Liver X receptor α-mediated regulation of lipogenesis by core and NS5A proteins contributes to HCV-induced liver steatosis and HCV replication.
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 LXRα-regulated expression of lipogenic genes. The effects of LXRα 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 LXRα, and leading to an increased expression of its lipogenic target genes sterol regulatory element binding protein-1c, peroxisome proliferator-activated receptor-γ, 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 LXRα was observed, whereas NS5A and core proteins indirectly upregulated LXRα through the phosphatidylinositol 3-kinase pathway. Finally, it was found that LXRα knockdown or agonist-mediated LXRα induction directly regulated HCV-induced lipogenesis and HCV replication efficiency in replicon-containing cells. Combined, our data suggest that LXRα-mediated regulation of lipogenesis by core and NS5A proteins may contribute to HCV-induced liver steatosis and to the efficient replication of HCV.
Institute of Biomedicine-IBIOMED, University of León, León, Spain.
María Victoria
MV
García-Mediavilla
Sandra
S
Pisonero-Vaquero
Elena
E
Lima-Cabello
Ignacio
I
Benedicto
Pedro Lorenzo
PL
Majano
Francisco
F
Jorquera
Javier
J
González-Gallego
Sonia
S
Sánchez-Campos
D000704:Analysis of Variance; D045744:Cell Line, Tumor; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D016174:Hepacivirus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D050155:Lipogenesis / Q000235:genetics / Q000502:physiology*; D000071518:Liver X Receptors; D051058:Oncogene Protein v-akt / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014758:Viral Core Proteins / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D000071518:Liver X Receptors; D051058:Oncogene Protein v-akt; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D051780:Sterol Regulatory Element Binding Protein 1; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; D019014:fas Receptor; C491901:FAS protein, human; C000605213:NR1H3 protein, human; C069130:nucleocapsid protein, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase