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Hepatitis C virus core protein induces spontaneous and persistent activation of peroxisome proliferator-activated receptor alpha in transgenic mice: implications for HCV-associated hepatocarcinogenesis.
Int J Cancer 2008; 122(1):124-31IJ

Abstract

Persistent infection of hepatitis C virus (HCV) can lead to a high risk for hepatocellular carcinoma (HCC). HCV core protein plays important roles in HCV-related hepatocarcinogenesis, because mice carrying the core protein exhibit multicentric HCCs without hepatic inflammation and fibrosis. However, the precise mechanism of hepatocarcinogenesis in these transgenic mice remains unclear. To evaluate whether the core protein modulates hepatocyte proliferation and apoptosis in vivo, we examined these parameters in 9- and 22-month-old transgenic mice. Although the numbers of apoptotic hepatocytes and hepatic caspase 3 activities were similar between transgenic and nontransgenic mice, the numbers of proliferating hepatocytes and the levels of numerous proteins such as cyclin D1, cyclin-dependent kinase 4 and c-Myc, were markedly increased in an age-dependent manner in the transgenic mice. This increase was correlated with the activation of peroxisome proliferator-activated receptor alpha (PPARalpha). In these transgenic mice, spontaneous and persistent PPARalpha activation occurred heterogeneously, which was different from that observed in mice treated with clofibrate, a potent peroxisome proliferator. We further demonstrated that stabilization of PPARalpha through a possible interaction with HCV core protein and an increase in nonesterified fatty acids, which may serve as endogenous PPARalpha ligands, in hepatocyte nuclei contributed to the core protein-specific PPARalpha activation. In conclusion, these results offer the first suggestion that HCV core protein induces spontaneous, persistent, age-dependent and heterogeneous activation of PPARalpha in transgenic mice, which may contribute to the age-dependent and multicentric hepatocarcinogenesis mediated by the core protein.

Authors+Show Affiliations

Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Japan. naopi@hsp.md.shinshu-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17764115

Citation

Tanaka, Naoki, et al. "Hepatitis C Virus Core Protein Induces Spontaneous and Persistent Activation of Peroxisome Proliferator-activated Receptor Alpha in Transgenic Mice: Implications for HCV-associated Hepatocarcinogenesis." International Journal of Cancer, vol. 122, no. 1, 2008, pp. 124-31.
Tanaka N, Moriya K, Kiyosawa K, et al. Hepatitis C virus core protein induces spontaneous and persistent activation of peroxisome proliferator-activated receptor alpha in transgenic mice: implications for HCV-associated hepatocarcinogenesis. Int J Cancer. 2008;122(1):124-31.
Tanaka, N., Moriya, K., Kiyosawa, K., Koike, K., & Aoyama, T. (2008). Hepatitis C virus core protein induces spontaneous and persistent activation of peroxisome proliferator-activated receptor alpha in transgenic mice: implications for HCV-associated hepatocarcinogenesis. International Journal of Cancer, 122(1), pp. 124-31.
Tanaka N, et al. Hepatitis C Virus Core Protein Induces Spontaneous and Persistent Activation of Peroxisome Proliferator-activated Receptor Alpha in Transgenic Mice: Implications for HCV-associated Hepatocarcinogenesis. Int J Cancer. 2008 Jan 1;122(1):124-31. PubMed PMID: 17764115.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatitis C virus core protein induces spontaneous and persistent activation of peroxisome proliferator-activated receptor alpha in transgenic mice: implications for HCV-associated hepatocarcinogenesis. AU - Tanaka,Naoki, AU - Moriya,Kyoji, AU - Kiyosawa,Kendo, AU - Koike,Kazuhiko, AU - Aoyama,Toshifumi, PY - 2007/9/4/pubmed PY - 2007/12/21/medline PY - 2007/9/4/entrez SP - 124 EP - 31 JF - International journal of cancer JO - Int. J. Cancer VL - 122 IS - 1 N2 - Persistent infection of hepatitis C virus (HCV) can lead to a high risk for hepatocellular carcinoma (HCC). HCV core protein plays important roles in HCV-related hepatocarcinogenesis, because mice carrying the core protein exhibit multicentric HCCs without hepatic inflammation and fibrosis. However, the precise mechanism of hepatocarcinogenesis in these transgenic mice remains unclear. To evaluate whether the core protein modulates hepatocyte proliferation and apoptosis in vivo, we examined these parameters in 9- and 22-month-old transgenic mice. Although the numbers of apoptotic hepatocytes and hepatic caspase 3 activities were similar between transgenic and nontransgenic mice, the numbers of proliferating hepatocytes and the levels of numerous proteins such as cyclin D1, cyclin-dependent kinase 4 and c-Myc, were markedly increased in an age-dependent manner in the transgenic mice. This increase was correlated with the activation of peroxisome proliferator-activated receptor alpha (PPARalpha). In these transgenic mice, spontaneous and persistent PPARalpha activation occurred heterogeneously, which was different from that observed in mice treated with clofibrate, a potent peroxisome proliferator. We further demonstrated that stabilization of PPARalpha through a possible interaction with HCV core protein and an increase in nonesterified fatty acids, which may serve as endogenous PPARalpha ligands, in hepatocyte nuclei contributed to the core protein-specific PPARalpha activation. In conclusion, these results offer the first suggestion that HCV core protein induces spontaneous, persistent, age-dependent and heterogeneous activation of PPARalpha in transgenic mice, which may contribute to the age-dependent and multicentric hepatocarcinogenesis mediated by the core protein. SN - 1097-0215 UR - https://www.unboundmedicine.com/medline/citation/17764115/Hepatitis_C_virus_core_protein_induces_spontaneous_and_persistent_activation_of_peroxisome_proliferator_activated_receptor_alpha_in_transgenic_mice:_implications_for_HCV_associated_hepatocarcinogenesis_ L2 - https://doi.org/10.1002/ijc.23056 DB - PRIME DP - Unbound Medicine ER -