Transcriptional Regulation of the Human Hepatic Lipase Gene: Relation to Glucose and Lipid Metabolism Deursen, D. van 2012-05-23 Doctoral Thesis

Hepatic Lipase (HL; EC 3.1.1.3) is an extracellular glycoprotein with phospholipase A1 and triacylglycerol hydrolase activity. The human HL protein is encoded by the LIPC gene on chromosome 15q21. Most of this protein is synthesized in the parenchymal cells of the liver and secreted into the space of Disse where it binds to heparin sulfate proteoglycans. Some synthesis of HL was also observed in macrophages. The HL protein is also present in the steroidogenic adrenal glands, ovaries and, in small amounts, in the testes. By using heparin, HL protein is displaced from its binding site. Human HL protein is a homodimer, the monomer has a molecular weight of 65 kDa. In the metabolism of plasma lipoproteins HL plays an important role; it mediates the conversion of high density lipoprotein subfraction 2 (HDL2) to high density lipoprotein subfraction 3 (HDL3), the conversion of intermediate density lipoprotein (IDL) to low density lipoproteins (LDL), and the formation of small dense LDL (sdLDL) from large buoyant LDL. HL has a role in postprandial lipid transport where it facilitates the clearance of remnant lipoproteins by the liver. In adrenals and ovaries the HL enzyme facilitates the delivery of HDL cholesterol for steroidogenesis, at least in the rat. HL expression is determined by genetic, hormonal and nutritional factors, and by body composition. HL activity is associated with a risk for Coronary Artery Diseases (CAD). Whether high HL expression is anti- or pro-atherogenic depends on other genetic or metabolic factors, e.g. concomitant hypertriglyceridemia [1,19]. Humans with visceral obesity and insulin resistance or type 2 diabetes show increased levels of HL expression. How HL gene expression is altered in insulin-resistant conditions is unknown. Relative to the common LIPC C-allele (referring to the C/T polymorphism at the -514 position), carriers of the T-allele have reduced post-heparin HL activity, and the T-allele is associated with dyslipidemia and insulin resistance in healthy controls and in Familial Combined Hyperlipidemia (FCH). In cell culture experiments using human HepG2 hepatoma cells, HL expression was found to be increased by elevated levels of fatty acids and glucose, conditions that prevail in insulin resistance. How these metabolic factors affect HL expression is largely unknown.
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