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PPARα activation is essential for HCV core protein–induced hepatic steatosis and hepatocellular carcinoma in mice
Naoki Tanaka, … , Frank J. Gonzalez, Toshifumi Aoyama
Naoki Tanaka, … , Frank J. Gonzalez, Toshifumi Aoyama
Published January 10, 2008
Citation Information: J Clin Invest. 2008;118(2):683-694. https://doi.org/10.1172/JCI33594.
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Research Article Hepatology

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

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Abstract

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.

Authors

Naoki Tanaka, Kyoji Moriya, Kendo Kiyosawa, Kazuhiko Koike, Frank J. Gonzalez, Toshifumi Aoyama

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Figure 1

Phenotype changes in transgenic mouse liver.

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Phenotype changes in transgenic mouse liver.
(A) Immunoblot analysis of ...
(A) Immunoblot analysis of HCV core protein expression in livers of 9-month-old mice. Because no significant individual differences in the same mouse group were found in the preliminary experiments, 10 mg of liver prepared from each mouse (n = 6 /group) was mixed and homogenized. Whole-liver lysate (50 μg protein) was loaded in each well. The band of actin was used as the loading control. Results are representative of 4 independent experiments. PC, lysate prepared from COS-1 cells overexpressing HCV core protein as a positive control. (B) Histological appearance of hematoxylin- and eosin-stained liver sections from 9-month-old HCVcpTg mice. Upper and lower rows show a lower (×40) and higher (×400) magnification, respectively. Microvesicular and macrovesicular steatosis was found only in Ppara+/+:HCVcpTg mice. No inflammation or hepatocyte degeneration was evident in any of the genotypes. (C) Histological appearance of hematoxylin- and eosin-stained liver sections from 24-month-old HCVcpTg mice. Upper and lower rows show a lower (×40) and higher (×400) magnification, respectively. Hepatic steatosis was marked in Ppara+/+:HCVcpTg mice, but not in other mice. Hepatic inflammation, fibrosis, and hepatocyte degeneration were not observed. In Ppara+/–:HCVcpTg and Ppara–/–:HCVcpTg mice, dysplastic hepatocytes and precancerous lesions were not detected throughout the entire liver. (D) Content of liver triglycerides. Results are expressed as the mean ± SD (n = 6/group) and compared between genotypes at the same age. *P < 0.05 compared with Ppara+/+ nontransgenic mice; **P < 0.05 compared with Ppara+/–:HCVcpTg mice; #P < 0.05 compared with Ppara–/–:HCVcpTg mice.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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