Lipoprotein lipase regulation

The best-known effect of APOE is the regulation of lipid metabolism (see Fig. 10.13). APOE is a constituent of TG-rich chylomicrons, VLDL particles and their remnants, and a subclass of HDL. In addition to its role in the transport of cholesterol and the metabolism of lipoprotein particles, APOE can be involved in many other physiological and pathological processes, including immunoregu-lation, nerve regeneration, activation of lipolytic enzymes (hepatic lipase, lipoprotein lipase, lecithin cholesterol acyltransferase), ligand for several cell receptors, neuronal homeostasis, and tissue repair (488,490). APOE is essential... 

Relevant heparin-binding enzymes not involved in the coagulation cascade are, for example, elastase, cathepsin G, superoxide dismutase, lipoprotein lipase and other lipases. The plasma clearing properties of heparin are associated with its binding to lipoprotein lipase and hepatic lipase when the enzymes are released from the surface of endothelial cells [11] and have been studied in view of a potential impact on the regulation of atherosclerosis. 

Merkel M, Eckel RH, Goldberg IJ (2002) Lipoprotein lipase genetics, lipid uptake, and regulation. J Lipid Res 43 1997-2006... 

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

CM and VLDL secreted by intestinal cells and VLDL synthesized and secreted in the liver have similar metabolic fates. After secretion into the blood, newly formed CM and VLDL take up apoprotein (apo-C) from HDL and are subsequently removed from the blood (plasma half-life of less than 1 h in humans [137]) primarily by the action of lipoprotein lipase (LPL). Lipoprotein lipase is situated mainly in the vascular bed of the heart, skeletal muscle, and adipose tissue and catalyzes the breakdown of core TG to monoglycerides and free fatty acids, which are taken up into adjacent cells or recirculated in blood bound to albumin. The activity of LPL in the heart and skeletal muscle is inversely correlated with its activity in adipose tissue and is regulated by various hormones. Thus, in the fasted state, TG in CM and VLDL is preferentially delivered to the heart and skeletal muscle under the influence of adrenaline and glucagon, whereas in the fed state, insulin enhances LPL activity in adipose tissue, resulting in preferential uptake of TG into adipose tissue for storage as fat. 

An, D., Pulinilkunnil, T., Qi, D., Ghosh, S., Abrahani, A., and Rodrigues, B. 2005. The metabolic switch AMPK regulates cardiac heparin-releasable lipoprotein lipase. Am J Physiol Endocrinol Metab 288(1) E246-E253. 

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). 

Figure 6-9. Regulation of triacylglycerol stores in adipose tissue. Left = in the fed state. Right = in the fasted state. TG = triacylglycerol FA = fatty acid LPL = lipoprotein lipase DHAP = dihydroxyacetone phosphate = stimulated by circled TG = triacylglycerol of chylomicrons and VLDL.

K.N. Frayn, S.W. Coppack, B.A. Fielding, and S.M. Humphreys, Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo implications for the control of fat storage and fat mobilization, Adv. Enzyme Regul., 1995, 35, 163—178. 

P.A. Kern, M. Saghizadeh, J.M. Ong, R.J. Bosch, R. Deem, and R.B. Simsolo, The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity weight loss, and relationship to lipoprotein lipase, J. Clin. Invest., 1995, 95, 2111-2119. 

It remains to be established whether manipulation of HDL levels will in itself alter the development of CHD. The components of HDL are derived from different sources. " " HDL (or its precursors) is produced by both the liver and intestine. The structural composition of HDL is regulated by LCAT and lipoprotein lipase. There is also non-enzymatic transfer of apolipoprotein (apo) C between HDL and VLDL, exchange of free... 

LDL-receptor deficiency. In the normal condition (a), VLDL produced by the liver loses triacylglycerol as free fatty acids (FFA) via lipoprotein lipase to peripheral tissues and then proceeds down the metabolic cascade to IDL and LDL. A major portion of these two lipoprotein species is taken up by the liver or peripheral tissues via the LDL (apo B, E) receptor. In individuals with down-regulated or genetically defective LDL receptors (b), the residence time in the plasma of IDL is increa.sed, a greater proportion being converted to LDL. LDL production and turnover time are increased, and total plasma cholesterol levels become grossly abnormal. 

This reaction is responsible for formation of most of the cholesteryl ester in plasma. The preferred substrate is phosphatidylcholine, which contains an unsaturated fatty acid residue on the 2-carbon of the glycerol moiety. HDL and LDL are the major sources of the phosphatidylcholine and cholesterol. Apo A-I, which is a part of HDL, is a powerful activator of LCAT. Apo C-I has also been implicated as an activator of this enzyme however, activation may depend on the nature of the phospholipid substrate. LCAT is synthesized in the liver. The plasma level of LCAT is higher in males than in females. The enzyme converts excess free cholesterol to cholesteryl ester with the simultaneous conversion of lecithin to lysolecithin. The products are subsequently removed from circulation. Thus, LCAT plays a significant role in the removal of cholesterol and lecithin from the circulation, similar to the role of lipoprotein lipase in the removal of triacylglycerol contained in chylomicrons and VLDL. Since LCAT regulates the levels of free cholesterol, cholesteryl esters, and phosphatidylcholine in plasma, it may play an important role in maintaining normal membrane structure and fluidity in peripheral tissue cells. 

Maheux P, et al. Relationship between insulin-mediated glucose disposal and regulation of plasma and adipose tissue lipoprotein lipase. Diabetolo-gia 1997 40 850-858. 

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