Impaired biliary lipid secretion in obese Zucker rats: leptin promotes hepatic cholesterol clearance

Human obesity is associated with elevated plasma leptin levels. Obesity is also an important risk factor for cholesterol gallstones, which form as a r esult of cholesterol hypersecretion into bile. Because leptin levels are co rrelated with gallstone prevalence, we explored the effects of acute leptin administration on biliary cholesterol secretion using lean (FA/-) and obes e (fa/fa) Zucker rats. Zucker (fa/fa) rats become obese and hyperleptinemic due to homozygosity for a missense mutation in the leptin receptor, which diminishes but does not completely eliminate responsiveness to leptin. Rats were infused intravenously for 12 h with saline or pharmacological doses o f recombinant murine leptin (5 mg.kg(-1).min(-1)) sufficient to elevate pla sma leptin concentrations to 500 ng/ml compared with basal levels of 3 and 70 ng/ml in lean and obese rats, respectively. Obesity was associated with a marked impairment in biliary cholesterol secretion. In biles of obese com pared with lean rats, bile salt hydrophobicity was decreased whereas phosph atidylcholine hydrophobicity was increased. High-dose leptin partially norm alized cholesterol secretion in obese rats without altering lipid compositi ons, implying that both chronic effects of obesity and relative resistance to leptin contributed to impaired biliary cholesterol elimination. In lean rats, acute leptin administration increased biliary cholesterol secretion r ates. Without affecting hepatic cholesterol contents, leptin downregulated hepatic activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reducta se, upregulated activities of both sterol 27-hydroxylase and cholesterol 7 alpha -hydroxylase, and lowered plasma very low-density lipoprotein cholest erol concentrations. Increased biliary cholesterol secretion in the setting of decreased cholesterol biosynthesis and increased catabolism to bile sal ts suggests that leptin promotes elimination of plasma cholesterol.