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

Abstract

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.

TGF‐β isoforms inhibit hepatitis C virus propagation in transforming growth factor beta/SMAD protein signalling pathway dependent and independent manners

“…The results agree with previous reports showing that in situ expressions of TGF‐β isoforms in the liver of HCV‐infected patients and the increased mRNA and protein expressions of TGF‐β1 and TGF‐β2 in HCV‐infected hepatocytes 6‐8 . Moreover, after HCV infection the increased expressions of TGF‐β2 at mRNA and protein levels were relatively higher compared to TGF‐β1 and TGF‐β3 (Figure 1B), which was consistent with previous studies 4‐8,22 …”

“…[6][7][8] Moreover, after HCV infection the increased expressions of TGF-β2 at mRNA and protein levels were relatively higher compared to TGF-β1 and TGF-β3 (Figure 1B), which was consistent with previous studies. [4][5][6][7][8]22 Then, we confirmed whether TGFβ isoforms still have the anti-HCV activities in HCVcc system. Following HCV infection and treatment of different concentrations of TGFβ isoforms for 72 hours, the level of HCV core protein in Huh7.5 cells was quantified with WB analysis.…”

Carvacrol, a Plant Metabolite Targeting Viral Protease (Mpro) and ACE2 in Host Cells Can Be a Possible Candidate for COVID-19

“…The role of activating PPAR-α and lipolysis has been shown to reduce the hepatitis C virus genotype-associated lipid metabolic disorder in liver diseases ( Patra et al, 2019 ). PPAR-α activation has also been shown to beneficially influence inflammatory alveolar epithelial cells and suggest the potential usefulness of PPAR-α in acute respiratory distress syndrome ( Hecker et al, 2015 ).…”

25-hydroxycholesterol: an integrator of antiviral ability and signaling

“…HCV genotype 3a induces higher expression of TGF-β and inhibition of PPARα expression and fatty acid oxidation. Besides, HCV-related lipid accumulation is associated with activation of TGF-β ( 118 ). Considering the regulatory effect of TGF-β on lipid production, in our previous study, we administrated 25HC to further investigate the role of TGF-β in a PDCoV-infected model in vitro .…”