title: Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice.
abstract: The biochemical differences between simple steatosis, a benign liver disease, and non-alcoholic steatohepatitis, which leads to cirrhosis, are unclear. Fat aussie is an obese mouse strain with a truncating mutation (foz) in the Alms1 gene. Chow-fed female foz/foz mice develop obesity, diabetes, and simple steatosis. We fed foz/foz and wildtype mice a high-fat diet. Foz/foz mice developed serum ALT elevation and severe steatohepatitis with hepatocyte ballooning, inflammation, and fibrosis; wildtype mice showed simple steatosis. Biochemical pathways favoring hepatocellular lipid accumulation (fatty acid uptake; lipogenesis) and lipid disposal (fatty acid beta-oxidation; triglyceride egress) were both induced by high-fat feeding in wildtype but not foz/foz mice. The resulting extremely high hepatic triglyceride levels were associated with induction of mitochondrial uncoupling protein-2 and adipocyte-specific fatty acid binding protein-2, but not cytochrome P4502e1 or lipid peroxidation. In this model of metabolic syndrome, transition of steatosis to steatohepatitis was associated with hypoadiponectinemia, a mediator of hepatic fatty acid disposal pathways.
authors.affiliation: John Curtin School of Medical Research, The Australian National University (ANU), Canberra, ACT, Australia.
authors.forename: Todor
authors.initials: T
authors.lastname: Arsov
authors.forename: Claire Z
authors.initials: CZ
authors.lastname: Larter
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nolan
authors.forename: Nikolai
authors.initials: N
authors.lastname: Petrovsky
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Narcissus C
authors.initials: NC
authors.lastname: Teoh
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Farrell
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004041:Dietary Fats / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology*; D050356:Lipid Metabolism; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009154:Mutation
chemical_list: C510001:Alms1 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D005227:Fatty Acids