Transgenic mice expressing HCV core protein develop hepatic steatosis and hepatocellular carcinoma (HCC), but the mechanism underlying this process remains unclear. Because PPARα is a central regulator of triglyceride homeostasis and mediates hepatocarcinogenesis in rodents, we determined whether PPARα contributes to HCV core protein–induced diseases. We generated PPARα-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 β-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 PPARα activation. In Ppara+/–:HCVcpTg mice, PPARα 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 PPARα activator, induced HCC with mitochondrial abnormalities and hepatic steatosis. Thus, our results indicate that persistent activation of PPARα is essential for the pathogenesis of hepatic steatosis and HCC induced by HCV infection.
Naoki Tanaka, Kyoji Moriya, Kendo Kiyosawa, Kazuhiko Koike, Frank J. Gonzalez, Toshifumi Aoyama
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Mechanisms of intrahepatic triglyceride accumulation
C Ress |
World journal of gastroenterology : WJG | 2016 |
PPARs and Mitochondrial Metabolism: From NAFLD to HCC
T Mello, M Materozzi, A Galli |
PPAR Research | 2016 |
The lipid droplet-associated protein perilipin 3 facilitates hepatitis C virus-driven hepatic steatosis
D Ferguson, J Zhang, MA Davis, RN Helsley, LL Vedin, RG Lee, RM Crooke, MJ Graham, DS Allende, P Parini, JM Brown |
Journal of lipid research | 2016 |
Hepatitis C virus G1b infection decreases the number of small low-density lipoprotein particles
C Kinoshita, T Nagano, N Seki, Y Tomita, T Sugita, Y Aida, M Itagaki, K Satoh, S Sutoh, H Abe, A Tsubota, Y Aizawa |
World journal of gastroenterology : WJG | 2016 |
HCV and Oxidative Stress: Implications for HCV Life Cycle and HCV-Associated Pathogenesis
R Medvedev, D Ploen, E Hildt |
Oxidative medicine and cellular longevity | 2016 |
Hepatitis B Surface Antigen Loss and Hepatocellular Carcinoma Development in Patients With Dual Hepatitis B and C Infection:
WT Yang, LW Wu, TC Tseng, CL Chen, HC Yang, TH Su, CC Wang, SF Kuo, CH Liu, PJ Chen, DS Chen, CJ Liu, JH Kao |
Medicine | 2016 |
Metabolic alterations and hepatitis C: From bench to bedside
ML Chang |
World journal of gastroenterology : WJG | 2016 |
Hepatocarcinogenesis associated with hepatitis B, delta and C viruses
E Shirvani-Dastgerdi, RE Schwartz, A Ploss |
Current Opinion in Virology | 2016 |
Hepatitis C virus promotes hepatocellular carcinogenesis by targeting TIPE2, a new regulator of DNA damage response
Y Wang, Y Jiang, J Zhou, W Song, J Li, M Wang, J Chen, R Xu, J Zhang, F Ma, YH Chen, Y Ma |
Tumor Biology | 2016 |
Age-dependent PPARα activation induces hepatic sulfatide accumulation in transgenic mice carrying the hepatitis C virus core gene
Y Tian, Y Yang, X Zhang, T Nakajima, N Tanaka, E Sugiyama, Y Kamijo, Y Lu, K Moriya, K Koike, FJ Gonzalez, T Aoyama |
Glycoconjugate Journal | 2016 |
Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection
G Levy, N Habib, MA Guzzardi, D Kitsberg, D Bomze, E Ezra, BE Uygun, K Uygun, M Trippler, JF Schlaak, O Shibolet, EH Sklan, M Cohen, J Timm, N Friedman, Y Nahmias |
Nature Chemical Biology | 2016 |