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Chylomicrons- synthesis and metabolic fate
What is the action of lipoprotein lipase and how is it activated or inhibited?
Answer- Triacylglycerols of Chylomicrons & VLDL are hydrolyzed by Lipoprotein Lipase.
1) Location-Lipoprotein lipase is located on the walls of blood capillaries, anchored to the endothelium by negatively charged proteoglycan chains of heparan sulfate (Figure-1). It has been found in heart, adipose tissue, spleen, lung, renal medulla, aorta, diaphragm, and lactating mammary gland, although it is not active in adult liver. It is not normally found in blood; however, following injection of heparin, lipoprotein lipase is released from its heparan sulfate binding into the circulation. Due to this reason heparin is also called ‘Clearing factor’. Reduced serum LPL activity, after an injection of intravenous heparin, confirms the diagnosis of either LPL or apoC-II deficiency.
Figure-1- Showing the attachment of lipoprotein lipase to the endothelial cells by proteoglycan chains of Heparan sulfate
2) Activators and Inhibitors-Both phospholipids and apo C-II are required as cofactors for lipoprotein lipase activity, while apo A-II and apo C-III act as inhibitors. In adipose tissue, insulin enhances lipoprotein lipase synthesis in adipocytes and its translocation to the luminal surface of the capillary endothelium.
3) Catalytic action-Hydrolysis takes place while the lipoproteins are attached to the enzyme on the endothelium. Triacylglycerol is hydrolyzed progressively through a diacylglycerol to a monoacylglycerol and finally to free fatty acids plus glycerol.
4) Fate of products of hydrolysis-Some of the released free fatty acids return to the circulation, attached to albumin, but the bulk is transported into the tissue . Glycerol is transported to liver for further utilization as a source of energy, as a substrate for gluconeogenesis or for reesterification to form triglycerides. In muscle, the fatty acids are oxidized to produce ATP and in adipose cells they are reformed into TG for storage (Figure-2)
The action of lipoprotein lipase forms remnant lipoproteins
Figure-2- showing an overview of action of lipoprotein lipase and the fate of products
Reaction with lipoprotein lipase results in the loss of approximately 90% of the triacylglycerol of chylomicrons and VLDL, with the formation of chylomicron and VLDL remnants or IDL (intermediate-density lipoprotein.
5) Organ specific variations in catalytic action-Heart lipoprotein lipase has a low Km( for triacylglycerol about one-tenth of that for the enzyme in adipose tissue. This enables the delivery of fatty acids from triacylglycerol to be redirected from adipose tissue to the heart in the starved state when the plasma triacylglycerol decreases. A similar redirection to the mammary gland occurs during lactation, allowing uptake of lipoprotein triacylglycerol fatty acid for milk fat synthesis. The VLDL receptor plays an important part in the delivery of fatty acids from VLDL triacylglycerol to adipocytes by binding VLDL and bringing it into close contact with lipoprotein lipase.
Clinical significance of diminished activity – The most common genetic defect leading to hypertriglyceridemia is a deficiency in LPL, which results in increased levels of both chylomicrons and VLDL. (TG levels >2000 mg/dL)- Type I- Hyperlipidemia (Chylomicronemia)
The cholesterol level may be normal or slightly elevated. LPL deficiency is inherited in an autosomal recessive pattern. Patients with LPL deficiency often present with recurrent episodes of pancreatitis in their childhood and may have other clinical signs of hypertriglyceridemia such as: xanthomas, hepatosplenomegaly, and lipemia retinalis.
1) LPL deficiency requires measurement of LPL activity in plasma following intravenous injection of heparin, which displaces the LPL from its heparan sulfate tether. However, heparin also releases hepatic lipase ( HL) into the plasma and the post-heparin plasma must be treated with antibodies specific to HL to remove it.
2) Alternatively, LPL can also be measured in adipose tissue, which has no HL activity.
3) A deficiency in apoC-II will also show evidence of decreased postheparin plasma LPL activity. An increase in LPL activity when normal apo C-II is added to the assay indicates that a defect in apoC-II is the culprit.
Q- Give a brief account of the synthesis and catabolism of chylomicrons.
Answer- By definition, chylomicrons are found in chyle formed only by the lymphatic system draining the intestine. They are responsible for the transport of all dietary lipids into the circulation. Small quantities of VLDL are also to be found in chyle; however, most of the plasma VLDL are of hepatic origin. They are the vehicles of transport of triacylglycerol from the liver to the extrahepatic tissues.
Synthesis of Chylomicrons – (Figure-4)
1) Synthesis of Apo B48
Chylomicrons contain Apo B48, synthesized in the rough endoplasmic reticulum (RER). The synthesis of apo B48 is the result of RNA editing process. Coding information can be changed at the mRNA level by RNA editing. In such cases, the coding sequence of the mRNA differs from that in the cognate DNA. In liver, the single apoB gene is transcribed into an mRNA that directs the synthesis of a 100-kDa protein, apoB100. In the intestine, the same gene directs the synthesis of the primary transcript; however, a cytidine deaminase converts a CAA codon in the mRNA to UAA at a single specific site. Rather than encoding glutamine, this codon becomes a termination signal, and a 48-kDa protein (apoB48) is the result. ApoB100 and apoB48 have different functions in the two organs (Figure-3)
Figure-3- showing RNA editing
Clinical Significance- In abetalipoproteinemia (a rare disease), lipoproteins containing apo B are not formed and lipid droplets accumulate in the intestine and liver(Due to non formation of VLDL)
2) Synthesis of lipids and formation of lipoprotein- Long-chain fatty acids are esterified to yield to triacylglycerol in the mucosal cells and together with the other products of lipid digestion, are incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol.
Figure-4 – Showing the Synthesis of Chylomicrons (RER- Rough endoplasmic reticulum, SER- smooth endoplasmic reticulum, G- Golgi apparatus, N- Nucleus, C-chylomicron.
3) Addition of Carbohydrate-Carbohydrate residues are added in the golgi apparatus.
4) Release and Transportation of Chylomicrons- After addition of carbohydrate residues in golgi apparatus, they are released from the cell by reverse pinocytosis. Chylomicrons pass into the lymphatic system and eventually enter the systemic circulation.
Catabolism of Chylomicrons
The clearance of chylomicrons from the blood is rapid, the half-time of disappearance being under 1 hour in humans. Larger particles are catabolized more quickly than smaller ones. Chylomicrons are acted upon by the enzyme lipoprotein lipase (Details given under Lipoprotein lipase- see figure-5). Reaction with lipoprotein lipase results in the loss of approximately 90% of the triacylglycerol of chylomicrons and in the loss of apo C (which returns to HDL) but not apo E, which is retained. The resulting chylomicron remnant is about half the diameter of the parent chylomicron and is relatively enriched in cholesterol and cholesteryl esters because of the loss of triacylglycerol.
Figure-5- Showing the metabolic fate of Chylomicrons The nascent chylomicrons acquire apo CII and E from HDL. After the action of lipoprotein lipase, apo CII is returned back to HDL while apo E is retained by the chylomicron remnants to get internalized through Apo B100,E receptors in the liver. Apo CII is an activator of lipoprotein lipase.
Chylomicron remnants are taken up by the liver by receptor-mediated endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed and metabolized. Uptake is mediated by apo E (Figure –4), via two apo E-dependent receptors, the LDL (apo B-100, E) receptor and the LRP (LDL receptor-related protein). Hepatic lipase has a dual role: (1) it acts as a ligand to facilitate remnant uptake and (2) it hydrolyzes remnant triacylglycerol and phospholipid.
The products released are re utilized for the synthesis of VLDL.
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