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

被引:27
作者
Atshaves, Barbara P. [1 ]
McIntosh, Avery L. [1 ]
Martin, Gregory G. [1 ]
Landrock, Danilo [2 ]
Payne, H. Ross [2 ]
Bhuvanendran, Shivaprasad [1 ]
Landrock, Kerstin K. [1 ]
Lyuksyutova, Olga I. [1 ]
Johnson, Jeffery D. [3 ]
Macfarlane, Ronald D. [3 ]
Kier, Ann B. [2 ]
Schroeder, Friedhelm [1 ]
机构
[1] Texas A&M Univ, Texas Vet Med Ctr, Dept Physiol & Pharmacol, College Stn, TX 77843 USA
[2] Texas A&M Univ, Texas Vet Med Ctr, Dept Pathobiol, College Stn, TX 77843 USA
[3] Texas A&M Univ, Texas Vet Med Ctr, Dept Chem, College Stn, TX 77843 USA
关键词
liver fatty acid binding protein; transgenic mice; cholesterol; CHAIN FATTY-ACID; GENE; EXPRESSION; DYNAMICS; METABOLISM; INTERACTS; PLASMA; DOMAIN; BILE; INTEGRATION;
D O I
10.1194/jlr.M900020-JLR200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1429 / 1447
页数:19
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