Lipases atherosclerosis

Breckenridge WC, Little JA, Alaupovic P, Wang CS, Kuksis A, Kakis G, Lindgren F, Gardiner G (1982) Lipoprotein abnormalities associated with a familial deficiency of hepatic lipase. Atherosclerosis 45 161-179... 

HDL concentrations vary reciprocally with plasma triacylglycerol concentrations and directly with the activity of lipoprotein lipase. This may be due to surplus surface constituents, eg, phospholipid and apo A-I being released during hydrolysis of chylomicrons and VLDL and contributing toward the formation of preP-HDL and discoidal HDL. HDLj concentrations are inversely related to the incidence of coronary atherosclerosis, possibly because they reflect the efficiency of reverse cholesterol transport. HDL, (HDLj) is found in... 

FIGURE 9. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. Acetyl CoA, acetyl coenzyme A Apo, apolipoprotein C, cholesterol CE, cholesterol ester FA, fatty acid HL, hepatic lipase HMG CoA, 3-hydroxy-3-methyglutaryl coenzyme A IDL, intermediate-density lipoprotein LCAT, lecithin-cholesterol acyltransferase LDL, low-density lipoprotein LPL, lipoprotein lipase VLDL, very low-density lipoprotein. 

Bruschke AV et al. The Asp9 Asn mutation in the lipoprotein lipase gene is associated with increased progression of coronary atherosclerosis. Circulation 1996 94 1913-1918. 

Santamarina-Fojo S, Haudenschild C, Amar M. The role of hepatic lipase in lipoprotein metabolism and atherosclerosis. Curr Opin Lipidol 1998 9 211-219. 

A common hepatic lipase gene promoter variant determines clinical response to intensive lipid lowering treatment. Atherosclerosis 2000 151 266. 

Familial lipoprotein lipase deficiency is characterized by a massive accumulation of chylomicrons and a corresponding increase in plasma triglycerides or a type I lipoprotein pattern. Presenting manifestations include repeated attacks of pancreatitis and abdominal pain, eruptive cutaneous xanthomatosis, and hepatosplenomegaly beginning in childhood. Symptom severity is proportional to dietary fat intake, and consequently to the elevation of chylomicrons. Accelerated atherosclerosis is not associated with this disease. 

The metabolism of VLDL by lipoprotein lipase in the capillaries in many tissues results in the formation of low density lipoprotein (LDL), which is atherogenic, so that diets high in sucrose are a risk factor for development of atherosclerosis. Many children in developed countries now consume large quantities of soft drinks containing sucrose or fructose. According to the above discussion, this could lead to atherosclerosis in later life. 

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. 

Ruel IL, Couture P, Cohn JS, Lamarche (2005) Plasma metabolism of apoB-containing lipoproteins in patients with hepatic lipase deficiency. Atherosclerosis 180 355-366... 

G. Olivecrona and T. Olivecrona, Triglyceride lipases and atherosclerosis, Curr. Opin. Lipidol. 6 (1995) 291-305. 

M46. Murase, T., and Hakura, H., Accumulation of intermediate density lipoprotein in plasma after intravenous administration of hepatic triglyceride lipase antibody in rats. Atherosclerosis 38, 293-300 (1981). 

Lipoprotein associated phospholipase A2(LpPLA2> is a serine dependent lipase of novel structure which is associated with the presence of LDL in plasma. It hydrolyses oxidised phospholipids to generate lysophosphatidylcholine and oxidised free fatty acids (Scheme 1), both of which are potent chemoattractants for circulating monocytes. Accumulation of lysophosphatidylcholine results in macrophage proliferation and the endolithial dysfunction observed in patients with atherosclerosis. Inhibition of LpPLA2 would thus be expected to stop plaque build-up and provide an attractive strategy in the treatment of atherosclerosis. 

A. Familial lipoprotein lipase deficiency (Type I lipoprotein pattern on electrophoresis). Serum triglycerides become elevated with particular elevation of chylomicrons. Tliere are xanthomas, rather than atherosclerosis. Pancreatitis may result from the action of pancreatic lipase on these elevated chylomicrons, with resultant excess triglyceride breakdown in the pancreas, pancreatic injury, and release of more pancreatic lipase. (Note that the body contains different kinds of lipases. There is a pancreatic lipase, which is a digestive enzyme a lipoprotein lipase, which is an extracellular enzyme that breaks down plasma triglycerides, thereby enabling fatty acids to enter cells and an intracellular lipase that breaks down stored triglycerides). 

Benlian, R, GenneB, J. L Foubert, L, Zhang, IL, Gagne, S., and Hayden, M. (1996). Premature atherosclerosis in patients with familial chylomicroncniia caused by mutations in the lipoprotein lipase gene. W. / Med. 335, 84S- 54. 

Lipoprotein and hepatic lipases are important enzymes involved in the metabolism of chylomicrons and various fractions of lipoproteins. Both have been the subject of attention, as evidenced by numerous reviews (e.g., Garfinkel and Schotz, 1987 Wang eta/., 1992). This interest stems from the fact that abnormal lipoprotein metabolism has been linked to various disorders, including hyperchylomicronemia, hypercholesterolemia, hypertriglyceridemia, obesity, diabetes, and premature atherosclerosis. Genetic defects in both HL and LPL are now known to be the cause of at least some familial disorders of lipoprotein metabolism. 

HDL, like LDL, is a cholesterol-rich particle, and is distinct from the other lipoprotein classes in that it does not contain apoB. HDL levels are inversely correlated with risk for atherosclerosis (Wilson et al., 1988). Nascent HDL particles are produced by direct synthesis (Hamilton, 1984), and excess surface remnants from chylomicrons and VLDL produced during the action of lipoprotein lipase (as noted above) enter the HDL density class. HDL appears to be involved in delivery of cholesterol to steroidogenic tissues as well as the removal of excess cholesterol from peripheral tissues and excretion from the system. This HDL-mediated removal of cholesterol has been termed reverse cholesterol transport (Glomset, 1968). Although apolipoproteins present in HDLs are cleared by the liver, the reverse cholesterol transport pathway has never been directly demonstrated. HDL can remove cholesterol from tissues, a process that may be partially mediated by interaction with a putative HDL receptor, with apoA-I as the ligand for that receptor (Oram el ai, 1983). The existence of an HDL receptor remains controversial saturable HDL binding may not be mediated by a specific apolipoprotein ligand and may not even be required for transfer of cholesterol from cells to... 

Atherosclerosis and Plasma Lipids - Lipoprotein lipases play a critical role in the metabolism of lipoproteins and thus may be involved in athero-genesis. Hypercholesterolemia in the cholesterol-fed rabbit was attributed to the accumulation of chylomicron remnants, which may be formed on the aorta wall by lipoprotein lipase and deposited in the deep layers of the arterial wall without prior release into the blood stream.13 On this basis, cholesterol-rich lipoproteins in plasma may be the product rather than the cause of the atherogenic process. However, the defect in Type III hyperlipoproteinemia (broad- disease) may be ineffective removal of chylomicron remnant particles from the arterial wall,11 due to a failure of the liver to recognize such particles.15... 

Endothelial Lipase A Novel Drug Target for HDL and Atherosclerosis ... 

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