The overall goal of the project during this period has been to understand, at a molecular level, how cholesterol from the diet is metabolized by the liver. To this end, three specific aims are proposed: 1) To further characterize the remnant removal pathway. Specifically, it appears that there are both LDL receptor-dependent and -independent pathways. We will use an antibody to the LDL receptor to eliminate its contribution to the process and then learn how remnant metabolism proceeds in the absence of the LDL receptor. We will attempt to visualize the process by electron microscopy and to purify the relevant binding site biochemically. The role of hepatic lipase in the removal process will be studied. 2) To study the consequences of LDL receptor-dependent and LDL receptor-independent remnant removal on hepatic lipid metabolism. Specifically, we will determine the amount and effects of non-LDL receptor-mediated remnant transport and attempt to explain the basis for the slower rate of degradation of remnants than beta-VLDL. 3) To characterize non-cholesterol mediated regulation of hepatic LDL receptors in liver and evaluate the consequence of this on remnant metabolism. Specifically, we will examine the mechanism whereby insulin and an as yet unidentified liver specific growth factor stimulate LDL receptors. We will conduct further studies of mechanisms of neoplasia-induced decrease in LDL receptors. The understanding achieved by these studies may eventually aid in the design of regimens that lead to the prevention of atherosclerosis and cholelithiasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038318-06
Application #
3237626
Study Section
Metabolism Study Section (MET)
Project Start
1986-07-01
Project End
1993-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Palo Alto Medical Foundation Research Institute
Department
Type
DUNS #
622276137
City
Palo Alto
State
CA
Country
United States
Zip Code
94301
Grosskopf, Itamar; Baroukh, Nadine; Lee, Sung-Joon et al. (2005) Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants. Arterioscler Thromb Vasc Biol 25:2573-9
Ishida, Tatsuro; Choi, Sungshin Y; Kundu, Ramendra K et al. (2004) Endothelial lipase modulates susceptibility to atherosclerosis in apolipoprotein-E-deficient mice. J Biol Chem 279:45085-92
Yu, Kenneth C-W; David, Christopher; Kadambi, Sujata et al. (2004) Endothelial lipase is synthesized by hepatic and aorta endothelial cells and its expression is altered in apoE-deficient mice. J Lipid Res 45:1614-23
Ishida, Tatsuro; Choi, Sungshin; Kundu, Ramendra K et al. (2003) Endothelial lipase is a major determinant of HDL level. J Clin Invest 111:347-55
Chen, Jean Y; Levy-Wilson, Beatriz; Goodart, Sheryl et al. (2002) Mice expressing the human CYP7A1 gene in the mouse CYP7A1 knock-out background lack induction of CYP7A1 expression by cholesterol feeding and have increased hypercholesterolemia when fed a high fat diet. J Biol Chem 277:42588-95
Yu, K C; Chen, W; Cooper, A D (2001) LDL receptor-related protein mediates cell-surface clustering and hepatic sequestration of chylomicron remnants in LDLR-deficient mice. J Clin Invest 107:1387-94
Yu, K C; Jiang, Y; Chen, W et al. (2000) Rapid initial removal of chylomicron remnants by the mouse liver does not require hepatically localized apolipoprotein E. J Lipid Res 41:1715-27
Yu, K C; Jiang, Y; Chen, W et al. (1999) Evaluation of the components of the chylomicron remnant removal mechanism by use of the isolated perfused mouse liver. J Lipid Res 40:1899-910
Cooper, A D (1999) Role of the enterohepatic circulation of bile salts in lipoprotein metabolism. Gastroenterol Clin North Am 28:211-29, viii
Donner, C; Choi, S; Komaromy, M et al. (1998) Accelerated lipoprotein uptake by transplantable hepatomas that express hepatic lipase. J Lipid Res 39:1805-15

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