Niemann-Pick C1-Like 1 deletion in mice prevents high-fat diet-induced fatty liver by reducing lipogenesis

Authors

Lin Jia, Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC
Yinyan Ma, Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC
Shunxing Rong, Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC
Jenna L. Betters, Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC
Ping Xie, Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC
Soonkyu Chung, Department of Food Science and Human Nutrition, University of Florida, Gainesville, FLFollow
Nanping Wang, Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC
Weiqing Tang, Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC
Liqing Yu, Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC

Date of this Version

2010

Citation

J Lipid Res. 2010 Nov; 51(11): 3135–3144.

Comments

Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc. Used by permission.

Abstract

Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal absorption of dietary and biliary cholesterol. Ezetimibe, by inhibiting NPC1L1 function, is widely used to treat hypercholesterolemia in humans. Interestingly, ezetimibe treatment appears to attenuate hepatic steatosis in rodents and humans without a defined mechanism. Overconsumption of a high-fat diet (HFD) represents a major cause of metabolic disorders including fatty liver. To determine whether and how NPC1L1 deficiency prevents HFD-induced hepatic steatosis, in this study, we fed NPC1L1 knockout (L1-KO) mice and their wild-type (WT) controls an HFD, and found that 24 weeks of HFD feeding causes no fatty liver in L1-KO mice. Hepatic fatty acid synthesis and levels of mRNAs for lipogenic genes are substantially reduced but hepatic lipoproteintriglyceride production, fatty acid oxidation, and triglyceride hydrolysis remain unaltered in L1- KO versus WT mice. Strikingly, L1-KO mice are completely protected against HFD-induced hyperinsulinemia under both fed and fasted states and during glucose challenge. Despite similar glucose tolerance, L1-KO relative WT mice are more insulin sensitive and in the overnightfasted state display significantly lower plasma glucose concentrations. In conclusion, NPC1L1 deficiency in mice prevents HFD-induced fatty liver by reducing hepatic lipogenesis, at least in part, through attenuating HFD-induced insulin resistance, a state known to drive hepatic lipogenesis through elevated circulating insulin levels.