Hepatitis C Virus Induces Proteolytic Cleavage of Sterol Regulatory Element Binding Proteins and Stimulates Their Phosphorylation via Oxidative Stress

Waris, Gulam; Felmlee, Daniel J.; Negro, Francesco; Siddiqui, Aleem

doi:10.1128/jvi.00125-07

Cited by 245 publications

(244 citation statements)

References 48 publications

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“…Accordingly, it is detectable in infected cells as a basal and a hyperphosphorylated form with apparent molecular weights of 56 and 58 kDa, respectively. 63 NS5A binds to the viral RNA and to numerous host factors and colocalizes with core in close upon expression of individual viral proteins such as core, NS2 or NS4B, [91][92][93][94] and its inhibition by 25-hydroxycholesterol causes a decrease in fatty acid biosynthesis and a subsequent block of HCV replication. 95 In agreement with this, the expression of fatty acid synthase (FASN) and other genes related to the synthesis and transport of fatty acids is upregulated in infected cells.…”

Section: Hcv Proteinsmentioning

confidence: 99%

Hepatitis c virus and host cell lipids: An intimate connection

Alvisi¹,

Madan²,

2011

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Section: Hcv Proteinsmentioning

confidence: 99%

Hepatitis c virus and host cell lipids: An intimate connection

Alvisi¹,

Madan²,

2011

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“…13 Direct viral perturbation of cholesterol biosynthetic pathways and their regulation is suggested from experimental in vitro and animal models. [14][15][16][17][18] HCV-mediated oxidative stress has been suggested as a possible causative mechanism leading to both HCV-associated hepatic steatosis and IR, and has also been linked to cholesterol regulation. 15,19 Finally, from the host perspective, it is not known why compensatory regulation to increase cholesterol synthesis appears inadequate to resolve HCV-associated hypolipidemia.…”

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confidence: 99%

Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

et al. 2012

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Hepatitis C virus (HCV) subverts host cholesterol metabolism for key processes in its lifecycle. How this interference results in the frequently observed, genotype-dependent clinical sequelae of hypocholesterolemia, hepatic steatosis, and insulin resistance (IR) remains incompletely understood. Hypocholesterolemia typically resolves after sustained viral response (SVR), implicating viral interference in host lipid metabolism. Using a targeted cholesterol metabolomic platform we evaluated paired HCV genotype 2 (G2) and G3 patient sera for changes in in vivo HCV sterol pathway metabolites. We compared HCV genotypic differences in baseline metabolites and following antiviral treatment to assess whether sterol perturbation resolved after HCV eradication. We linked these metabolites to IR and urine oxidative stress markers. In paired sera from HCV G2 (n 5 13) and G3 (n 5 20) patients, baseline sterol levels were lower in G3 than G2 for distal metabolites (7-dehyrocholesterol (7DHC) 0.017 versus 0.023 mg/dL; P adj 5 0.0524, cholesterol 140.9 versus 178.7 mg/dL; P adj 5 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [D55.2 mg/dL; P adj 5 0.0015], 7DHC [D0.0075 mg/dL; P adj 5 0.0026], lathosterol [D0.0430 mg/dL P adj 5 0.0405]). In contrast, lanosterol was unchanged after SVR (P 5 0.9515). Conclusion: HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms. (HEPATOLOGY 2012;56:49-56)

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“…21,22 Moreover, it has been described that HCV gene expression may activate the LXRa signaling pathway in in vivo and in vitro models. 15,23 Based on these data, it is conceivable that LXRa may be a key regulator of hepatic lipogenesis in HCV infection.…”

mentioning

confidence: 99%

“…[11][12][13] Other HCV proteins, such as NS2, NS4B, and NS5A, have also been shown to be able to modulate lipogenic gene expression. [14][15][16] However, the precise functions of HCV proteins in the development of fatty liver remain unknown.…”

mentioning

confidence: 99%

Liver X receptor α-mediated regulation of lipogenesis by core and NS5A proteins contributes to HCV-induced liver steatosis and HCV replication

García‐Mediavilla

Pisonero-Vaquero

Lima-Cabello

et al. 2012

Laboratory Investigation

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Molecular mechanisms contributing to hepatitis C virus (HCV)-associated steatosis are not well established, although HCV gene expression has been shown to alter host cell cholesterol/lipid metabolism. As liver X receptors (LXRs) play a role as key modulators of metabolism signaling in the development of steatosis, we aimed to investigate in an HCV in vitro model the effect of HCV NS5A protein, core protein, and viral replication on the intracellular lipid accumulation and the LXRa-regulated expression of lipogenic genes. The effects of LXRa siRNA or agonist GW3965 treatment on lipogenesis and HCV replication capacity in our HCV replicon system were also examined. NS5A-and core-expressing cells and replicon-containing cells exhibited an increase of lipid accumulation by inducing the gene expression and the transcriptional activity of LXRa, and leading to an increased expression of its lipogenic target genes sterol regulatory element binding protein-1c, peroxisome proliferator-activated receptor-g, and fatty acid synthase. Transcriptional induction by NS5A protein, core protein, and viral replication occurred via LXR response element activation in the lipogenic gene promoter. No physical association between HCV proteins and LXRa was observed, whereas NS5A and core proteins indirectly upregulated LXRa through the phosphatidylinositol 3-kinase pathway. Finally, it was found that LXRa knockdown or agonist-mediated LXRa induction directly regulated HCV-induced lipogenesis and HCV replication efficiency in replicon-containing cells. Combined, our data suggest that LXRa-mediated regulation of lipogenesis by core and NS5A proteins may contribute to HCV-induced liver steatosis and to the efficient replication of HCV.

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Hepatitis C Virus Induces Proteolytic Cleavage of Sterol Regulatory Element Binding Proteins and Stimulates Their Phosphorylation via Oxidative Stress

Cited by 245 publications

References 48 publications

Hepatitis c virus and host cell lipids: An intimate connection

Hepatitis c virus and host cell lipids: An intimate connection

Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

Liver X receptor α-mediated regulation of lipogenesis by core and NS5A proteins contributes to HCV-induced liver steatosis and HCV replication

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