PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice.
Transgenic mice expressing HCV core protein develop hepatic steatosis and hepatocellular carcinoma (HCC), but the mechanism underlying this process remains unclear. Because PPARalpha is a central regulator of triglyceride homeostasis and mediates hepatocarcinogenesis in rodents, we determined whether PPARalpha contributes to HCV core protein-induced diseases. We generated PPARalpha-homozygous, -heterozygous, and -null mice with liver-specific transgenic expression of the core protein gene (Ppara(+/+):HCVcpTg, Ppara(+/-):HCVcpTg, and Ppara(-/-):HCVcpTg mice. Severe steatosis was unexpectedly observed only in Ppara(+/+):HCVcpTg mice, which resulted from enhanced fatty acid uptake and decreased mitochondrial beta-oxidation due to breakdown of mitochondrial outer membranes. Interestingly, HCC developed in approximately 35% of 24-month-old Ppara(+/+):HCVcpTg mice, but tumors were not observed in the other genotypes. These phenomena were found to be closely associated with sustained PPARalpha activation. In Ppara(+/-):HCVcpTg mice, PPARalpha activation and the related changes did not occur despite the presence of a functional Ppara allele. However, long-term treatment of these mice with clofibrate, a PPARalpha activator, induced HCC with mitochondrial abnormalities and hepatic steatosis. Thus, our results indicate that persistent activation of PPARalpha is essential for the pathogenesis of hepatic steatosis and HCC induced by HCV infection.
Tanaka
Naoki
N
Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan. naopi@hsp.md.shinshu-u.ac.jp
Moriya
Kyoji
K
Kiyosawa
Kendo
K
Koike
Kazuhiko
K
Gonzalez
Frank J
FJ
Aoyama
Toshifumi
T
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology*; D049109:Cell Proliferation; D002994:Clofibrate / Q000494:pharmacology; D004249:DNA Damage; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000473:pathology / Q000821:virology*; D019698:Hepatitis C, Chronic / Q000150:complications*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D014280:Triglycerides; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D002994:Clofibrate