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

Lin Jia, Yinyan Ma, Shunxing Rong, Jenna L. Betters, Ping Xie, Soonkyu Chung, Nanping Wang, Weiqing Tang, Liqing Yu

Research output: Contribution to journalArticle

47 Scopus citations

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. Over-consumption 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 lipoprotein-triglyceride 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 overnight-fasted 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.

Original languageEnglish (US)
Pages (from-to)3135-3144
Number of pages10
JournalJournal of lipid research
Volume51
Issue number11
DOIs
StatePublished - Nov 2010

Keywords

  • Ezetimibe
  • Insulin resistance
  • Intestinal cholesterol absorption
  • Nonalcoholic fatty liver disease
  • Obesity

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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