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

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.

• Authors: Lin Jia, Yinyan Ma, Shunxing Rong, Jenna L Betters, Ping Xie, Soonkyu Chung, Nanping Wang, Weiqing Tang, Liqing Yu
• Journal: Journal of lipid research (J Lipid Res) Vol. 51 Issue 11 Pg. 3135-44 (Nov 2010) ISSN: 1539-7262 [Electronic] United States
• PMID: 20699423 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dietary Fats
• Fatty Acids
• Membrane Transport Proteins
• Npc1l1 protein, mouse
• Cholesterol

Topics

• Animals
• Cholesterol (metabolism)
• Dietary Fats (adverse effects)
• Fatty Acids (biosynthesis)
• Fatty Liver (etiology, genetics, metabolism, prevention & control)
• Gene Deletion
• Gene Knockout Techniques
• Insulin Resistance
• Lipogenesis (genetics)
• Liver (metabolism)
• Male
• Membrane Transport Proteins (deficiency, genetics)
• Mice
• Obesity (etiology, prevention & control)
• Oxidative Stress (genetics)