Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3.
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.
Kawaguchi
Takumi
T
Second Department of Medicine, Kurume University School of Medicine. 67 Asahi-machi, Kurume 830-0011, Japan. takumi@med.kurume-u.ac.jp
Yoshida
Takafumi
T
Harada
Masaru
M
Hisamoto
Takao
T
Nagao
Yumiko
Y
Ide
Tatsuya
T
Taniguchi
Eitaro
E
Kumemura
Hiroto
H
Hanada
Shinichiro
S
Maeyama
Michiko
M
Baba
Shinji
S
Koga
Hironori
H
Kumashiro
Ryukichi
R
Ueno
Takato
T
Ogata
Hisanobu
H
Yoshimura
Akihiko
A
Sata
Michio
M
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
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