Elevated plasma cholesterol is a well established risk factor for atherosclerosis and coronary artery disease. HDL has been shown to protect against developing atherosclerosis. In lipoprotein metabolism the role of HDL is to transport cholesterol to the liver to be disposed of. Hepatic lipase (HL) is a major determinant of HDL cholesterol levels. The proposed research will be based on recent evidence which shows that HL stimulates direct selective HDL cholesterol ester (CE) uptake by the liver cells. The mechanism of HDL cholesterol ester uptake by the liver cells, and the mechanism by which HL stimulates this uptake, will be studied. The following questions will be addressed: 1) What are the characteristics of HL stimulated direct selective HDL CE uptake? The role of HL will be verified using cells with and without HL. HL knockout hepatocytes and heparin-treated hepatocytes will be used as cells lacking HL. HL antibodies will also be used to block HL action. These experiments will determine if HL action amplifies HDL cholesterol uptake by the liver cell. 2) Is this uptake mediated by the putative HDL receptor, scavenger receptor class B type 1? To study if this uptake mediated by SRB1, antibodies will be used to block this receptor. Experiments where the putative HDL receptor and HL are regulated independently will be carried out to address separately the roles of these factors in HDL CE uptake. 3) Are the cell surface proteoglycans participating in this uptake? The role of cell surface proteoglycans will be addressed by using cells lacking these structures. 4) What is the mechanism of HL-stimulated direct selective HDL CE uptake? It will be determined if lipolytic activity of HL, phospholipid and/or triglyceride hydrolysis, is needed for the stimulation of direct selective HDL cholesterol ester uptake by the liver cells. A hypothesis that HL can have a nonlipolytic role in this pathway will be addressed using inactive mutant HL. These experiments will explore the possibility that HL enhances HDL binding to hepatocyte cell surface resulting in an increase in CE uptake without hydrolyzing HDL lipids.
Krugner-Higby, Lisa; Shelness, Gregory S; Holler, Allyson (2006) Heritable, diet-induced hyperlipidemia in California mice (Peromyscus californicus) is due to increased hepatic secretion of very low density lipoprotein triacylglycerol. Comp Med 56:468-75 |
Zou, Liqun; Shen, Mei; Arad, Michael et al. (2005) N488I mutation of the gamma2-subunit results in bidirectional changes in AMP-activated protein kinase activity. Circ Res 97:323-8 |
Thuren, T (2000) Hepatic lipase and HDL metabolism. Curr Opin Lipidol 11:277-83 |