Lipoprotein lipase synthesis

Lipoprotein lipase, like many enzymes, has several isozymic forms that differ from one tissue to the next. Insulin is known to enhance lipoprotein lipase synthesis in the capillary endotheliiun next to adipocytes, whereas it has no such effect in the myocardium. Why might this have come about ... 

Increased lipid synthesis/inhibi-tion of lipolysis Activation of lipoprotein lipase (LPL)/induc-tion of fatty acid synthase (FAS)/inactivation of hormone sensitive lipase (HSL) Facilitated uptake of fatty acids by LPL-dependent hydrolysis of triacylglycerol from circulating lipoproteins. Increased lipid synthesis through Akt-mediated FAS-expression. Inhibition of lipolysis by preventing cAMP-dependent activation of HSL (insulin-dependent activation of phosphodiesterases )... 

TNF (17.5) Monocyte/macrophage, lymphocyte, neutrophil, endothelium, fibroblast, keratinocyte Activation of T and B cells, natural killer cells, neutrophils, and osteoblasts. Stimulation of endothelial cells to release chemotactic proteins, NO and PGI2. Tumoricidal activity. Induces fever, sleep, hepatic acute phase protein synthesis, catabolism, ACTH release. Lead to myocardial depression, hypotension/shock, hypercoagulability, and death. Stimulates production of IL-1, IL-6, IL-8, IFN-y, and H202. Suppression of cytochrome P-450, thyroglobulin, and lipoprotein lipase. Induces complement activation, release of eicosanoids, including PAF. Procoagulant activity. 

Mechanism of Action An antihyperlipidemic that enhances synthesis of lipoprotein lipase and reduces triglyceride-rich lipoproteins and VLDLs. Therapeutic Effect Increases VLDL catabolism and reduces total plasma triglyceride levels. Pharmacokinetics Well absorbed from the GI tract. Absorption increased when given with food. Protein binding 99%. Rapidly metabolized in the liver to active metabolite. Excreted primarily in urine lesser amount in feces. Not removed by hemodialysis. Half-life 20 hr. 

Twelve reviews cover the structure, synthesis, and metabolism of lipoproteins, regulation of cholesterol synthesis, and the enzymes LCAT and lipoprotein lipase. 

VLDLs are produced in the liver (Figure 18.17). They are composed predominantly of triacylglycerol, and their function is to carry this lipid from the liver to the peripheral tissues. There, the triacylglycerol is degraded by lipoprotein lipase, as discussed for chylomicrons (see p. 226). [Note "Fatty liver" (hepatic steatosis) occurs in conditions in which there is an imbalance between hepatic triacylglycerol synthesis and the secretion of VLDL. Such conditions include obesity, uncontrolled diabetes mellitus, and chronic ethanol ingestion.]... 

Decreased uptake of fatty acids In fasting, lipoprotein lipase activity of adipose tissue is low. Consequently, circulating triacyl-glycerol of lipoproteins is not available for triacylglycerol synthesis in adipose tissue. 

In six patients with renal transplants treated with sirolimus, mean total plasma cholesterol, triglyceride, and apolipoprotein concentrations increased (1067). The authors suggested that sirolimus increases lipase activity in adipose tissue and reduces lipoprotein lipase activity, resulting in increased hepatic synthesis of triglycerides, increased secretion of VLDL, and increased hypertriglyceridemia. 

VLDLs are synthesized in the liver and transport triacylglycerols, cholesterol and phospholipids to other tissues, where lipoprotein lipase hydrolyzes the triacylglycerols and releases the fatty acids for uptake. The VLDL remnants are transformed first to IDLs and then to LDLs as all of their apoproteins other than apoB-100 are removed and their cholesterol esterified. The LDLs bind to the LDL receptor protein on the surface of target cells and are internalized by receptor-mediated endocytosis. The cholesterol, which is released from the lipoproteins by the action of lysosomal lipases, is either incorporated into the cell membrane or re-esterified for storage. High levels of intracellular cholesterol decrease the synthesis of the LDL receptor, reducing the rate of uptake of cholesterol, and inhibit HMG CoA reductase, preventing the cellular synthesis of cholesterol. 

LCAT), which catalyzes the synthesis of cholesterol esters (F14, S46, S59) apoA-II, which activates hepatic triglyceride lipase (J2) and apoC-II, which activates lipoprotein lipase, responsible for the hydrolysis of triglycerides in chylomicrons and VLDL (H20, L5). Their mode of action is considered in Section 4 when the individual apolipoproteins are discussed. 

Chylomicrons are triglyceride rich and contain apolipoprotein B-48 and the A types. The latter are synthesized in the intestinal tract cells. Additional apoproteins are transferred to the chylomicrons from HDL in circulation the apoE and apoC types. Their site of synthesis is the liver. The chylomicrons are subject to degradation by lipoprotein lipase in the peripheral tissue, especially adipose tissue. Lipoprotein lipase activity is increased by increased blood insulin levels. This enzyme is extracellular, attached to the capillary endothelial cells, and activated by ApoC-II, which is present in the chylomicrons. Lipoprotein lipase causes the hydrolysis of triglycerides, thus decreasing chylomicron size... 

In addition to its effects on synthesis of milk proteins themselves, prolactin also induces the production in the mammary gland of other proteins/enzymes involved in production of milk components. Lactose synthetase and enzymes of lipid metabolism, including acetyl-CoA carboxylase and lipoprotein lipase, are among these inducible enzymes [75]. 

In general, drugs act to reduce the concentration of cholesterol within hepatocytes, causing a compensatory increase in low-density lipoprotein-receptors (LDL-R) on their surface, and increased uptake of cholesterol-rich LDL particles from the bloodstream (see Fig. 25.1). Statins decrease the synthesis of cholesterol and the secretion of VLDL and increase the activity of hepatic LDL-receptors. Bile-acidbinding resins deplete the bile acid and thus the cholesterol pool. Fibrates decrease the secretion of VLDL and increase the activity of lipoprotein lipase, thereby increasing the removal of tri-... 

The liver synthesizes two enzymes involved in intra-plasmic lipid metabolism hepatic triglyceride lipase (HTL) and lecithin-cholesterol-acyltransferase (LCAT). The liver is further involved in the modification of circulatory lipoproteins as the site of synthesis for cholesterol-ester transfer protein (CETP). Free fatty acids are in general potentially toxic to the liver cell. Therefore they are immobilized by being bound to the intrinsic hepatic fatty acid-binding protein (hFABP) in the cytosol. The activity of this protein is stimulated by oestrogens and inhibited by testosterone. Peripheral lipoprotein lipase (LPL), which is required for the regulation of lipid metabolism, is synthesized in the endothelial cells (mainly in the fatty tissue and musculature). 

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