HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M300029-JLR200v1 44/6/1232    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hyogo, H. Articles by Cohen, D. E. Search for Related Content PubMed PubMed Citation Articles by Hyogo, H. Articles by Cohen, D. E. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 44, 1232-1240, June 2003
Copyright © 2003 by Lipid Research, Inc.

Restoration of gallstone susceptibility by leptin in C57BL/6J ob/ob mice

Hideyuki Hyogo^1,*, Suheeta Roy^* and David E. Cohen^2,*,

^* Departments of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461
Biochemistry, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461

² To whom correspondence should be addressed. e-mail: dcohen{at}aecom.yu.edu

The absence of leptin due to the ob mutation leads to obesity and confers resistance to diet-induced cholesterol gallstone formation in otherwise susceptible C57BL/6J mice. To investigate contributions of obesity and leptin to gallstone susceptibility, C57BL/6J ob/ob mice were treated daily with i.p. saline or recombinant murine leptin at low (1 µg/g bw) or high (10 µg/g bw) doses and were pair-fed a lithogenic diet (15% dairy fat, 1.25% cholesterol, 0.5% cholic acid). Weight loss in ob/ob mice increased in proportion to leptin dose, indicating that the lithogenic diet did not impair leptin sensitivity. In a dose-dependent manner, leptin promoted cholesterol crystallization and gallstone formation, which did not occur in saline-treated mice. Notwithstanding, leptin decreased biliary lipid secretion rates without enriching cholesterol in bile. Leptin did not affect bile salt hydrophobicity, but did increase the biliary content of the most abundant molecular species of phosphatidylcholine, 16:0–18:2. Treatment with leptin down-regulated 3-hydroxy-3-methylglutaryl CoA reductase and prevented cholesterol from accumulating in liver. Consistent with increased hepatic clearance, leptin decreased plasma HDL cholesterol concentrations. This was accommodated in liver without up-regulation of cholesterol 7-hydroxylase or Acat. These data suggest that despite the lithogenic diet, endogenous sources constitute a significant proportion of biliary cholesterol during leptin-induced weight loss.

Kinetic factors related to cholesterol nucleation, gallbladder contractility, or mucin secretion may have accounted for leptin-induced gallstone formation.

Abbreviations: Cyp7A1, cholesterol 7-hydroxylase; FPLC, fast protein liquid chromatography

Supplementary key words bile salts • phospholipids • bile • liver • obesity

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. J. Lloyd, J. McCormick, J. Helmering, K. W. Kim, M. Wang, P. Fordstrom, S. A. Kaufman, R. A. Lindberg, and M. M. Veniant Generation and characterization of two novel mouse models exhibiting the phenotypes of the metabolic syndrome: Apob48-/-Lepob/ob mice devoid of ApoE or Ldlr Am J Physiol Endocrinol Metab, March 1, 2008; 294(3): E496 - E505. [Abstract] [Full Text] [PDF]

				N. S. Sabeva, E. J. Rouse, and G. A. Graf Defects in the Leptin Axis Reduce Abundance of the ABCG5-ABCG8 Sterol Transporter in Liver J. Biol. Chem., August 3, 2007; 282(31): 22397 - 22405. [Abstract] [Full Text] [PDF]