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J. Biol. Chem., Vol. 278, Issue 44, 43224-43228, October 31, 2003

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Leptin Induces the Hepatic High Density Lipoprotein Receptor Scavenger Receptor B Type I (SR-BI) but Not Cholesterol 7-Hydroxylase (Cyp7a1) in Leptin-deficient (ob/ob) Mice^*

Thomas Lundåsen, Wei Liao, Bo Angelin, and Mats Rudling

From the Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine and Molecular Nutrition Unit, Center for Nutrition and Toxicology, Novum, Karolinska Institutet at Huddinge University Hospital, S-141 86 Stockholm, Sweden

Cholesterol elimination from the body involves reverse cholesterol transport from peripheral tissues in which the elimination of high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol by the liver and subsequent biliary excretion as free cholesterol and bile acids are important. In situations of peripheral fat and cholesterol accumulation, such as obesity, these pathways may be overloaded, contributing to increased cholesterol deposition. Leptin has an important role in obesity, suppressing food intake and increasing energy expenditure. This hormone, which is absent in genetically obese ob/ob mice, is also thought to be involved in the coordination of lipid excretion pathways, although available data are somewhat inconsistent. We therefore studied the expression of the hepatic HDL receptor, scavenger receptor class B type I (SR-BI), and the LDL receptor as well as the rate-limiting enzyme in bile acid synthesis, cholesterol 7-hydroxylase (Cyp7a1), in leptin-deficient ob/ob mice and their wild-type controls. In ob/ob mice, protein levels of both LDL receptor and SR-BI were reduced, whereas LDL receptor mRNA levels were increased and those of SR-BI were reduced, regardless of challenge with a 2% cholesterol diet. In ob/ob mice, the enzymatic activity and mRNA for Cyp7a1 were reduced, and the increase in response to dietary cholesterol was blunted. Upon short-term (2 days) treatment with leptin, a dose-dependent increase was seen in the SR-BI protein and mRNA, whereas the Cyp7a1 protein and mRNA were reduced. Our findings indicate that leptin is an important regulator of hepatic SR-BI expression and, thus, HDL cholesterol levels, whereas it does not stimulate Cyp7a1 and bile acid synthesis.

Received for publication, March 14, 2003 , and in revised form, July 11, 2003.

^* This work was supported by Swedish Medical Research Council Grants 03X-7137, 32X-14053, and 14GX-13571, the Swedish Foundation for Strategic Research, the Lisa and Johan Grönberg Foundation, the Swedish Heart-Lung Foundation, and the Karolinska Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by American Heart Association National Scientist Development Grant 0235286N. Present address: Division of Endocrinology and Metabolism, Dept. of Medicine, University of California San Diego, La Jolla, CA 92093.

To whom correspondence should be addressed. Tel.: 46-8-585-82345; Fax: 46-8-711-0710; E-mail: mats.rudling{at}cnt.ki.se.

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