J. Lipid Res.
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J. Lipid Res., doi:10.1194/jlr.M300029-JLR200
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Submitted on January 21, 2003
Revised on March 20, 2003
Accepted on March 20, 2003

Restoration of Gallstone Susceptibility by Leptin in C57BL/6J ob/ob Mice

Hideyuki Hyogo, Suheeta Roy, and David E. Cohen

Medicine and Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461

Corresponding Author: 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 (1µg/g b.w.) or high (10µg/g b.w.) 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 downregulated 3-hydroxy-3-methylglutaryl CoA reductase and prevented cholesterol from accumulating in liver. Consistent with increased hepatic clearance, leptin decreased plasma high density lipoprotein cholesterol concentrations. This was accommodated in liver without upregulation of cholesterol 7alpha -hydroxylase or acyl-CoA:cholesterol acyl transferase. 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.


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