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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 4

Increased hepatocyte proliferation in Ppara+/+:HCVcpTg mice at 24 months of age.

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Increased hepatocyte proliferation in Ppara+/+:HCVcpTg mice at 24 months...
(A) Liver-to-body-weight ratio. Results are expressed as the mean ± SD (n = 6/group). (B) Numbers of proliferating hepatocytes. Two thousand hepatocytes were examined in each mouse, and hepatocyte nuclei positive for anti-PCNA antibody were counted. Results are expressed as the mean ± SD (n = 6/group). For A and B, comparisons are designated as follows: *P < 0.05 compared with Ppara+/+ nontransgenic mice; **P < 0.05 compared with Ppara+/–:HCVcpTg mice; #P < 0.05 compared with Ppara–/–:HCVcpTg mice. (C) Numbers of apoptotic hepatocytes. Liver sections were subjected to TUNEL staining, and TUNEL-positive hepatocyte nuclei were counted in 2,000 hepatocytes from each mouse. Results are expressed as the mean ± SD (n = 6/group). (D) Caspase 3 activity. Results are expressed as the mean ± SD (n = 6/group). (E) Immunoblot analysis of oncogene products and cell cycle regulators. The same sample used in Figure 1A (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. The band intensity was quantified densitometrically, normalized by that of actin, and subsequently normalized by that in Ppara+/+ nontransgenic mice. The mean value of the fold changes is expressed under each band. (F) Immunoblot analysis of phosphorylated ERK1/2 and total ERK1/2. The same samples in Figure 4E (50 μg protein) were used.

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