Overexpression of sterol carrier protein-2 differentially alters hepatic cholesterol accumulation in cholesterol-fed mice

Although in vitro studies suggest a role for sterol carrier protein-2 (SCP-2) in cholesterol trafficking and metabolism, the physiological significance of these observations remains unclear. This issue was addressed by examining the response of mice overexpressing physiologically relevant levels of SCP-2 to a cholesterol-rich diet. While neither SCP-2 overexpression nor cholesterol-rich diet altered food consumption, increased weight gain, hepatic lipid, and bile acid accumulation were observed in wild-type mice fed the cholesterol-rich diet. SCP-2 overexpression further exacerbated hepatic lipid accumulation in cholesterol-fed females (cholesterol/ cholesteryl esters) and males (cholesterol/ cholesteryl esters and triacyglycerol). Primarily in female mice, hepatic cholesterol accumulation induced by SCP-2 overexpression was associated with increased levels of LDLreceptor, HDL-receptor scavenger receptor-B1 (SR-B1) (as well as PDZK1 and/ or membrane-associated protein 17 kDa), SCP-2, liver fatty acid binding protein (L-FABP), and 3 alpha-hydroxysteroid dehydrogenase, without alteration of other proteins involved in cholesterol uptake (caveolin), esterification (ACAT2), efflux (ATP binding cassette A-1 receptor, ABCG5/ 8, and apolipoprotein A1), or oxidation/ transport of bile salts (cholesterol 7 alpha-hydroxylase, sterol 27 alpha-hydroxylase, Na+/taurocholate cotransporter, Oatp1a1, and Oatp1a4). The effects of SCP-2 overexpression and cholesterol-rich diet was downregulation of proteins involved in cholesterol transport (L-FABP and SR-B1), cholesterol synthesis (related to sterol regulatory element binding protein 2 and HMG-CoA reductase), and bile acid oxidation/ transport (viaOapt1a1, Oatp1a4, and SCP-x). Levels of serum and hepatic bile acids were decreased in cholesterol-fed SCP-2 overexpressionmice, especially in females, while the total bile acid pool was minimally affected. Taken together, these findings support an important role for SCP-2 in hepatic cholesterol homeostasis.-Atshaves, B. P., A. L. McIntosh, G. G. Martin, D. Landrock, H. R. Payne, S. Bhuvanendran, K. K. Landrock, O. I. Lyuksyutova, J. D. Johnson, R. D. Macfarlane, A. B. Kier, and F. Schroeder. Overexpression of sterol carrier protein-2 differentially alters hepatic cholesterol accumulation in cholesterol-fed mice. J. Lipid Res. 2009. 50: 1429-1447.