Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice.
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.
Arsov
Todor
T
John Curtin School of Medical Research, The Australian National University (ANU), Canberra, ACT, Australia.
Larter
Claire Z
CZ
Nolan
Christopher J
CJ
Petrovsky
Nikolai
N
Goodnow
Christopher C
CC
Teoh
Narcissus C
NC
Yeh
Matthew M
MM
Farrell
Geoffrey C
GC
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
C510001:Alms1 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D005227:Fatty Acids