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

Obesity results in hepatic fat accumulation, i.e., steatosis. Besides the fat overload, impaired fatty acid β-oxidation also promotes steatosis. Fatty acid β-oxidation takes place in mitochondria and peroxisomes. Usually very long chain and branched-chain fatty acids are first oxidized in peroxisomes, and the resultant short chain fatty acids are further oxidized in 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. However, it was previously reported that HFD-induced obesity in the Pex16AdipoQ-Cre mice was more severe than in the wild type mice, which was not observed until 27 weeks of HFD feeding. Thus, liver initiates the development of obesity, which is enhanced by abnormal adipocytes. HFD increased liver mass in the Pex16fl/fl mice but somehow reduced the already enlarged liver mass in the Pex16Alb-Cre mice. 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.