PH 8 East 101-B
Division of Molecular Medicine
622 West 168th Street
New York, NY 10032
The molecular mechanisms of hepatic High Density Lipoprotein Metabolism and Cholesterol transport.
We are taking molecular and transgenic approaches to study hepatic HDL metabolism and the effects of obesity on lipoprotein metabolism in the liver. HDL mediates the transport of cholesterol from peripheral tissues to the liver for excretion in bile in a process called reverse cholesterol transport.
The primary focus of our work is to understand how Scavenger Receptor Class B Type 1 (SR-BI), an authentic HDL receptor that is highly expressed in the liver and steroidogenic tissues, mediates the selective uptake of HDL cholesterol. SR-BI appears to mediate rapid transport of HDL free cholesterol and cholesteryl ester into bile, suggesting that SR-BI has an important role in HDL cholesterol transport across the cell. SR-BI activity in the liver was shown to be anti-atherogenic. We have found that SR-BI is localized to the basolateral and apical membranes of primary hepatocytes as well as in MDCK cells expressing SR-BI. In an effort to better understand the polar expression of SR-BI in the liver, we are currently identifying the basolateral tareting motifs on SR-BI and plan to isolate the targeting machinery.
Obesity is often associated with abnormalities in plasma lipoprotein levels or turnover. We are using ob/ob mice as a model to study HDL metabolism in obesity. We found that ob/ob mice have a hepatic defect in HDL protein and lipid uptake that is reversible by leptin.
Our other main interest is in identifying the proteins that assemble to form a large molecular weight membrance complex with SR-BI. One such protein termed PDZK1 appears to play an essential role in SR-BI function in the liver. We propose that obesity might alter the levels or activities of proteins found in a complex with SR-BI leading to dysfunction of SR-BI and increased risk for atherosclerosis.
Silver DL, Wang N, Xiao X, and Tall AR (2001). HDL particle uptake mediated by SR-BI results in selective sorting of HDL cholesterol from protein and polarized cholesterol secretion. J. Biol. Chem. 2001 276: 25287-25293.
Silver DL, Wang N, Tall AR (2000) Defective HDL Particle Uptake in ob/ob Hepatocytes Causes Decreased Recycling, Degradation, and Selective Lipid Uptake. J. Clin. Invest. 105: 151-159.
Silver DL, Jiang X-c, and Tall AR (1999) Increased High Density Lipoprotein (HDL), Defective Hepatic Catabolism of ApoA-I and ApoA-II, and Decreased ApoA-I mRNA in ob/ob Mice. J. Biol. Chem. 274: 4140-4146.
Silver DL and Tall AR (2001). The cellular biology of SR-BI. Current Opinion in Lipidology. Oct 12: 497-504.