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Journal of Lipid Research, Vol. 50, 1429-1447, July 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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

Barbara P. Atshaves^*, Avery L. McIntosh^*, Gregory G. Martin^*, Danilo Landrock, H. Ross Payne, Shivaprasad Bhuvanendran^*, Kerstin K. Landrock^*, Olga I. Lyuksyutova^*, Jeffery D. Johnson, Ronald D. Macfarlane, Ann B. Kier and Friedhelm Schroeder^1,*

^* Department of Physiology and Pharmacology, Texas A&M University, Texas Veterinary Medical Center, College Station, TX 77843-4466
Department of Pathobiology, Texas A&M University, Texas Veterinary Medical Center, College Station, TX 77843-4466
Department of Chemistry, Texas A&M University, Texas Veterinary Medical Center, College Station, TX 77843-4466

This work was supported in part by the U.S. Public Health Service, National Institutes of Health Grants GM31651 (F.S. and A.B.K.), DK41402 (F.S. and A.B.K.), and DK70965 (B.P.A.). The helpful technical assistance of Ms. Meredith Dixon was much appreciated.

Published, JLR Papers in Press, March 16, 2009.

¹ To whom correspondence should be addressed. e-mail: fschroeder{at}cvm.tamu.edu

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 LDL-receptor, 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-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-hydroxylase, sterol 27-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 (via Oapt1a1, Oatp1a4, and SCP-x). Levels of serum and hepatic bile acids were decreased in cholesterol-fed SCP-2 overexpression mice, 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.

Supplementary key words liver fatty acid binding protein • transgenic mice • cholesterol

Abbreviations: 3-HSD, 3-hydroxysteroid dehydrogenase; ABCA-1, ATP binding cassette A-1 receptor; apoA1, apolipoprotein A1; CYP27A1, sterol 27-hydroxylase; CYP7A1, cholesterol 7-hydroxylase; L-FABP, liver fatty acid binding protein; LXR-, liver X receptor-; MAP-17, membrane-associated protein 17 kDa; Ntcp, Na⁺/taurocholate cotransporter; Oatp, organic anion transporting polypeptide 1; PDZK1, postsynaptic density protein/Drosophila disc large tumor suppressor (dlg)/tight junction protein (ZO1); RCT, reverse cholesterol transport; SCP, sterol carrier protein; SHP, short heterodimer partner; SR-B1, scavenger receptor-B1; SREBP-2, sterol regulatory element binding protein 2; WT, wild type

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