Mitochondrial Proteins That Regulate Apoptosis and Necrosis Are Induced in Mouse Fatty Liver

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Abstract
Fatty liver is common in nonalcoholic, obese individuals and in lean people who consume alcohol chronically. Although fatty liver is typically benign, a subset of individuals with steatosis develop steatohepatitis and eventually cirrhosis. The disparate outcomes of fatty liver suggest that it reflects a generally beneficial, adaptive response to obesity or alcohol–related stress, but may also increase hepatocyte vulnerability to other challenges. Thus, both protective factors (e.g., Bcl–2 and Bcl–xL) and factors that promote hepatocyte death by apoptosis (e.g., Bax) or necrosis (e.g., UCP2) may be increased in fatty livers. To evaluate this possibility, hepatocyte apoptosis, necrosis, and the expression of factors that regulate cellular viability were assessed in two models of fatty liver (i.e., genetically obese [ob/ob] mice and ethanol [EtOH]–fed lean mice). Findings in mice with fatty livers were compared with lean, control mice that did not have hepatic steatosis. Immunohistochemistry showed striking induction of hepatocyte proteins that promote (e.g., Bax) and inhibit (e.g., Bcl–2 and Bcl–xL) apoptosis in both groups with fatty liver. Both models of fatty liver also increased hepatic transcripts for UCP2, a mitochondrial uncoupling protein, and the protein itself was induced in ob/ob hepatocytes. Despite the up–regulation of factors that threaten cell viability, hepatocyte death was not increased in either ob/ob or EtOH–fed mice, confirming that the liver's protective responses were sufficient under the conditions studied. However, if UCP2 induction reduces the efficiency of adenosine triphosphate (ATP) synthesis, this initially harmless response might enhance the vulnerability of hepatocytes to necrosis