Hepatitis C Virus Core Protein Upregulates Serine Phosphorylation of Insulin Receptor Substrate-1 and Impairs the Downstream Akt/Protein Kinase B Signaling Pathway for Insulin Resistance

Banerjee, Sutapa; Saito, Ko; Ait-Goughoulte, Malika; Meyer, Keith; Ray, Ratna B.; Ray, Ranjit

doi:10.1128/jvi.01672-07

Cited by 160 publications

(134 citation statements)

References 68 publications

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“…Several cellular lesions have been associated with insulin resistance, but the precise mechanism by which HCV induces insulin resistance remains elusive with numerous viewpoints and opinions [30] . Impairment of IRS-1 and IRS-2 expression has been observed in the liver of patients with chronic HCV infection, as well as in HCV core transgenic mice, and from in vitro cell culture system [35][36][37][38] . HCV mediates dysfunction of the insulin signaling pathways via several distinct mechanisms, such as upregulating the expression of suppressors of cytokine signaling 3 expression [35] , down regulation of peroxisome proliferator-activated receptors gamma (PPARγ) [36] , activation of mammalian target of rapamycin (mTOR)/S6K1 pathway [38] , and increased tumor necrosis factor-α (TNF-α) secretion [39] .…”

Section: Resistancementioning

confidence: 99%

Hepatitis C virus infection and insulin resistance

Bose¹

2014

WJD

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Approximately 170 million people worldwide are chronically infected with hepatitis C virus (HCV). Chronic HCV infection is the leading cause for the development of liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and is the primary cause for liver transplantation in the western world. Insulin resistance is one of the pathological features in patients with HCV infection and often leads to development of type Ⅱ diabetes. Insulin resistance plays an important role in the development of various complications associated with HCV infection. Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis, steatosis, HCC and resistance to anti-viral treatment. Thus, HCV associated insulin resistance is a therapeutic target at any stage of HCV infection. HCV modulates normal cellular gene expression and interferes with the insulin signaling pathway. Various mechanisms have been proposed in regard to HCV mediated insulin resistance, involving up regulation of inflammatory cytokines, like tumor necrosis factor-α, phosphorylation of insulin-receptor substrate-1, Akt, up-regulation of gluconeogenic genes like glucose 6 phosphatase, phosphoenolpyruvate carboxykinase 2, and accumulation of lipid droplets. In this review, we summarize the available information on how HCV infection interferes with insulin signaling pathways resulting in insulin resistance.© 2014 Baishideng Publishing Group Co., Limited. All rights reserved.Key words: Hepatitis C virus; Insulin resistance; Insulin receptor substrate 1; Protein kinase B; mammalian target of rapamycin/S6K1; Suppressor of cytokine signaling 3; Glucose transporter-4; Lipid metabolism; Antiviral therapy Core tip: Insulin resistance is one of the pathological features in patients with hepatitis C virus (HCV) infection and often leads to development of type Ⅱ diabetes. Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis, steatosis, hepatocellular carcinoma and resistance to anti-viral treatment. In this review, we summarize the available information on how HCV infection interferes with insulin signaling pathways.Bose SK, Ray R. Hepatitis C virus infection and insulin resistance. World J Diabetes 2014; 5(1): 52-58 Available from: URL:

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Section: Resistancementioning

confidence: 99%

Hepatitis C virus infection and insulin resistance

Bose¹

2014

WJD

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“…Much of the published literature in this area has focused on the HCV core protein, which has been proposed to cause IR in hepatocytes by reducing the level or activity of molecules involved in insulin signaling, particularly IRS-1 and IRS-2. However, there is considerable disagreement concerning which of these molecules is more important, and whether altered signaling results from changes in IRS expression, degradation, or altered activity [64,[71][72][73][74][75] .…”

Section: Direct Effects Of Hcv In Modulating Insulin Signaling Hcv Comentioning

confidence: 99%

“…The authors therefore speculated that IR in the context of HCV genotype 1 infection is due to core-induced induction of the TORC1 mTOR/raptor complex, resulting in reduced IRS-1 signaling [75] . A different group has shown reduced insulin signaling in core-expressing cells, due to JNKmediated inhibitory phosphorylation of IRS-1 at serine 312 [72] . Although intriguing, the relevance of IRS-1 serine phosphorylation to clinical HCV-induced IR has yet to be confirmed.…”

Section: Direct Effects Of Hcv In Modulating Insulin Signaling Hcv Comentioning

confidence: 99%

Molecular mechanisms of insulin resistance in chronic hepatitis C

Douglas

George²

2009

WJG

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It is now widely recognized that chronic hepatitis C (CHC) is associated with insulin resistance (IR) and type 2 diabetes, so can be considered a metabolic disease. IR is most strongly associated with hepatitis C virus (HCV) genotype 1, in contrast to hepatic steatosis, which is associated with genotype 3 infection. Apart from the well-described complications of diabetes, IR in CHC predicts faster progression to fibrosis and cirrhosis that may culminate in liver failure and hepatocellular carcinoma. More recently, it has been recognized that IR in CHC predicts a poor response to antiviral therapy. The molecular mechanisms for the association between IR and HCV infection are not well defined. This review will elaborate on the clinical associations between CHC and IR and summarize current knowledge regarding the molecular mechanisms that potentially mediate HCV-associated IR.

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“…S1 A), supporting the role of TLR4 in LPS-induced hepatitis and mortality in NS5A mice. Next, we validated whether NS5A expression augmented LPSinduced signal transduction via TLR4 by assessing the interaction of TGF-␣-activated kinase 1 (TAK1) with TNFR-associated factor 6 (TRAF6) or IL-1 receptor-associated kinase-1 (IRAK1), the signaling events immediately downstream of LPS-TLR4-CD14 binding (13). Coimmunoprecipitation analysis of liver protein extracts readily detected enhanced TAK1-TRAF6 and TAK1-IRAK1 interactions in NS5A mice given LPS, whereas these protein-protein interactions were not observed in WT or Tlr4 Ϫ/Ϫ NS5A mice under the same immunoblotting condition (Fig.…”

Section: Ns5amentioning

confidence: 99%

“…The core protein also inhibits microsomal triglyceride transfer protein activity and very low-density lipoprotein (VLDL) secretion (11), which may underlie the genesis of fatty liver. The core protein also induces insulin resistance in mice and cell lines, and this effect may be mediated by degradation of insulin receptor substrates (IRS) 1 and 2 via up-regulation of SOCS3 (12) in a manner dependent on PA28␥ 73 or via IRS serine phosphorylation (13). Thus, these core-induced perturbations, such as oxidant stress and insulin resistance, which are also known risk factors for ALD, may contribute to the synergism reproduced in alcoholfed core transgenic mice (14).…”

mentioning

confidence: 99%

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Machida

Tsukamoto²,

Mkrtchyan³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

207

220

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Alcohol synergistically enhances the progression of liver disease and the risk for liver cancer caused by hepatitis C virus (HCV). However, the molecular mechanism of this synergy remains unclear. Here, we provide the first evidence that Toll-like receptor 4 (TLR4) is induced by hepatocyte-specific transgenic (Tg) expression of the HCV nonstructural protein NS5A, and this induction mediates synergistic liver damage and tumor formation by alcohol-induced endotoxemia. We also identify Nanog, the stem/progenitor cell marker, as a novel downstream gene up-regulated by TLR4 activation and the presence of CD133/Nanog-positive cells in liver tumors of alcohol-fed NS5A Tg mice. Transplantation of p53-deficient hepatic progenitor cells transduced with TLR4 results in liver tumor development in mice following repetitive LPS injection, but concomitant transduction of Nanog shorthairpin RNA abrogates this outcome. Taken together, our study demonstrates a TLR4-dependent mechanism of synergistic liver disease by HCV and alcohol and an obligatory role for Nanog, a TLR4 downstream gene, in HCV-induced liver oncogenesis enhanced by alcohol.

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Hepatitis C Virus Core Protein Upregulates Serine Phosphorylation of Insulin Receptor Substrate-1 and Impairs the Downstream Akt/Protein Kinase B Signaling Pathway for Insulin Resistance

Abstract: Chronic hepatitis C virus (HCV) infection has a significantly increased prevalence of type 2 diabetes mellitus (T2DM).

Cited by 160 publications

References 68 publications

Hepatitis C virus infection and insulin resistance

Hepatitis C virus infection and insulin resistance

Molecular mechanisms of insulin resistance in chronic hepatitis C

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

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