Abstract

Objective: In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. In contrast, aberrantly high levels of triglycerides (TG) in the blood (“hypertriglyceridemia”) represent a hallmark of the Metabolic Syndrome and type II diabetes. As hypertriglyceridemia has been identified as an important risk factor for cardiovascular complications, this study aimed at the identification of molecular mechanisms in aberrant TG elevation under these conditions.

Research Design and Methods: To determine the importance of hepatic lipid handling for systemic dyslipidemia, we profiled the expression patterns of various hepatic lipid transporters and receptors under healthy and type II diabetic conditions. A differentially expressed lipoprotein receptor was functionally characterized by generating acute, liver-specific loss- and gain-of-function animal models.

Results: Here we show that the hepatic expression of lipid transporter lipolysis-stimulated lipoprotein receptor (LSR) is specifically impaired in mouse models of obesity and type II diabetes, and can be restored by leptin replacement. Experimental imitation of this pathophysiological situation by liver-specific knockdown of LSR promotes hypertriglyceridemia and elevated apolipoprotein (Apo) B and E serum levels in lean wild-type and ApoE knockout mice. In contrast, genetic restoration of LSR expression in obese animals to wild-type levels improves serum TG levels and serum profiles in these mice.

Conclusions: The dysregulation of hepatic LSR under obese and diabetic conditions may provide a molecular rationale for systemic dyslipidemia in type II diabetes and the Metabolic Syndrome, and represent a novel target for alternative treatment strategies in these patients.