A Dramatic Alteration in the Cholesterol Metabolism in An HCV Infected-Liver: th

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A Dramatic Alteration in the Cholesterol Metabolism in An HCV

Infected-Liver: the Implications for HCV Infection and Treatment

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 LXRá.

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 LXRá 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.