Leptin Promotes Biliary Cholesterol Elimination during Weight Loss in ob/ob Mice by Regulating the Enterohepatic Circulation of Bile Salts

Hideyuki Hyogo,Suheeta Roy,Beverly Paigen,David E Cohen

doi:10.1074/jbc.m203912200

Abstract

Leptin administration to obese C57BL/6J (ob/ob) mice results in weight loss by reducing body fat. Because adipose tissue is an important storage depot for cholesterol, we explored evidence that leptin-induced weight loss in ob/ob mice was accompanied by transport of cholesterol to the liver and its elimination via bile. Consistent with mobilization of stored cholesterol, cholesterol concentrations in adipose tissue remained unchanged during weight loss. Plasma cholesterol levels fell sharply, and microscopic analyses of gallbladder bile revealed cholesterol crystals as well as cholesterol gallstones. Surprisingly, leptin reduced biliary cholesterol secretion rates without affecting secretion rates of bile salts or phospholipids. Instead, cholesterol supersaturation of gallbladder bile was due to marked decreases in bile salt hydrophobicity and not to hypersecretion of biliary cholesterol per se, such as occurs in humans during weight loss. In addition to regulating bile salt composition, leptin treatment decreased bile salt pool size. The smaller, more hydrophilic bile salt pool was associated with substantial decreases in intestinal cholesterol absorption. Within the liver, leptin treatment reduced the activity of 3-hydroxy-3-methylglutaryl-CoA reductase, but it did not change activities of cholesterol 7alpha-hydroxylase or acyl-CoA:cholesterol acyltransferase. These data suggest that leptin regulates biliary lipid metabolism to promote efficient elimination of excess cholesterol stored in adipose tissue. Cholesterol gallstone formation during weight loss in ob/ob mice appears to represent a pathologic consequence of an adaptive response that prevents absorption of biliary and dietary cholesterol.

Highlights

Bile is the route for cholesterol elimination from the body, and reverse cholesterol transport is the metabolic pathway for movement of cholesterol from peripheral tissues to the liver for biliary secretion [1]
Cholesterol that is mobilized when adipose tissue mass contracts must be transported to the liver for elimination via bile [26]
We have explored molecular mechanisms of hepatic cholesterol elimination using ob/ob mice in which weight loss was induced by chronic leptin administration

Summary

Introduction

Bile is the route for cholesterol elimination from the body, and reverse cholesterol transport is the metabolic pathway for movement of cholesterol from peripheral tissues to the liver for biliary secretion [1]. In the hepatic bile of saline-treated mice, we observed increases in both absolute and relative cholesterol concentrations at 14 and 28 days.

Results

Conclusion