Role of leptin in hepatic cholesterol metabolism

Abstract

Cholesterol homeostasis is altered in obese individuals, as well as obese rodents with defects in leptin or its receptor. The obese Zucker rat (fa/fa) possesses several defects including increased total plasma cholesterol levels and decreased biliary cholesterol secretion. Obesity in Zucker rats is due to a missense mutation in the leptin receptor, which diminishes, but does not eliminate, responsiveness to leptin. We hypothesized that leptin resistance may contribute to the alterations in cholesterol homeostasis observed in obese Zucker rats. We therefore explored a role for leptin on key aspects of cholesterol metabolism. Lean and obese Zucker rats were administered a bolus of saline or leptin (150mugs) and then infused intravenously for 6 h with saline or pharmacological doses of recombinant murine leptin (5mug/kg/min). Biliary lipid secretion rates were then measured during 5 h of biliary drainage. Leptin infusion decreased very low density lipoprotein (VLDL) cholesterol, down-regulated cholesterol synthetic and up-regulated catabolic enzyme activities, and increased biliary cholesterol secretion. Reduced rates of cholesterol biosynthesis combined with increased catabolism to bile salts discount the possibility that leptin promoted biliary secretion of newly formed cholesterol. No significant differences were observed in hepatic lipid contents between the treatment groups, indicating that leptin did not mobilize cholesterol stored within the liver. In the Zucker rat, leptin-induced uptake of lipoprotein-derived cholesterol presumably serves to down-regulate hepatic cholesterol synthesis, up-regulate bile salt synthesis and increase biliary secretion. Additional studies of leptin's effects on conscious Sprague Dawley rats indicate that leptin has distinct effects on cholesterol metabolism in this strain, including increased liver triglyceride concentrations after peripheral leptin infusion and increased hepatic cholesterol after central leptin infusion. In accordance with results in Zucker rats, hepatic cholesterol biosynthetic enzyme activities were decreased by both intravenous and intracerebroventricular leptin administration. The mechanisms responsible for leptin's effects are currently under investigation and should provide valuable insight into pathways regulating cholesterol elimination.