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A Dramatic Alteration in the Cholesterol Metabolism in An HCV Infected-Liver: the Implications for HCV Infection and Treatment
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Reported by Jules Levin
DDW
May 17-22, 2008
San Diego, CA
Makoto Nakamuta1,2, Tatsuya Fujino2, Ryoko Yada2, Masayoshi Yada3, Tsuyoshi Yoshimoto1, Ryosuke Takemoto1,2, Kunitaka Fukuizumi1,2, Naohiko Harada1,2, Nobito Higuchi4, Masaki Kato4, Kazuhiro Kotoh4, Munechika Enjoji4
1. Gastroenterology, Kyushu Medical Centre, National Hospital Organization, Fukuoka, Japan, 2. Clinical Research Institute, Kyushu Mecial Center, National Hospital Organization, Fukuoka, Japan, 3. Hepatology, Iizuka Hospital, Iizuka, Japan, 4. Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
ABSTRACT from Program book
Background/Aims: Recently, a close relationship between HCV infection and the cholesterol metabolism has been reported: namely, HCV infects hepatocytes via LDL receptor (LDLR); The LDL levels inversely are correlated with the HCV levels; statin suppresses HCV replication in vitro; The LDL levels affect the outcome of IFN treatment. In human HCV infection, however, little is known about the cholesterol metabolism in hepatocytes. We therefore investigated the cholesterol metabolism related-gene expression in the HCV-infected liver.
Methods: We performed real-time PCR using samples obtained from an HCV-infected liver (n=70, genotype 1b=44, genotype 2=26) and also from a normal liver (n=10). The target genes for a real-time PCR analysis were as follows: LDLR, HMG-CoA reductase (HMG-CoAR), MTP, SREBP-2, and LXR_.
Results:
The expression of LDLR dramatically decreased by 98% in the HCV-infected liver in comparison to the normal liver. In contrast, the expression of HMG-CoA reductase was enhanced 2-fold in the HCV-infected liver. The expression of SREBP-2, which positively regulates the expression of LDLR and HMG-CoAR synchronously, decreased by 70%. The expression of MTP and LXR_ increased 3-fold and 1.5-fold, respectively. No major difference in the gene expression patterns were observed between HCV genotype 1b and 2.
Conclusion: These data indicate cholesterol accumulation in the HCV-infected liver. Cholesterol accumulation generally leads a down-regulation of HMG-CoAR; however, such accumulation was was observed to be inversely up-regulated in the infected liver, suggesting that HCV might directly affect cholesterol synthesis. These data also suggest that cholesterol metabolism modulators, such as statin and ezetimibe, might therefore beneficially affect HCV therapy. We are now investigating the relationship between the effects of IFN+ribavirin therapy and the gene expression.
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