title: Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3.
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.
authors.affiliation: Second Department of Medicine, Kurume University School of Medicine. 67 Asahi-machi, Kurume 830-0011, Japan. takumi@med.kurume-u.ac.jp
authors.forename: Takumi
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Masaru
authors.initials: M
authors.lastname: Harada
authors.forename: Takao
authors.initials: T
authors.lastname: Hisamoto
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nagao
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ide
authors.forename: Eitaro
authors.initials: E
authors.lastname: Taniguchi
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kumemura
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Hanada
authors.forename: Michiko
authors.initials: M
authors.lastname: Maeyama
authors.forename: Shinji
authors.initials: S
authors.lastname: Baba
authors.forename: Hironori
authors.initials: H
authors.lastname: Koga
authors.forename: Ryukichi
authors.initials: R
authors.lastname: Kumashiro
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Ogata
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Michio
authors.initials: M
authors.lastname: Sata
mesh_terms: D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005814:Genes, Viral; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D006946:Hyperinsulinism / Q000821:virology; D015151:Immunoblotting; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000821:virology; D008107:Liver Diseases / Q000378:metabolism / Q000821:virology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D025481:Phosphofructokinase-2 / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins / Q000096:biosynthesis*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018076:DNA, Complementary; D005947:Glucose; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D025481:Phosphofructokinase-2; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D025801:Ubiquitin; C526292:IRS1 protein, human; C526297:IRS2 protein, human; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; C106644:SOCS3 protein, human; C494918:AKT1 protein, human