Hepatocyte-Specific PEX16 Abrogation in Mice Leads to Hepatocyte Proliferation, Alteration of Hepatic Lipid Metabolism, and Resistance to High-Fat Diet (HFD)-Induced Hepatic Steatosis and Obesity

Abstract

Obesity results in hepatic fat accumulation, i.e., steatosis. In addition to fat overload, impaired fatty acid β-oxidation also promotes steatosis. Fatty acid β-oxidation takes place in the mitochondria and peroxisomes. Usually, very long-chain and branched-chain fatty acids are the first to be oxidized in peroxisomes, and the resultant short chain fatty acids are further oxidized in the mitochondria. Peroxisome biogenesis is regulated by peroxin 16 (PEX16). In liver-specific PEX16 knockout (Pex16Alb-Cre) mice, hepatocyte peroxisomes were absent, but hepatocytes proliferated, and liver mass was enlarged. These results suggest that normal liver peroxisomes restrain hepatocyte proliferation and liver sizes. After high-fat diet (HFD) feeding, body weights were increased in PEX16 floxed (Pex16fl/fl) mice and adipose-specific PEX16 knockout (Pex16AdipoQ-Cre) mice, but not in the Pex16Alb-Cre mice, suggesting that the development of obesity is regulated by liver PEX16 but not by adipose PEX16. HFD increased liver mass in the Pex16fl/fl mice but somehow reduced the already enlarged liver mass in the Pex16Alb-Cre mice. The basal levels of serum triglyceride, free fatty acids, and cholesterol were decreased, whereas serum bile acids were increased in the Pex16Alb-Cre mice, and HFD-induced steatosis was not observed in the Pex16Alb-Cre mice. These results suggest that normal liver peroxisomes contribute to the development of liver steatosis and obesity.