PPARα activation is essential for HCV core protein–induced hepatic steatosis and hepatocellular carcinoma in mice.

Takana, N. et al. J. Clin. Invest. 118(2): 683-694 (2008)

Speaker: Po-Shun Wang (王柏舜)                                 Time: 13:00-14:00, Apr. 23, 2008

Commentator: Dr. Kung-Chia Young (楊孔嘉老師)               Place: Room 601

Abstract:

HCV core protein is a multifunctional protein because hepatic steatosis and hepatocellular carcinoma (HCC) are developed in HCV core protein–expressing transgenic (HCVcpTg) mice ⁽¹⁾. Hepatic steatosis, also called fatty liver, is the process characterized by the abnormal deposition oftriglyceride within hepatocytes. Peroxisome proliferator-activated receptor α (PPARα) is a member of the steroid/nuclear receptor superfamily and highly expressed in the liver. It modulates constitutive expression of genes encoding fatty acid-metabolizing enzymes ⁽²⁾. The authors reported the role of PPARα in the formation of hepatic steatosis and HCC in the HCVcpTg mice. Three HCVcpTg mice bearing PPARα-homozygous (Ppara^+/+), PPARα-heterozygous (Ppara^+/–), or PPARα-null (Ppara^–/–) were generated. The authors observed that severe hepatic steatosis and HCC were developed only in Ppara^+/+:HCVcpTg mice, which resulted from increased fatty acid uptake and impaired mitochondrial β-oxidation caused by the breakdown of mitochondrial outer membranes. Moreover, HCC were developed in nearly 35% of 24-month-old Ppara^+/+:HCVcpTg mice, whereas tumors were not found in the other two genotypes. These phenomena were strongly related to the persistent PPARα activation. Intriguingly, Ppara^+/–:HCVcpTg mice with only one functional Ppara allele do not exhibit the hallmarks of PPARα activation and do not develop HCC. However, long-term treatment of these mice with clofibrate, an exogenous PPARα agonist, induced PPARα activation and HCC development. In conclusion, the authors reveal that potent and persistent PPARα activation is critical for the development of severe steatosis and HCC under HCV-infected conditions.

References:

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2.      Aoyama, T., et al. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor α (PPARα). J. Biol. Chem. 273:5678-5684 (1998).