induction is due to inhibition of COX-2. Breast and stomach cancer growth may also be inhibited by COX inhibitors.

The brain damage associated with Alzheimer’s disease appears to be largely mediated by inflammatory responses; some epidemiological data have suggested a reduced incidence of Alzheimer’s disease in individuals taking COX inhibitors.

Q.11- What is the reason for Aspirin induced Asthma ?

Answer- Aspirin inhibits the COX pathway and consequently diverts arachidonic acid metabolites to the LO pathway. This also leads to a decrease in the levels of PGE2, the anti-inflammatory PG. LTC4 synthase overexpression further increases the number of cysteinyl LTs, tilting the balance toward inflammation.(Figure-10)

Q.12- What is the biochemical basis of PG induced of dysmenorrhea  ?

Answer- Primary dysmenorrhea results from increased stores of prostaglandin precursors, which are generated by sequential stimulation of the uterus by estrogen and progesterone. During menstruation these precursors are converted to prostaglandins, which cause intense uterine contractions, decreased blood flow, and increased peripheral nerve hypersensitivity, resulting in pain.

Q.13- Discuss the pharmacological applications of Eicosanoids.

Answer- In practice, when eicosanoids have beneficial effects, they are used as drugs called prostaglandinomimetics; when they have adverse effects, one tries to inhibit their biosynthesis or their effects. The pharmacological applications of Prostaglandins can be summarized as follows-

1)     Cardiovascular uses- PGI2 or prostacyclin, called now epoprostenol has several properties: pulmonary and systemic arterial vasodilator, platelet anti-aggregating, gastric protective effects. In sustained continuous intravenous infusion it induces appreciable results in the treatment of primitive pulmonary arterial hypertension. Iloprost, a stable analog of PGI2, is used for the treatment of severe peripheral vascular disease. Alprostadil (PGE1) is indicated for keeping the ductus arteriosus open until surgery in neonates carrying certain cardiac malformations. Because of its vasodilator effect, Alprostadil is also used for the treatment of erectile dysfunction.

2)     Digestive Uses- Misoprostol, an analog of PGE1, has antisecretory and cytoprotector gastric effects. It decreases acid secretion and increases pepsin, mucin and bicarbonate secretion and improves microcirculation. It is indicated in the treatment of gastro duodenal ulcer and for the prevention of NSAID-induced ulcers. Its principal secondary effect is diarrhea. It is contra-indicated for pregnant women. 

3)     Gynecological and obstetrical uses – The derivatives used in gynecology and obstetrics have an activity which resembles that of the prostaglandins E1 and E2.  They induce cervical dilatation and uterine contractions, particularly in late pregnancy. E1 type are used for cervical dilatation for exploring uterus or for abortion. E2 type in low dosage are used for induction of labor and in high dosage are used for medical termination of pregnancy or to illicit abortion.

4)     Ophthalmologic Use- Latanoprost, a prodrug analog of F2 alpha prostaglandin, administered in ophthalmic solution, lowers intraocular pressure by increasing aqueous humor outflow.

5)     Anti- inflammatory use- Inhibitors of cyclo-oxygenases have antiinflammatory properties and include nonsteroidal antiinflammatory drugs or NSAID. The useful effects in therapeutics are-

  • anti-inflammatory effect
  • analgesic effect
  • antipyretic effect
  • inhibition of platelet aggregation and decrease of thromboembolic risk (well-known with aspirin at low doses)
  • Hypocalcemic effect (during hypercalcemia.)
  • inhibition of colic tumor development

Adverse effects:

  • Gastro duodenal ulcerations and digestive bleeding due primarily to COX-1 inhibition
  • Prolongation of pregnancy (if the NSAID is taken by the pregnant woman in late pregnancy)
  • Premature closure of the ductus arteriosus
  • Aggravation of renal impairment by insufficient vasodilator prostaglandin synthesis to counter the vasoconstrictive effect of catecholamines and angiotensin, retention of salt and water and increase of blood pressure  
  • Aggravation of a heart failure.

6)     Ulcerative Colitis- Mesalamine also called mesalazine or 5 aminosalicyclic acid has antiinflammatory properties in the colon and is used in the treatment of ulcerative colitis (Crohn’s disease). Its mechanism of action is complex and as yet incompletely known: in addition to cyclo-oxygenases, it also inhibits lipoxygenases.

7)     Bronchial Asthma- PGE2 agonists and leukotrienes receptor antagonists are used for the treatment of bronchial asthma.

Figure-10- showing the biochemical basis of Aspirin induced bronchial asthma 

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Case details

A boy was born normal but started flinching at loud noises (enhanced startle response) at the age of 6 months. The child initially could sit up, but then regressed so that he could not roll over or recognize his parents.

Ophthalmological examination revealed a central red area of the retina surrounded by white tissue (Cherry red spot).

What is the treatment for this disease?

Case Discussion

The child is suffering from Tay Sach’s disease (GM2 Gangliosidosis). The disease is named after the British ophthalmologist Warren Tay who first described the red spot on the retina of the eye, and the American neurologist Bernard Sachs who described the cellular changes of Tay-Sachs and noted an increased prevalence in the Eastern European Jewish (Ashkenazi) population

Basic Concept

Gangliosides have been isolated from the ganglion cells, neuronal bodies, dendrites, spleen and RBC stroma. The highest concentration is found in the grey matter of brain. Structurally they contain a long chain fatty acid, alcohol sphingosine, a carbohydrate moiety which is usually glucose/ and or galactose, and at least one molecule of N-acetyl –Neuraminic acid (NANA)(Figure-1). Four important types of Gangliosides are GM-1, GM-2, GM-3 and GD-3.GM-1 is more complex ganglioside and is known to be the receptor for cholera toxin in human intestine. Gangliosides are mainly components of membranes. They also serve as receptors for circulating hormones and thereby influence various biochemical processes in the cells.

Case details

The GM2 Gangliosidosis  also called Tay-Sach’s disease results from the deficiency of ß-hexosaminidase activity and the lysosomal accumulation of GM2 gangliosides, particularly in the central nervous system, causing severe effects (neurodegeneration).The child in the given case was born normal but developed progressive deterioration of the neurological functions. This is characteristic of this disease

Tay-Sachs disease

Biochemical defect

There is deficiency of ß hexosaminidase A enzyme. This Lysosomal enzyme removes amino hexose groups from Gangliosides, Subsequently the other components are hydrolyzed by other specific enzymes. In its deficiency the gangliosides are  not degraded  thus accumulate in various tissues especially nervous tissue.

 

[ß-Hexosaminidase occurs as two isozymes: ß-hexosaminidase A, which is composed of one a and one ß subunit, and ß-hexosaminidase B, which has two ß subunits. ß-hexosaminidase deficiencyA results from mutations in the a subunit and causes Tay-Sachs disease, whereas mutations in the ß-subunit gene result in the deficiency of both ß-hexosaminidase A and B and cause Sandhoff disease.]

 t (Small)

Figure-2- Cherry red spot on the macula

Inheritance

It is inherited as an autosomal recessive traits, with a predilection in the Ashkenazi Jewish population, where the carrier frequency is about 1/25.

Clinical symptoms and Classification

Tay-Sachs disease is classified in variant forms, based on the time of onset of neurological symptoms.

Infantile TSD patients with this disease are born normal, but they develop loss of motor skills, increased startle reaction, macular pallor and retinal cherry red spot(Figure-2).Affected children develop normally till the age of 5-6 months, then decreased eye contact, hyperacusis (Exaggerated startle response) to noise are noted. Progressive development of idiocy and blindness are diagnostic of this disease and they are due to wide-spread injury to ganglion cells, in brain and retina. The cherry red spot about the macula is due to destruction of retinal ganglion cells exposing the underlying vasculature(Figure-2). Macrocephaly not associated with hydrocephalus may be there. Convulsions are seen in severe cases.

Juvenile TSD. Extremely rare, Juvenile Tay-Sachs disease usually presents itself in children between 2 and 10 years of age. They develop cognitive, motor, speech difficulties (dysarthria), swallowing difficulties (dysphagia), unsteadiness of gait (ataxia), and spasticity. Patients with Juvenile TSD usually die between 5–15 years.

Adult/Late Onset TSD. A rare form of the disorder, known as Adult Onset Tay-Sachs disease or Late Onset Tay-Sachs disease (LOTS), occurs in patients in their 20s and early 30s. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of LOTS, which present in adolescence or early adulthood, include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly schizophrenic-like psychosis.

Diagnosis

The diagnosis of infantile Tay-Sachs disease is usually suspected in an infant with neurologic features and a cherry-red spot.

Enzymatic Assays-Definitive diagnosis is by determination of the level of ß-hexosaminidase A in isolated blood leukocytes.

Fine needle Aspiration Cytology of brain tissue – can show the degree of neuronal degeneration. FNAC has a great potential for diagnosis and follow-up of Tay-Sachs disease

Prenatal screening-Future at-risk pregnancies for both disorders can be monitored by prenatal diagnosis by amniocentesis or chorionic villus sampling.

Carrier screening– Identification of carriers within families is also possible by ß-hexosaminidase A and B determination. Indeed, for Tay-Sachs disease, carrier screening of all couples in whom at least one member is of Ashkenazi Jewish descent is recommended before the initiation of pregnancy to identify couples at risk. These studies can be conducted by the determination of the level of ß-hexosaminidase A activity in peripheral leukocytes or plasma.

Treatment

No cure for this disease. Symptomatic treatment is given. Enzyme replacement therapy and Gene therapy are under trial. Although experimental work is underway, no current medical treatment exists for infantile TSD. Patients receive palliative care to ease the symptoms. Infants are given feeding tubes when they can no longer swallow. Improvements in palliative care have somewhat lengthened the survival of children with TSD, but no current therapy is able to reverse or delay the progress of the disease.

Prognosis

Prognosis is bad and death occurs in early years of life.

 

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Case Details

A 25 –year-old women presents, with a history that includes-

a) Hepatosplenomegaly with eventual removal of spleen

b) Bone and joint pains with several fractures of femur.

c) A liver biopsy that shows wrinkled looking cells with accumulation of Glucosyl ceramide,

What would be the likely diagnosis for this patient?

Case discussion

The patient is suffering from Gaucher disease. It is an inherited disorder of Cerebroside metabolism.

Basic concept

Cerebrosides occur in large amount in the white matter of brain and in the myelin sheath of nerves. Structurally, Cerebrosides contain a carbohydrate which is generally galactose or sometimes glucose, a high molecular weight fatty acid, an alcohol which is sphingosine or Dihydro sphingosine (See the structure below-figure-1).There is no glycerol, no phosphoric acid and no nitrogenous base. Individual cerebrosides are differentiated by the type of fatty acid present in them.

Figure-1- showing structure of Glucocerebroside(Glucosyl Ceramide). Sphingosine+ Fatty acid(Oleic acid in the given structure) is Ceramide. Ceramide can be further attached with either Glucose or Galactose.

Gaucher disease

This disease is a multisystem lipidosis characterized by hematological changes, organomegaly and skeletal involvement, the latter is usually manifested in the form of bone pains and multiple fractures. It is the most common genetic disorder among Ashkenazi Jews. It is the commonest Lysosomal storage disease.

Inheritance

It is Autosomal recessive in nature.

Biochemical defect

Gaucher’s disease results from deficient activity of Lysosomal Hydrolase, β- Glucocerebrosidase. The enzyme defect results in accumulation of undegraded glycolipid in the form of Glucosyl ceramide in the cells of reticuloendothelial system (figure-2). This progressive accumulation results in infiltration of bone marrow, hepatosplenomegaly and skeletal complications.

Figure-2- showing the formation of Gaucher cell

Clinical features

There are three clinical sub types depending upon the presence of, absence of or progression of neurological complications-

1)Type-1- It accounts for 99 % of cases. The age of onset is variable, from early childhood to late adulthood. The patients present with easy bruising due to thrombocytopenia, chronic fatigue due to anemia, hepatomegaly with or without impaired liver functions. Progressive enlargement of spleen is there which can become massive. Clinical bone involvement is apparent which is manifested in the form of bone pains, or pathological fractures.  The hall-mark of Gaucher’s disease is gaucher cells in the reticuloendothelial system, particularly in the bone marrow. These cells have a typical appearance, they are 20-100μm in diameter, wrinkled looking due to the presence of intracytoplasmic inclusion bodies(figure-2 and 3). The presence of these cells is highly diagnostic of Gaucher’s disease.

Figure3– showing Gaucher cell

2) Type 2 is less common, it is characterized by neurodegeneration, extreme visceral involvement and death within 2 years of life. The death is due to respiratory compromise.

3) Type 3- is intermediate in presentation to type 1 and 2. Neurological involvement is there but occurs later in life with decreased severity as compared to Type 2.

Laboratory Diagnosis

The following studies are indicated in gaucher disease:

  • Enzyme activity testing: Diagnosis can be confirmed  through measurement of Glucocerebrosidase activity in peripheral blood leukocytes. A finding of less than 15% of mean  normal activity is diagnostic.
  • Genotype testing: Molecular diagnosis  can be helpful, especially in Ashkenazi patients, in whom 6 GBA mutations account for most disease alleles.
  • CBC count: Obtain CBC count and differential to assess the degree of cytopenia.
  • Liver function enzyme testing: Minor elevations of liver enzyme levels are common, even in patients who are mildly affected with Gaucher disease; however, the presence of jaundice or impaired hepatocellular synthetic function merits a full hepatic evaluation. 

Imaging Studies

  • Ultrasonography: Ultrasonography of the abdomen can reveal the extent of organomegaly.
  • MRI
    • MRI is more accurate than ultrasonography in determining organ size.
    • Hip MRI may be useful in revealing early avascular necrosis.
    • MRI may be useful in delineating the degree of marrow infiltration and evaluating spinal involvement.
  • Radiography
    • Skeletal radiography can be used to detect and evaluate skeletal manifestations of Gaucher disease.
    • Perform chest radiography to evaluate pulmonary manifestations.
  • Bone marrow examination for the presence of Gaucher’s cells is diagnostic.
  • Liver biopsy – Liver biopsy is occasionally performed to assess unexplained hepatomegaly.

Treatment

 1) Enzyme replacement therapy (ERT) by recombinant β- Glucocerebrosidase is currently done. This preparation is highly effective in reversing the visceral and hematologic manifestations of gaucher disease. However, skeletal disease is slow to respond, and pulmonary involvement is relatively resistant to the enzyme.

2) Surgical Care

Partial and total Splenectomy was once advocated in the treatment of patients with Gaucher disease. However, with the availability of ERT, this procedure is no longer necessary in most patients.

3) Bone marrow transplant is also helpful.

4) Gene replacement is the permanent cure.

Prognosis

  • Many individuals with Gaucher disease have few manifestations and a normal life expectancy without any intervention.
  • The prognosis for symptomatic patients with type 1 or type 3 Gaucher disease who receive treatment is very good, with a decrease in organomegaly and an eventual rise in hemoglobin levels and platelet counts.
  • Skeletal disease is slow to respond to ERT and widely varies.
  • Some patients describe symptomatic improvement within the first year of treatment, although a much longer period of ERT is required to achieve a radiologic response.
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Q.1- Define and classify lipids.

Answer- The lipids are a heterogeneous group of compounds, including fats, oils, steroids, waxes, and related compounds, that are related more by their physical than by their chemical properties. They have the common property of being (1) relatively insoluble in water and (2) soluble in nonpolar solvents such as ether and chloroform.

Classification- The lipids are classified as –

1. Simple lipids: Esters of fatty acids with various alcohols.

a) Fats: Esters of fatty acids with glycerol. Oils are fats in the liquid state.

b) Waxes: Esters of fatty acids with higher molecular weight monohydric alcohols

2. Complex lipids: Esters of fatty acids containing groups in addition to an alcohol and a fatty acid

a. Phospholipids: Lipids containing, in addition to fatty acids and an alcohol, a phosphoric acid residue. They frequently have nitrogen-containing bases and other substituents, eg, in glycerophospholipids the alcohol is glycerol and in Sphingophospholipid the alcohol is sphingosine.

b. Glycolipids (glyco sphingolipids): Lipids containing a fatty acid, sphingosine, and carbohydrate.

c. Other complex lipids: Lipids such as sulfolipids and amino lipids. Lipoproteins may also be placed in this category.

3. Precursor and derived lipids: These include fatty acids, glycerol, steroids, other alcohols, fatty aldehydes, and ketone bodies, hydrocarbons, lipid-soluble vitamins, and hormones.

Q.2- Give a brief account of the nomenclature and the biological importance of fatty acids.

Answer- Fatty acids are the key constituents of lipids. Chemically they are aliphatic carboxylic acids. Fatty acids occur mainly as esters in natural fats and oils but do occur in the unesterified form as free fatty acids, a transport form found in the plasma. Fatty acids that occur in natural fats are usually straight-chain derivatives containing an even number of carbon atoms. The chain may be saturated (containing no double bonds) or unsaturated (containing one or more double bonds).

Nomenclature- Fatty acids are hydrocarbon chains of various lengths and degrees of unsaturation that terminate with carboxylic acid groups. The systematic name for a fatty acid is derived from the name of its parent hydrocarbon by the substitution of oic for the final e. For example, the C18 saturated fatty acid is called octadecanoic acid because the parent hydrocarbon is octadecane. A C18 fatty acid with one double bond is called octadecenoic acid; with two double bonds, octadecadienoic acid; and with three double bonds, octadecatrienoic acid. The notation 18:0 denotes a C18 fatty acid with no double bonds, whereas 18:2 signifies that there are two double bonds.

Carbon atoms are numbered from the carboxyl carbon (carbon No. 1). The carbon atoms adjacent to the carboxyl carbon (Nos. 2, 3, and 4) are also known as the alpha, beta, and  gamma carbons, respectively, and the terminal methyl carbon is known as the ώ or n-carbon.(Figure-1)

The position of a double bond is represented by the symbol ∆ followed by a superscript number.

eg. ∆ 9 indicates a double bond between carbons 9 and 10 of the fatty acid;

For example, cis-∆9 means that there is a cis double bond between carbon atoms 9 and 10; trans-∆2 means that there is a trans double bond between carbon atoms 2 and 3. Alternatively, the position of a double bond can be denoted by counting from the distal end, with the ώ-carbon atom (the methyl carbon) as number 1.

 ώ 9 indicates a double bond on the ninth carbon counting from the ώ-carbon.

 

Figure-1-(a) showing the ionized structure of a fatty acid and the numbering of carbon  atoms in a fatty acid 

(b) showing the structure of ώ3 fatty acid

In animals, additional double bonds are introduced only between the existing double bond (eg, 9, 6, or 3) and the carboxyl carbon, leading to three series of fatty acids known as the ώ9, ώ6, andώ3 families, respectively.

Examples of fatty acids-

1) Saturated fatty acids- Saturated fatty acids may be envisaged as based on acetic acid (CH3 —COOH) as the first member of the series in which —CH2 — is progressively added between the terminal CH3 — and —COOH groups. Other higher members of the series are known to occur, particularly in waxes. Fatty acids in biological systems usually contain an even number of carbon atoms, typically between 14 and 24. The 16- and 18-carbon fatty acids are most common. The hydrocarbon chain is almost invariably unbranched in animal fatty acids. A few branched-chain fatty acids have also been isolated from both plant and animal sources. Some of the saturated fatty acids of biological significance are as follows-

S.No. Number of carbon atoms Common Name Systematic Name Formula
1 2 Acetic acid Ethanoic acid CH3COOH
2 4 Butyric acid Butanoic acid CH3(CH2)2COOH
3 6 Caproic acid Hexanoic acid CH3(CH2)4COOH
4 8 Caprylic acid Octanoic acid CH3(CH2)6COOH
5 10 Capric acid Decanoic acid CH3(CH2)8COOH
6 12 Lauric acid Dodecanoic acid CH3(CH2)10COOH
7 14 Myristic acid Tetradecanoic acid CH3(CH2)12COOH
8 16 Palmitic acid Hexadecanoic acid CH3(CH2)14COOH
9 18 Stearic acid Octadecanoic acid CH3(CH2)16COOH
10 20 Arachidic acid Eicosanoic acid CH3(CH2)18COOH
12 22 Behenic acid Docosanoic acid CH3(CH2)20COOH
13 24 Lignoceric acid Tetracosanoicacid CH3(CH2)22COOH

 

Palmitic acid is present both in plant and animal fat, while butyric acid is abundantly present in butter. 

2) Unsaturated fatty acids

The alkyl chain of a fatty acid may contain one or more double bonds. The configuration of the double bonds in most unsaturated fatty acids is cis. The double bonds in polyunsaturated fatty acids are separated by at least one methylene group.

Unsaturated fatty acids may further be divided as follows-

(1) Monounsaturated (monoethenoid, monoenoic) acids, containing one double bond.

(2) Polyunsaturated (polyethenoid, polyenoic) acids, containing two or more double bonds.

S.No. Number of carbon atomsNumber and Location of double bond Family Common Name Systematic Name Formula
(A) Monoenoic acids (one double bond) 
1 16:1;9 7 PalmitoleicAcid cis-9-Hexadecenoic CH3(CH2)5CH=CH(CH2)7COOH
2 18:1;9 9 Oleic acid cis-9-Octadecenoic  CH3(CH2)7CH=CH(CH2)7COOH
3
 18:1;9
9 Elaidic acid trans 9- Octadecanoic  CH3(CH2)7CH=CH(CH2)7COOH
(B) Dienoic acids (two double bonds) 
1 18:2;9,12 6 Linoleic all-cis-9,12-Octadecadienoic  CH3(CH2)4 CH=CH CH2CH=CH(CH2)7COOH
(C) Trienoic acids (three double bonds) 
1 18:3;6,9,12 6 Gamma-Linolenic all-cis-6,9,12-Octadecatrienoic  CH3(CH2)4 CH=CHCH2 CH=CHCH2CH=CH (CH2)4COOH
2 18:3;9,12,15 3  Alpha-Linolenic all-cis-9,12,15Octadecatrienoic  CH3(CH2) CH=CH CH2CH=CH CH2 CH=CH(CH2)7COOH
(D) Tetraenoic acids (four double bonds) 
20:4;5,8,11,14 6 Arachidonic all-cis-5,8,11,14-Eicosatetraenoic  CH3(CH2)3CH2CH=CH CH2CH=CH CH2 CH=CH CH2CH=CH(CH2)3COOH
(E) Pentaenoic acids (five double bonds) 
20:5;5,8,11,14,17 3 Timnodonic all-cis-5,8,11,14,17-Eicosapentaenoic  CH3 CH2 CH=CH CH2CH=CH CH2 CH=CH CH2 CH=CH CH2CH=CH(CH2)3COOH
(F) Hexaenoic acids (six double bonds) 
22:6;4,7,10,13,16,19 3 Cervonic acid all-cis-4,7,10,13,16,19-Docosahexaenoic  CH3 CH2 CH=CH CH2 CH=CH CH2CH=CH CH2 CH=CH CH2 CH=CH CH2CH=CH(CH2)2COOH

 

Biological Importance of fatty acids-  

1-Fatty acids are the building blocks of dietary fats. The human body stores such fats in the form of triglycerides.

2)- Fatty acids are also required for the formation of  membrane lipids such as phospholipids and glycolipids.

3) -They are required for the esterificaton of cholesterol to form cholesteryl esters.

4) They act as fuel molecules and are oxidized to produce energy.

 

Q.3-What are Essential fatty acids ? Discuss the significance of essential fatty acids.

 Answer-Essential fatty acids-

Although animals and humans are not able to produce them naturally, some polyunsaturated fatty acids such as Linoleic and Linolenic acids are essential for normal life functions. They are therefore characterized as essential fatty acids. Arachidonic acid is considered as semi essential fatty acid since it can be synthesized from Linoleic acid .

Polyunsaturated fatty acids are produced by various plants. They reach man through the food chain, either directly through the consumption of fruit and vegetables, or by eating the flesh or eggs of animals, birds or fish that have eaten plants containing the polyunsaturated fatty acids.

Essential polyunsaturated fatty acids can be classified as belonging to one of two “families”, the omega-6 family or the omega-3 family. Fatty acids belonging to these two families differ not only in their chemistry, but also in their natural occurrence and biological functions. Omega-6 oils are found in cooking oils such as corn oil and soy bean oil. Omega-3, on the other hand, is heavily represented in the marine food chain. The most important source is fat fish.

Significance of essential fatty acids

1)  Components of cell membranes- Deficiencies of essential polyunsaturated fatty acids may cause a wide variety of symptoms, including retarded growth in children, reduced fertility and pathologic changes in the skin. The reason behind these apparently unrelated symptoms is the central role that polyunsaturated fatty acids play in the composition and structure of the cell membrane, which is very important for maintaining normal cell functions.

2)  Precursors of Eicosanoids- Another important function of polyunsaturated fatty acids containing 20 carbon atoms (C20) and particularly Arachidonic acid (omega-6) and eicosapentaenoic acid (omega-3) is that they can be converted to locally functioning transmitter substances like prostaglandins and leukotrienes that are important for biological processes such as blood clotting, inflammatory reactions and muscle contractions.

3) Brain growth- Another important function of polyunsaturated fatty acids is that they are vital components of brain tissue and other nerves. The omega-3 fatty acid, docosahexaenoic acid (DHA), is particularly important. A normal adult brain contains more than 20 grams of DHA.

4)  Role in vision-DHA also plays an important role in the composition of the retina of the eye. It is therefore also of major importance for vision. Healthy adults have a certain ability to metabolize alfa-Linolenic acid to EPA and DHA. Children do not have this ability and are entirely dependent on receiving these essential elements through diet. The ability to metabolize EPA and DHA may also be reduced in elderly people.

5) Cardioprotective role- Marine omega-3 fatty acids lower serum triglyceride levels, reduces blood pressure and stabilizes the rhythm of the heart. They are off use both as a prophylaxis and as an adjunct treatment for cardiovascular diseases.

6) Rheumatoid Arthritis-There is also growing appreciation for clinical documentation on the reduction of symptoms in patients suffering from rheumatoid arthritis.

7)  Dementia and Depression- A high dietary intake of marine omega-3 has been linked to a delay in the development of senile dementia and possibly to reducing symptoms that have already manifested themselves. There have also been reports of positive effects from the dietary intake of omega-3 fatty acids in patients suffering from depression. Dietary marine omega-3 has also been associated to delay the development of cerebral dementia in elderly people.

8) Other diseases

Recent scientific publications have reported positive effects on a number of clinical conditions, including migraine, heart arrhythmia, mental cognition in adults and attention deficit/ hyperactivity disorder in children.

Q.4- What is the relationship between melting point and

(i) degree of unsaturation and

(ii) the hydrophobic chain length of fatty acids?

Answer- Melting point is affected by the chain length and the degree of unsaturation.

1) Degree of unsaturation-Unsaturated fatty acids have lower melting points than saturated fatty acids of the same length. For example, the melting point of Stearic acid (C18- saturated) is 69.6°C, whereas that of oleic acid (which contains one cis double bond) is 13.4°C.The melting points of polyunsaturated fatty acids of the C18 series are even lower.

2)  Chain length-Chain length also affects the melting point, as illustrated by the fact that the melting temperature of Palmitic acid (C16) is 6.5 degrees lower than that of Stearic acid (C18). Thus, short chain length and unsaturation enhance the fluidity of fatty acids and of their derivatives.

Biochemical basis

The hydrocarbon chains in saturated fatty acids are, fairly straight and can pack closely together, making these fats solid at room temperature. (Figure-2) Oils, mostly from plant sources, have some double bonds between some of the carbons in the hydrocarbon tail, causing bends or “kinks” in the shape of the molecules.

 A type of geometric isomerism occurs in unsaturated fatty acids, depending on the orientation of atoms or groups around the axes of double bonds, which do not allow rotation. If the acyl chains are on the same side of the bond, it is cis-, as in oleic acid; if on opposite sides, it is trans-, as in Elaidic acid, the trans isomer of oleic acid (Figure-2). Naturally occurring unsaturated long-chain fatty acids are nearly all of the cis configuration, the molecules being “bent” 120 degrees at the double bond. Thus, oleic acid has an L shape, whereas Elaidic acid remains “straight.” Increase in the number of cis double bonds in a fatty acid leads to a variety of possible spatial configurations of the molecule—eg, Arachidonic acid, with four cis double bonds, has “kinks” or a U shape.

This has profound significance for molecular packing in membranes and on the positions occupied by fatty acids in more complex molecules such as phospholipids. Because of the kinks in the hydrocarbon tails, unsaturated fats can’t pack as closely together, making them liquid at room temperature.

The membrane lipids, which must be fluid at all environmental temperatures, are more unsaturated than storage lipids. Lipids in tissues that are subject to cooling, eg, in hibernators or in the extremities of animals, are more unsaturated. The carbon chains of saturated fatty acids form a zigzag pattern when extended, as at low temperatures. At higher temperatures, some bonds rotate, causing chain shortening, which explains why biomembranes become thinner with increases in temperature.

Trans fatty acids are present in certain foods, arising as a by-product of the saturation of fatty acids during hydrogenation, or “hardening,” of natural oils in the manufacture of margarine. An additional small contribution comes from the ingestion of ruminant fat that contains trans fatty acids arising from the action of micro-organisms in the rumen.

Naturally-occurring unsaturated vegetable oils have almost all cis bonds, but using oil for frying causes some of the cis bonds to convert to trans bonds. If oil is used only once only a few of the bonds do this so it’s not too bad. However, if oil is constantly reused, more and more of the cis bonds are changed to trans until significant numbers of fatty acids with trans bonds build up. The reason this is of concern is that fatty acids with trans bonds are carcinogenic. The levels of trans fatty acids in highly-processed, lipid-containing products such as margarine are quite high,

 

 

Figure-2- showing the zigzag pattern of extended fatty acids. The cis double bond produces a kink in the chain as shown above.

 

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Q.1- Name the fused ring system present in cholesterol.

Answer-Cyclo-pentano-per hydro-phenanthrene ring.

Q.2- Which alcohol is generally present in waxes?                  

Answer-Cetyl alcohol.

Q.3- Name the vitamins which act as alcohols to esterify fatty acids.

Answer- Vitamin A and D.

Q.4- Spontaneous oxidation of polyunsaturated fatty acids present in the biological membranes is called —-                                       

Answer- Lipid peroxidation..

Q.5- Which glycolipid is abundantly present in the white matter of brain?

Answer- Galactosyl ceramide

Q.6- Which lipoprotein transports cholesterol from liver to peripheral tissues?

Answer-LDL (Low density Lipoprotein).

Q.7- Which reaction is catalysed by LCAT?                    

Answer-Esterification of cholesterol

Lecithin+ Cholesterol—-Lysolecithin +Ester cholesterol.

 Q.8- Name two tri-enoic fatty acids.                      

Answer-Alpha and gamma Linolenic acids.

 Q.9- Give two biologically significant features of Phospholipase A2

Answer-Required for release of Arachidonic acid for the formation of Eicosanoids and provides fatty acid for the esterification of cholesterol in reverse cholesterol transport.

 Q.10- Low dose of Aspirin promotes the relative increase in the synthesis of prostacyclins, Is it true or false ?

Answer- True

 Q.11-The surface tension of dietary fat droplets in the intestine is decreased by — ?

Answer- Phospholipids and bile salts.

 Q.12- What is the advantage of taking low dose Aspirin?

Answer- Prevents thrombus formation and is recommended to high risk patients or to those who have a family history of IHD.

 Q.13-In which form are the fats stored in the body for long-term storage of energy,

Answer- Triacyl glycerol.

 Q.14- While comparing the potential energy of lipids and carbohydrates on weight basis, is it correct to say that lipids provide considerably more energy than carbohydrates?

Answer- yes, it is correct. Lipids provided 9.5 K. cal/G  energy as compared to 4.0 K. cal/G produced from the complete oxidation of carbohydrates.

 Q.15- A child presented with hyperacusis, regression of milestones and progressive blindness. What could be the possible defect?

Answer-Tay Sach disease-GM2 Gangliosidosis, deficiency of Hexosaminidase A enzyme.

 Q.16- The fluidity of the biological membranes is increased by the increase/ decrease in the degree of unsaturation of the component fatty acids.            

Answer- Fluidity of the biological membranes is increased by increase in the degree of unsaturation of component fatty acids.

 Q.17- What are the uses of Liposomes?      

Answer- They act as drugcarriers for the specific target sites without causing side effects. Also used for gene therapy.

 Q.18- Which phospholipid in a reservoir for second messenger?     

Answer-PhosphatidylInositol

 Q.19- Give two examples of unsaturated fatty acids      

Answer-Oleic. Linoleic,Linolenic acid etc.

 Q.20-What are sulfolipids and where are they present in the body?

Answer-Sulfated Galactosylceramides are sulfolipids and they are present abundantly in the nervous tissue.

 Q.21- What does the notation 18:0 signify?

Answer- Saturated fattyacid with 18 carbon atoms.

 Q.22- What are the components of a Glycero phospholipid?

Answer-Glycerol, two fatty acids, phosphoric acid, a nitrogenous base or other components

 Q.23- What are neutral lipids?

 Answer- Because they are uncharged, Acylglycerols (glycerides), cholesterol, and cholesteryl esters are termed neutral lipids.

 Q.24-What is an alpha carbon in a fatty acid?

 Answer-The carbon atoms adjacent to the carboxyl carbon.

 Q.25-Which fatty acid is present in Oxynervon?  

Answer-Hydroxy Nervonic acid.

 Q.26- What is the difference between Cervonic acid and Cerebronic acid?

Answer- Cervonic acid is polyunsaturated fatty acid while Cerebronic acid is Hydroxy fatty acid.

 Q.27-Which of the following is an animal sterol?

Ergo sterol, Stigma sterol, Sitosterol, Cholesterol               

Answer- Cholesterol.

 Q.28-Which of the following contains a five membered ring-?

Plasmalogen,Glycolipids, Sphingomyelin and Prostaglandins

Answer-Prostaglandins.

 Q.29-Prostacyclins increase the concentration of c- AMP, is it true or false?

Answer- It is true.

 Q.30-What is the cause of osmotic diarrhoea after PG( Prostaglandin) administration?

Answer -There is PG induced increase in the volume of pancreatic and Intestinal secretions resulting in osmotic diarrhea.

 Q.31-What are the components of a triacylglycerol?

Answer-Glycerol+ 3 fatty acids.

 Q.32-Name the different kinds of lipases present in the human body ?

Answer- Lingual, gastric, pancreatic and intestinal lipases are digestive lipases for the digestion of triacylglycerols, while there are phospholipases of different kinds besides hormone sensitive lipase present in the adipose tissue and Lipoprotein lipase for the digestion of lipoproteins.

 Q.33-What are the sources of fatty acids?

 Answer- Diet, Endogenous synthesis and derived from adipose tissue by adipolysis.

 Q.34-At which position is the fatty acid attached to the cholesterol ring,?

Answer- 3 rd position (Esterified to OH group present at the 3rdposition).

 Q.35-What is the product of a reaction of a fatty acid with alkali ?

 Answer-  Salt. This property is used for soap formation and for cleaning the chocked drains using an alkali.

 Q.36-Define rancidity.

Answer-The unpleasant taste and odour developed by fats on ageing is called rancidity.

 Q.37-What are the components of Slow releasing/Reacting substance of Anaphylaxis ?

Answer-LTC4, LTD4 and LTE4.

 Q.38-What is the site of cleavage of Sphingomyelinase enzyme?

Answer-Removal of phosphoryl choline from ceramide

 Q.39-Based on the nature of fatty acids present, how many types of Cerebrosides are there in the human system?

Answer- 4 types- Kerasin (Lignoceric acid), Cerebron (Cerebronicacid), Nervon (Nervonic acid) and Oxynervon (Hydroxy derivative of Nervonic acid ).

 Q.40-Which out of the two COX enzymes I and II is inducible?

Answer- It is COX II.

 Q.41- Name a sphingolipid                                            

Answer-Sphingomyelin.

 Q.42-All are conditions of hypercholesterolemia except

Anemia,Diabetes Mellitus, Hypothyroidism, Nephrotic syndrome

Answer- Anemia, there is low cholesterol level in blood.

 Q.43-Name a selective COX inhibitor                            

Answer- Celecoxib and Rofecoxib.

 Q.44-Name the drugs which can inhibit Prostaglandin synthesis

Answer- Steroids and NSAIDs.

 Q.45-Give the therapeutic uses of PGs

Answer-Termination of pregnancy, Treatment of asthma hypertension etc.

 Q.46-Why do oils float on the surface of water?

Answer-Oils have lesser specific gravity than water.

 Q.47-What is the systematic name of Alpha Linolenic acid

Answer- all cis- octadectrienoic acid-18;∆3, 9,12,15.

 Q.48-What is the main function of HDL?

 Answer- Transportation of cholesterol from peripheral tissues to liver, It is called Good cholesterol.

 Q.49-Butter is rich in short and medium chain fatty acids, Is it True or false?

Answer- It is true.

 Q.50-Name the disease caused due to deficiency of Beta Glucosidase enzyme .

Answer-Gaucher’s disease.

 Q.51-What is the difference between Cerebrosides and Globosides?

Answer-Cerebrosides contain a single monosaccharide while Globosides contain more than one monosaccharide; it may be Lactosyl oroligosaccharide ceramide.

 Q.52-Which phospholipid is present in the mitochondrial membrane?

Answer-Cardiolipin.

 Q.53-Which phospholipid has unsaturated long chain alcohol in ether linkage  with the first hydroxyl group of glycerol ?                                         

Answer- Plasmalogen.

 Q.54-What is the basis of removing grease stains with petrol?

Answer-Petrol is an organic solvent, and grease is a wax. Petrol makes a soluble complex with grease.

 Q.55-What are the clinical manifestations in Essential fatty acids deficiency?

 Answer- Growth retardation,dermatitis, fatty liver and impaired vision.

 Q.56-Why are prostaglandins not conventionally used as drugs?

Answer-Short duration of action, rapidly destroyed and non specific in action.

 Q.57- Name the compound lipids.

Answer-Phospholipids, glycolipids, sulfolipids, amino lipids and lipoproteins.

 Q.58-Name any odd chain fatty acid.          

Answer-Propionic acid, Valeric acid.

 Q.59-Why is alkali used for opening the choked drains?

Answer- Alkali causes Saponification of fats forming water soluble soaps resulting in reopening of the blocked drains.

 Q.60-Name the phospholipids which act as lipotropic agents

Answer- All but most importantly, Phosphatidyl choline,Phosphatidyl ethanolamine and Phosphatidyl Inositol.

 Q.61-What is the defect in Niemann pick’s disease?

Answer-Deficiency of Sphingomyelinase enzyme.

 Q.62-What is the diagnostic hall-mark of Gaucher disease ?

Answer-Presence of Gaucher cells in bone marrow aspiration biopsy

 Q.63-Infants placed on low-fat diet due to a variety of reasons generally develop skin rashes and other symptoms. What is the reason for it?  

Answer- Essential fatty acid deficiency.

 Q.64-Which out of the following is an inter mediate both for the synthesis of phospholipids and Triacylglycerols-

Diacylglycerol, Cholesterol, Choline , Inositol               

Answer- Diacyl glycerol.

 Q.65- What is the risk associated with increased levels of serum total cholesterol?     

Answer-Atherosclerosis.

 Q.66-Why is cyclo-oxygenase enzyme called the suicidal enzyme?

Answer-It catalyzes its self-destruction.

 Q.67-Namea saturated fatty acid with 18 carbon atoms abundantly present in the body tissues.                                                                   

Answer- Stearic acid.

 Q.68-Which   fatty acid should have the least melting point out of the followings?

Stearic acid, Arachidonic acid, Timnodonic acid            

Answer-Timnodonic acid, since it has five double bonds; more the degree of unsaturation, lesser is the melting point.

Q.69- A 3 year child was brought with hepatosplenomegaly and mental retardation. Biopsy revealed accumulation of sphingomyelin. What is the defect?

Answer The child is suffering from -Niemann Pick’s disease.

 Q.70-Name the polar derivative of cholesterol

Answer- Bile salts.

 Q.71-A female patient with 34 weeks of pregnancy has to under go Emergency caesarean section for the delivery of the baby but the L:S ratio of amniotic fluid is 1:1. What is the significance of this ratio and what is recommended to this female?

Answer-   L/S ratio should be >2-5:1 for adequate fetal lung maturity. In the given patient L/S ratio of 1: 1 indicates fetal lung immaturity, Injections of glucocorticoids are recommended for her..

 Q.72- What is meant by Total cholesterol? 

 Answer-Free cholesterol+ Esterified cholesterol.

 Q.73-Why can’t essential fatty acids be synthesized by the human body?

Answer- Humans lacks the enzyme to incorporate double bond between the existing double bond and the methyl end (ω end).

Q.74-Name a fatty acid with 18 carbon atoms and a single double bond in trans configuration                                               

Answer-Elaidic acid.

 Q.75-Why is LDLc called a bad cholesterol?                 

Answer- Since it transports cholesterol from liver to peripheral tissues and excess of LDL can result in atheroma formation increasing the risk for IHD, Stroke or Peripheral vascular disease.

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Q.1- Endogenously synthesized triacylglycerols are transported from liver to extra hepatic tissues by which of the following lipoproteins?
a) Chylomicrons
b) VLDL
c) LDL
d) HDL     
Q.2- All of the following have 18 carbon atoms except –
a) Linoleic acid
b) Palmitic acid
c) Linolenic acid
d) Stearic acid        
Q.3- Sphingosine is not present in-
a) Cerebrosides
b) Gangliosides
c) sphigomyelin
d) Plasmalogen                         
Q.4- Triacylglycerols are-
a) Energy rich compounds
b) Nonpolar in nature
c) Can be stored in unlimited amounts
d) All of the above           
Q.5- All are essential fatty acids except-              
a)Linoleic,
b) Linolenic
c) Arachidonic acid
d) Stearic acid        
Q.6- The deficiency of Lung surfactant, Dipalmitoyllecithin (DPL) causes, Respiratory Distress Syndrome. DPL is a –
a) Cerebroside
b) Ganglioside
c) Phospholipid
d) Lipoprotein
Q.7- Choose the correct statement
a) The melting point of a fatty acid increases with the increasing degree of unsaturation in the hydrophobic chain
b) Most of the naturally fatty acids have trans double bonds
c) Arachidonic acid is a relatively nonessential fatty acid
d) The membrane lipids are rich in saturated fatty acids.
Q.8- Which out of the following fatty acids is a precursor of series -1 Eicosanoids?
a) Linoleic acid
b) Arachidonic acid
c) Eicosapentaenoic acid
d) Linolenic acid
Q.9- What is the cause of hyper acidity on long-term usage of Aspirin?
a) Inhibition of cyclo oxygenase
b) Increased synthesis of PGs
c) Inhibition of Phospholipase A2
d) All of the above
Q.10- Which nitrogenous base out of the following is present in lecithin —?
a) Choline
b) Adenine
c) Ethanolamine
d) Any of the above
Q.11- Cholesterol is a precursor of all except-
a)Bile salts,
b)Bilirubin
c) Steroids
d) vitamin D                             
Q.12- Glycerol is used for the synthesis of all except-
a) Glucose.,
b) Phospholipids,
c) Glycolipids,
d) Triacylglycerol             
Q.13- Which out of the following is a fatty acid with 16 carbon atoms and one double bond?
a) Palmitoleic acid
b) Oleic acid
c) Erucic acid
d) Elaidic acid
Q.14-Which out of the following is an ώ 3 fatty acid?
a) α Linolenic acid
b) Linoleic acid
c) Palmitic acid
d) Arachidonic acid
Q.15- Fats on keeping fora long time under go spontaneous hydrolysis, what is this process called?
a) Saponification
b) Hydrolytic Rancidity
c) Decomposition
d) All of the above
Q.16-  Which out of the following enzymes is deficient  in Gaucher’s disease?    
a) Beta Glucosidase
b) Beta Galactosidase
c) Hexosaminidase A
d) Neuraminidase
Q.17- Prostcyclins are synthesized in- ———?      
a) Platelets   
b) Endothelial cells
c) Gastric mucosa
d) Basophils
Q.18- Cyclo-oxygenase is inhibited by all except——–? 
a) Aspirin
b) Indomethacin
c) Brufen
d) Zileuton
Q.19- The normal level of serum Total cholesterol is———–?
a) 150-220 mg/dl
b) 100-200 mg/dl
c) 1.5-2.5g/dl
d) 20-40 mg/dl
Q.20- Choose out of the followings, a fatty acid with 20 carbon atoms and five double bonds-
a) Timnodonic acid
b) Arachidonic acid
c) Clupanodonic acid
d) Nervonic acid
Q.21- Which type of lipid is a receptor for cholera toxin in the intestine?
a) GM2 Ganglioside
b) GM1 Ganglioside
c) Sphingomyelin
d) Galactocerebroside
Q.22- The significance of estimating L: S ratio of amniotic fluid in a pregnant female lies in evaluating-
a) Fetal heart rate                                         
b) Fetal lung maturity
c) Fetal head size
d) Expected date of delivery
Q.23- Iodine number is a measure of-
a) Degree of unsaturation of a fat
b) Degree of rancidity of a fat
c) Measure of volatile fatty acids in a fat
d) Measure of number of –OH groups in a fat
Q.24-Which phospholipid out of the following is antigenic in nature -?     
a) Cardiolipin
b) Lecithin
c) Plasmalogen
d) Cephalin
Q.25- Which out of the followings is not a derived lipid?
a) Ketone body
b) PGE2  
c) Diacylglycerol,
d) Galactosyl ceramide              
Q.26- What are the components of a ceramide?                      
a) Sphingosine+ fatty acid
b) Glycerol+Fatty acids+Phosphoric acid
c) Glycerol+Fatty acids+Phosphoric acid+Nitrogenous base
d) Sphingosine+ fatty acids+Phosphoric acid
Q.27- Choose the incorrect statement-
a) The chemical name of Arachidonic acid is Eicosa penta enoic acid       
b) Cyclo-oxygenase and peroxidase are the components of PG-H synthase complex
c) Oleic acid is represented by 18;1,∆9
d) NSAIDs act by inhibiting Phospholipase A2 enzyme.
 Answers-
1-(b)- VLDL
2-(b)- Palmitic acid
3-(d)- Plasmalogen
4-(d) All of the above
5-(d) Stearic acid
6-(c) Phospholipid
7-(c) Arachidonic acid
8-(a) Linoleic acid
9-(a)- Inhibition of cyclo-oxygenase enzyme
10-(a) Choline
11-(b) Bilirubin
12-(c) Glycolipids
13-(a) –Palmitoleic acid
14-(a)-α– Linolenic acid
15-(b)-Hydrolytic Rancidity
16-(a) Beta Glucosidase
17-(b)-Endothelial cells
18-(d)-Zileuton
19-(a) 150-220 mg/dL
20-(a) Timnodonic acid
21-(b) GM1- Ganglioside
22-(b) Fetal lung maturity
23-(a)- Degree of unsaturation
24-(a)- Cardiolipin
25-(a)- Galactosyl Ceramide
26-(a)- Sphingosine+Fatty acid
27-(d) NSAIDs act by inhibiting Phospholipase A2 enzyme
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