Age-dependent PPARα activation induces hepatic sulfatide accumulation in transgenic mice carrying the hepatitis C virus core gene.
Sulfatides, a type of glycosphingolipid, are associated with carcinogenesis. Peroxisome proliferator-activated receptor α (PPARα) is involved in the regulation of sulfatide metabolism as well as in cancer development. We previously reported that transgenic (Tg) mice expressing hepatitis C virus core protein (HCVcp) exhibited age-dependent PPARα activation and carcinogenesis in liver. However, the metabolism of sulfatides in hepatocellular carcinoma is unknown. To examine the relationship between sulfatide metabolism, carcinogenesis, HCVcp, and PPARα, age-dependent changes of these factors were examined in HCVcpTg, PPARα inhibitor-treated HCVcpTg, and non-Tg mice. The sulfatide content in liver, the hepatic expression of two key enzymes catalyzing the initial and last reactions in sulfatide synthesis, the hepatic expression of known sulfatide-transferring protein, oxidative stress, and hepatic PPARα expression and its activation were age-dependently increased in HCVcpTg mice. The increased synthesis and accumulation of sulfatides and PPARα activation were significantly enhanced in liver cancer lesions. These changes were attenuated by PPARα inhibitor treatment and not observed in non-Tg mice. These results suggest that HCVcp-induced age-dependent PPARα activation increases synthesis of sulfatides and the resulting sulfatide accumulation affects HCV-related liver cancer. The monitoring of hepatic sulfatide content and the modulation of sulfatide generation by intervention using a PPARα inhibitor might be useful for the prediction and prevention of HCV-related hepatocarcinogenesis, respectively.
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, 390-8621, Japan.
Yangyang
Y
Tian
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, 390-8621, Japan.
Yang
Y
Yang
Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China.
Xiaowei
X
Zhang
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, 390-8621, Japan.
Takero
T
Nakajima
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, 390-8621, Japan.
Naoki
N
Tanaka
Department of Nutritional Science, Prefectural College, Nagano, Nagano, 380-8525, Japan.
Eiko
E
Sugiyama
Department of Nephrology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan. yujibeat@shinshu-u.ac.jp.
Yuji
Y
Kamijo
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, 390-8621, Japan.
Yu
Y
Lu
Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
Kyoji
K
Moriya
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
Kazuhiko
K
Koike
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Frank J
FJ
Gonzalez
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, 390-8621, Japan.
Toshifumi
T
Aoyama
D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016174:Hepacivirus / Q000235:genetics*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D013433:Sulfoglycosphingolipids / Q000378:metabolism*; D014758:Viral Core Proteins / Q000096:biosynthesis* / Q000235:genetics
D009363:Neoplasm Proteins; D047493:PPAR alpha; D013433:Sulfoglycosphingolipids; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus
Cancer; Core protein; HCV; PPARα; Sphingolipid; Sulfatide