{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T09:55:39Z","timestamp":1791107739403,"version":"4.1.0"},"reference-count":50,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2012,6,1]],"date-time":"2012-06-01T00:00:00Z","timestamp":1338508800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>Hepatitis C virus (HCV) infection significantly increases the prevalence of type 2 diabetes mellitus (T2DM). Insulin receptor substrate 1 (IRS-1) plays a key role in insulin signaling, thus enabling metabolic regulation in mammalian cells. We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR\/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. Inhibition of IRS-1 expression was observed in HCV-infected hepatocytes compared to that in a mock-infected control. The status of the tuberous sclerosis complex (TSC-1\/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. Interestingly, the phosphoS6K1 level was higher in HCV-infected hepatocytes, suggesting a novel mechanism for IRS-1 inhibition. Ectopic expression of TSC-1\/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR\/S6K1 signaling pathway. Proteasome inhibitor MG 132 recovered IRS-1 and TSC1\/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. Together, these observations suggested that HCV infection activates the mTOR\/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance.<\/jats:p>","DOI":"10.1128\/jvi.00050-12","type":"journal-article","created":{"date-parts":[[2012,3,29]],"date-time":"2012-03-29T02:35:51Z","timestamp":1332988551000},"page":"6315-6322","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":114,"title":["Hepatitis C Virus Activates the mTOR\/S6K1 Signaling Pathway in Inhibiting IRS-1 Function for Insulin Resistance"],"prefix":"10.1128","volume":"86","author":[{"given":"Sandip K.","family":"Bose","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA"},{"name":"Molecular Microbiology &amp; Immunology, Saint Louis University, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubham","family":"Shrivastava","sequence":"additional","affiliation":[{"name":"Pathology, Saint Louis University, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Meyer","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratna B.","family":"Ray","sequence":"additional","affiliation":[{"name":"Pathology, Saint Louis University, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjit","family":"Ray","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA"},{"name":"Molecular Microbiology &amp; Immunology, Saint Louis University, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2005.02597.x"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2001.24432"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101521200"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.12.9047"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb01045.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(06)00122-9"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(05)80631-2"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST0370223"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hep.2003.09.012"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02344-09"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01672-07"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.2002.1460"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.52.10.1531"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-002-0085-3"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205838200"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/jemt.20227"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1179\/acb.2007.019"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2006.02729.x"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00146-11"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5407.1544"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1879"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.2174\/092986708784534956"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00220-X"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202678200"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-5491.1995.tb00466.x"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209153200"},{"key":"e_1_3_2_28_2","first-page":"369","article-title":"Hepatocellular carcinoma: an emerging problem with hepatitis C","volume":"92","author":"Jeffers L","year":"2000","unstructured":"JeffersL. 2000. Hepatocellular carcinoma: an emerging problem with hepatitis C. J. Natl. Med. Assoc. 92:369\u2013371.","journal-title":"J. Natl. Med. Assoc."},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.80.9.4633-4639.2006"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2008.12.029"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63408-6"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjgastroenterol.2003.06.002"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hci001"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0772"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.2.5.446"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc05-1995"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510290235"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44026"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.11.010"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.2000.0295"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb996"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2003.11.056"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/372182a0"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0706517104"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6609"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/36116"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.2337\/db06-1355"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200317222"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb999"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806480200"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(01)81297-6"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00050-12","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00050-12","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T15:10:56Z","timestamp":1646493056000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.00050-12"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,6]]},"references-count":50,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2012,6]]}},"alternative-id":["10.1128\/JVI.00050-12"],"URL":"https:\/\/doi.org\/10.1128\/jvi.00050-12","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,6]]},"assertion":[{"value":"2012-01-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-03-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-05-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}