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Citations to this article

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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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 Total
Citations: 2 3 6 6 2 4 8 4 7 11 9 13 7 13 6 9 9 3 122
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article in year 2013 (7)

Title and authors Publication Year
Chronic ethanol consumption decreases serum sulfatide levels by suppressing hepatic cerebroside sulfotransferase expression in mice
H Kanbe, Y Kamijo, T Nakajima, N Tanaka, E Sugiyama, L Wang, ZZ Fang, A Hara, FJ Gonzalez, T Aoyama
Archives of Toxicology 2013
Metabolic factors and chronic hepatitis C: a complex interplay
FS Macaluso, M Maida, MG Minissale, TL Vigni, S Attardo, E Orlando, S Petta
BioMed Research International 2013
Modulation of mitogen-activated protein kinase-activated protein kinase 3 by hepatitis C virus core protein
HT Ngo, LV Pham, JW Kim, YS Lim, SB Hwang
Journal of virology 2013
HCV and oxidative stress in the liver
AV Ivanov, B Bartosch, OA Smirnova, MG Isaguliants, SN Kochetkov
Viruses 2013
Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis
LP Bechmann, D Vetter, J Ishida, RA Hannivoort, UE Lang, P Kocabayoglu, MI Fiel, U Muñoz, GL Patman, F Ge, S Yakar, X Li, L Agius, YM Lee, W Zhang, KY Hui, D Televantou, GJ Schwartz, D LeRoith, PD Berk, R Nagai, T Suzuki, HL Reeves, SL Friedman
Journal of Hepatology 2013
Mouse models for liver cancer
L Bakiri, EF Wagner
Molecular Oncology 2013
Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum
ZZ Fang, KW Krausz, N Tanaka, F Li, A Qu, JR Idle, FJ Gonzalez
Archives of Toxicology 2013

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