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Q- Comment upon the degradation of cholesterol, Is it a source of energy ?

Answer- Cholesterol is not a source of energy , the ring structure of cholesterol cannot be metabolized to CO2 and H2O. Rather the intact sterol is eliminated from the body by conversion to bile acids and bile salts, and by secretion of cholesterol in to the bile, which transports it to the intestine for elimination.

Figure-1-Showing the structure of Coprostanol


Figure-2- Showing the structure of Cholestanol

Some of the cholesterol in the intestine is acted upon by bacteria before excretion. The primary compounds made are the isomers of Coprostanol (Figure-1)and Cholestanol (Figure-2) which are reduced derivatives of cholesterol. Together with cholesterol , these compounds make the bulk of the feces.

Q.-How does cholesterol liberated from LDL ( beta-lipoprotein) within the cell control the cell’s cholesterol metabolism? Discuss the clinical state associated with absent or reduced LDL uptake.

Answer- Cholesterol is transported in plasma in lipoproteins, and in humans the highest proportion is found in LDL.

Dietary cholesterol- Cholesteryl ester in the diet is hydrolyzed to cholesterol, which is then absorbed by the intestine together with dietary unesterified cholesterol and other lipids. With cholesterol synthesized in the intestines, it is then incorporated into chylomicrons. Of the cholesterol absorbed, 80–90% is esterified with long-chain fatty acids in the intestinal mucosa. Ninety-five percent of the chylomicron cholesterol is delivered to the liver in chylomicron remnants, and most of the cholesterol secreted by the liver in VLDL is retained during the formation of IDL and ultimately LDL (Figure-3)which is taken up by the LDL receptor in liver and extrahepatic tissues.

LDL Receptor- The LDLs (containing cholesteryl esters) are taken up by cells by a process known as receptor-mediated endocytosis. The LDL receptor mediates this endocytosis and is important to cholesterol metabolism.

LDL (apo B-100, E) receptors occur on the cell surface in pits that are coated on the cytosolic side of the cell membrane with a protein called clathrin. The glycoprotein receptor spans the membrane, the B-100 binding region being at the exposed amino terminal end.

Figure-3- Showing the structure of LDL. The outer hydrophilic shell is made up of Apo B100 , phospholipids and free cholesterol while the inner hydrophobic core is made up of Triglycerides and Cholesteryl esters.

 The LDL receptor gene is located on the short arm of chromosome 19, and the protein is composed of 860 amino acids. It is the primary determinant of hepatic LDL uptake, which normally processes approximately 70% of circulating LDL. Two ligands on LDL bind to the receptor, apolipoprotein B-100 (apoB-100) and apoE. and is, therefore, more accurately termed the B,E receptor. ApoE is found on most lipoproteins other than LDL, including very low-density lipoprotein (VLDL) and chylomicrons and their remnants, intermediate-density lipoprotein (IDL), and a subclass of high-density lipoprotein (HDL). The LDL receptor binds apoE with higher affinity than apoB-100, and some mutations in the receptor may spare uptake of LDL by allowing binding to apoE.


 Figure- 4- Showing uptake of LDL. The enzyme ACAT, uses mono unsaturated fatty acid for esterification of cholesterol (Oleic acid)

After LDL binding to the LDL receptor, the ligand-receptor complexes cluster on the plasma membrane in coated pits, which then invaginate forming coated vesicles. These coated vesicles are internalized and clathrin, the protein composing the lattice in membrane coated pits, is removed. These vesicles are now called endosomes and these endosomes fuse with the lysosome. The LDL receptor–containing membrane buds off and is recycled to the plasma membrane. Fusion of the lysosome and endosome releases lysosomal proteases that degrade the apoproteins into amino acids. Lysosomal enzymes also hydrolyze the cholesteryl esters to free cholesterol and fatty acids.

Fate of released free cholesterol(Regulation of cholesterol metabolism by internalized cholesterol)

1)The free cholesterol is released into the cell’s cytoplasm, and this free cholesterol is then available to be used by the cell. It may be used for the formation of bile acids, steroid  hormones, vitamin D or may be used as component of biological membranes depending upon the cell type.

2) Excess cholesterol is reesterified by acyl-CoA:cholesterol acyltransferase (ACAT), which uses fatty acyl-CoA as the source of activated fatty acid.

3) Free cholesterol affects cholesterol metabolism by inhibiting cholesterol biosynthesis. Cholesterol inhibits the enzyme hydroxy-methylglutaryl-CoA reductase (HMG-CoA reductase), which catalyzes an early rate-limiting step in cholesterol biosynthesis. HMG-CoA reductase is the target of the statin drugs in wide use for treating patients with elevated cholesterol levels.

4)  In addition, free cholesterol inhibits the synthesis of the LDL receptor, thus limiting the amount of LDLs that are taken up by the cell. This influx of cholesterol inhibits the transcription of the genes encoding HMG-CoA synthase—HMG-CoA reductase and other enzymes involved in cholesterol synthesis as well as the LDL receptor itself via the SREBP pathway, and thus coordinately suppresses cholesterol synthesis and uptake.

 cholesterol metabolism

 Figure-5- Showing the LDL uptake and the fate of free cholesterol

Clinical Significance of reduced LDL uptake

Familial hypercholesterolemia (FH)- FH is a disorder of absent or grossly malfunctioning low-density lipoprotein (LDL) receptors. LDL receptor function ranges from completely absent to approximately 25% of normal receptor activity.

In the absence of a functioning LDL receptor, LDL cholesterol levels are greatly elevated in individuals with this disease.

Also, when LDL is not internalized by hepatocytes, hepatic synthesis of cholesterol is not suppressed. This leads to further cholesterol production despite high levels of circulating cholesterol. Therefore, circulating cholesterol levels are increased dramatically. The total and LDLc levels of infants and children with homozygous FH are higher than 600 mg/dL. In patients with heterozygous FH, half the LDL receptors are normal and half are rendered ineffective by the mutation. These patients’ total cholesterol and LDLc levels are twice as high as the population average. LDLc levels of 200-400 mg/dL are common.

High levels of LDLc increase cholesterol uptake in nonhepatic cells that is independent of LDL receptors. These scavenger pathways allow cholesterol uptake by monocytes and macrophages, leading to foam cell formation, plaque deposition in the endothelium of coronary arteries, and premature CAD. Cholesterol also accumulates in other areas, particularly the skin, causing Xanthelasmas and a variety of xanthomas.

Homozygous children may have symptoms consistent with ischemic heart disease, peripheral vascular disease, cerebrovascular disease, or aortic stenosis. 

Healthy diet, regular exercise, and maintenance of desirable weight  along with pharmacological intervention is required for treating hypercholesterolemia.

Prognosis depends heavily on the extent to which LDLc levels can be reduced. Patients with homozygous FH have and extremely limited life expectancy without major medical intervention.



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