Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Hepatology

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

  • Text
  • PDF
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

×

Figure 6

Persistent PPARα activation in Ppara+/+:HCVcpTg mice.

Options: View larger image (or click on image) Download as PowerPoint
Persistent PPARα activation in Ppara+/+:HCVcpTg mice.
               
(A...
(A) PPARα mRNA levels. Total RNA was prepared from each mouse, and PPARα mRNA levels were determined by RT-PCR, normalized by those of GAPDH, and subsequently normalized by those of 9-month-old Ppara+/+ nontransgenic mice. Results are expressed as the mean ± SD (n = 6 /group). (B) Immunoblot analysis of nuclear PPARα. The nuclear fraction obtained from each mouse (100 μg protein) was loaded in each well. The band of histone H1 was used as the loading control. Results are representative of 6 independent experiments. The band intensity was quantified densitometrically, normalized by that of histone H1, and subsequently normalized by that in 9-month-old Ppara+/+ nontransgenic mice. The mean value is expressed under each band. *P < 0.05 compared with nontransgenic mice of the same age and Ppara genotype. (C) Pulse-chase experiments for 3, 6, and 12 h and pulse-label (P) experiments for nuclear PPARα using isolated mouse hepatocytes. Left: labeled PPARα bands on x-ray film. Pulse-label and pulse-chase experiments were performed as described in Methods. Results are representative of 4 independent experiments. Right: half-life of PPARα. The band intensity was measured densitometrically and subsequently normalized by that of the pulse-label experiments. The percentage of the band intensity was plotted, and the half-life of PPARα was calculated. Results obtained from 4 independent experiments are expressed as the mean ± SD. *P < 0.05 compared with nontransgenic mice in the same Ppara genotype.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts