Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice
Copyright policy )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.
- Flinders Medical Centre Australia
- University of Washington Medical Center United States
- University of Sydney Australia
- Australian National University Australia
- Flinders University Australia
fatty acid binding protein, uncoupling protein 2, alanine aminotransferase, lipid peroxide, microsomal triglyceride transfer protein, Cell Cycle Proteins, adipocyte, 0601 Biochemistry and Cell Biology, Mice, Animals, Non-alcoholic steatohepatitis, Metabolic Syndrome, 0304 Medicinal and Biomolecular Chemistry, saturated fatty acid, Fatty Acids, Keywords: adiponectin, Lipid Metabolism, Metabolic syndrome, Adaptation, Physiological, Dietary Fats, alanine aminotransferase Adiponectin, DNA-Binding Proteins, Fatty Liver, 1101 Medical Biochemistry and Metabolomics, Mutation, cytochrome P450 2E1, fatty acid, triacylglycerol, Hepatic lipid partitioning, Lipotoxicity
fatty acid binding protein, uncoupling protein 2, alanine aminotransferase, lipid peroxide, microsomal triglyceride transfer protein, Cell Cycle Proteins, adipocyte, 0601 Biochemistry and Cell Biology, Mice, Animals, Non-alcoholic steatohepatitis, Metabolic Syndrome, 0304 Medicinal and Biomolecular Chemistry, saturated fatty acid, Fatty Acids, Keywords: adiponectin, Lipid Metabolism, Metabolic syndrome, Adaptation, Physiological, Dietary Fats, alanine aminotransferase Adiponectin, DNA-Binding Proteins, Fatty Liver, 1101 Medical Biochemistry and Metabolomics, Mutation, cytochrome P450 2E1, fatty acid, triacylglycerol, Hepatic lipid partitioning, Lipotoxicity
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