Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3

Takumi Kawaguchi, Takafumi Yoshida, Masaru Harada, Takao Hisamoto, Yumiko Nagao, Tatsuya Ide, Eitaro Taniguchi, Hiroto Kumemura, Shinichiro Hanada, Michiko Maeyama, Shinji Baba, Hironori Koga, Ryukichi Kumashiro, Takato Ueno, Hisanobu Ogata, Akihiko Yoshimura, Michio Sata

Research output: Contribution to journalArticlepeer-review

459 Citations (Scopus)

Abstract

The pathogenesis of hepatitis C virus (HCV)-associated insulin resistance remains unclear. Therefore, we investigated mechanisms for HCV-associated insulin resistance. Homeostasis model assessment for insulin resistance was increased in patients with HCV infection. An increase in fasting insulin levels was associated with the presence of serum HCV core, the severity of hepatic fibrosis and a decrease in expression of insulin receptor substrate (IRS) 1 and IRS2, central molecules of the insulin-signaling cascade, in patients with HCV infection. Down-regulation of IRS1 and IRS2 was also seen in HCV core-transgenic mice livers and HCV core-transfected human hepatoma cells. Carbobenzoxy-L- leucyl-L-leucyl-L-leucinal, a potent proteosomal proteolysis inhibitor, blocked down-regulation of IRS1 and IRS2 in HCV core-transfected hepatoma cells. In human hepatoma cells, HCV core up-regulated suppressor of cytokine signaling (SOCS) 3 and caused ubiquitination of IRS1 and IRS2. HCV core-induced down-regulation of IRS1 and IRS2 was not seen in SOCS3-/- mouse embryonic fibroblast cells. Furthermore, HCV core suppressed insulin-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase and Akt, activation of 6-phosphofructo-2-kinase, and glucose uptake. In conclusion, HCV infection changes a subset of hepatic molecules regulating glucose metabolism. A possible mechanism is that HCV core-induced SOCS3 promotes proteosomal degradation of IRS1 and IRS2 through ubiquitination.

Original languageEnglish
Pages (from-to)1499-1508
Number of pages10
JournalAmerican Journal of Pathology
Volume165
Issue number5
DOIs
Publication statusPublished - 2004 Nov

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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