Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice

Biochem Biophys Res Commun. 2006 Apr 21;342(4):1152-9. doi: 10.1016/j.bbrc.2006.02.032. Epub 2006 Feb 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Cell Cycle Proteins
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • Dietary Fats / metabolism*
  • Fatty Acids / metabolism*
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology*
  • Lipid Metabolism*
  • Metabolic Syndrome / metabolism*
  • Metabolic Syndrome / pathology*
  • Mice
  • Mutation


  • Alms1 protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Dietary Fats
  • Fatty Acids