title: 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.affiliation: Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Ma
authors.forename: Shunxing
authors.initials: S
authors.lastname: Rong
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Betters
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Soonkyu
authors.initials: S
authors.lastname: Chung
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
authors.forename: Weiqing
authors.initials: W
authors.lastname: Tang
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D005227:Fatty Acids / Q000096:biosynthesis; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D007333:Insulin Resistance; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000517:prevention & control; D018384:Oxidative Stress / Q000235:genetics
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D002784:Cholesterol