Expression of genes involved in lipogenesis is not increased in patients with HCV genotype 3 in human liver

Desmond, Paul; Slavin, John; Congiu, M

doi:10.1111/j.1365-2893.2010.01283.x

Cited by 16 publications

(10 citation statements)

References 45 publications

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“…This is consistent with the absence of a direct relationship in vivo between steatosis and the presence of HCV proteins within steatotic hepatocytes [22]. Furthermore, the specific induction of higher SREBP1 levels by a genotype 3 core protein in vitro [25] was not confirmed in a recent analysis of gene expression in the livers of human patients infected with HCV of various genotypes [29]. Our findings are consistent with those of Piodi et al [14], suggesting that host factors play a greater role in the development of severe liver steatosis than viral factors in patients infected with a genotype 3 virus, contrary to the conclusions of the clinical studies previously addressing this question.…”

Section: Discussionsupporting

confidence: 63%

Viral Sequence Variation in Chronic Carriers of Hepatitis C Virus Has a Low Impact on Liver Steatosis

et al. 2012

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Most clinical studies suggest that the prevalence and severity of liver steatosis are higher in patients infected with hepatitis C virus (HCV) genotype 3 than in patients infected with other genotypes. This may reflect the diversity and specific intrinsic properties of genotype 3 virus proteins. We analyzed the possible association of particular residues of the HCV core and NS5A proteins known to dysregulate lipid metabolism with steatosis severity in the livers of patients chronically infected with HCV. We used transmission electron microscopy to quantify liver steatosis precisely in a group of 27 patients, 12 of whom were infected with a genotype 3 virus, the other 15 being infected with viruses of other genotypes. We determined the area covered by lipid droplets in liver tissues and analyzed the diversity of the core and NS5A regions encoded by the viral variants circulating in these patients. The area covered by lipid droplets did not differ significantly between patients infected with genotype 3 viruses and those infected with other genotypes. The core and NS5A protein sequences of the viral variants circulating in patients with mild or severe steatosis were evenly distributed throughout the phylogenic trees established from all the collected sequences. Thus, individual host factors seem to play a much greater role than viral factors in the development of severe steatosis in patients chronically infected with HCV, including those infected with genotype 3 viruses.

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Section: Discussionsupporting

confidence: 63%

Viral Sequence Variation in Chronic Carriers of Hepatitis C Virus Has a Low Impact on Liver Steatosis

et al. 2012

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“…PPAR␣ mRNA and protein levels are significantly decreased in hepatitis C-associated steatohepatitis compared with that in nonsteatotic livers (47). Chronic HCV genotype 3a infection is associated with an alteration of PPAR␣ in liver biopsy specimens of steatosis patients (48). PPAR␣ in human liver is regulated by miR-21 and miR-27 (49).…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β Acts as a Regulatory Molecule for Lipogenic Pathways among Hepatitis C Virus Genotype-Specific Infections

Patra

Sasaki

Meyer

et al. 2019

J Virol

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Hepatitis C virus (HCV) infection promotes metabolic disorders, and the severity of lipogenic disease depends upon the infecting virus genotype. Here, we have examined HCV genotype 1-, 2-, or 3-specific regulation of lipid metabolism, involving transforming growth factor β (TGF-β)-regulated phospho-Akt (p-Akt) and peroxisome proliferator-activated receptor alpha (PPARα) axes. Since HCV core protein is one of the key players in metabolic regulation, we also examined its contribution in lipid metabolic pathways. The expression of regulatory molecules, TGF-β1/2, phospho-Akt (Ser473), PPARα, sterol regulatory element-binding protein 1 (SREBP-1), fatty acid synthase (FASN), hormone-sensitive lipase (HSL), and acyl dehydrogenases was analyzed in virus-infected hepatocytes. Interestingly, HCV genotype 3a exhibited much higher activation of TGF-β and p-Akt, with a concurrent decrease in PPARα expression and fatty acid oxidation. A significant and similar decrease in HSL, unlike in HCV genotype 1a, was observed with both genotypes 2a and 3a. Similar observations were made from ectopic expression of the core genomic region from each genotype. The key role of TGF-β was further verified using specific small interfering RNA (siRNA). Together, our results highlight a significant difference in TGF-β-induced activity for the HCV genotype 2a- or 3a-induced lipogenic pathway, exhibiting higher triglyceride synthesis and a decreased lipolytic mechanism. These results may help in therapeutic modalities for early treatment of HCV genotype-associated lipid metabolic disorders. IMPORTANCE Hepatic steatosis is a frequent complication associated with chronic hepatitis C virus (HCV) infection and is a key prognostic indicator for progression to fibrosis and cirrhosis. Several mechanisms are proposed for the development of steatosis, especially with HCV genotype 3a. Our observations suggest that transforming growth factor β (TGF-β) and peroxisome proliferator-activated receptor alpha (PPARα)-associated mechanistic pathways in hepatocytes infected with HCV genotype 2a and 3a differ from those in cells infected with genotype 1a. The results suggest that a targeted therapeutic approach for enhanced PPARα and lipolysis may reduce HCV genotype-associated lipid metabolic disorder in liver disease.

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“…These results are consistent with previous studies in which genotype 1b or genotype 2a HCV replication systems induced lipogenic genes, 15,25 but differ from data obtained in patients infected with HCV genotype 3, in which steatosis was not associated with induction of genes involved in lipogenesis. 51 Similarly, overexpression of LXRa in HCV-replicating cells seems to be mediated by PI3K/AKT pathway activation. Although the LXRa-mediated lipogenesis observed in replicon-containing cells could be partially induced by the expression of HCV NS5A and core proteins, other HCV proteins, such as NS2 and NS4B, may contribute to higher LXRa levels, and increased SREBP-1c and FAS expression, as previously indicated.…”

Section: Discussionmentioning

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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Expression of genes involved in lipogenesis is not increased in patients with HCV genotype 3 in human liver

Cited by 16 publications

References 45 publications

Viral Sequence Variation in Chronic Carriers of Hepatitis C Virus Has a Low Impact on Liver Steatosis

Viral Sequence Variation in Chronic Carriers of Hepatitis C Virus Has a Low Impact on Liver Steatosis

Transforming Growth Factor β Acts as a Regulatory Molecule for Lipogenic Pathways among Hepatitis C Virus Genotype-Specific Infections

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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