title: Small heterodimer partner attenuates profibrogenic features of hepatitis C virus-infected cells.
abstract: OBJECTIVE
  An atypical orphan nuclear receptor small heterodimer partner (SHP) is known to be regulated by AMP-activated protein kinase (AMPK). Both of them inhibit TGF-β and Smad signalling and exhibit antifibrotic activity in the liver. However, little is known about the protective effects of SHP and AMPK against hepatitis c virus (HCV)-induced hepatic fibrosis.
  
  
  METHODS
  Levels of SHP, p-AMPK and fibrotic markers in HCV-infected human liver and in Huh-7.5 cells infected with HCV genotype 2a (JFH-1) were investigated. The effect of adenovirus-mediated overexpression of SHP (Ad-SHP) and AMPK activation via metformin and 5-amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) on fibrotic gene expression was evaluated in HCV-infected cells. Finally, we examined the effect of Ad-SHP and AMPK activators on invasion and activation of LX2 human HSCs induced by conditioned media from HCV-infected hepatocyte (CM).
  
  
  RESULTS
  In HCV-infected human livers and Huh-7.5 cells infected with HCV, SHP mRNA and protein levels were diminished compared with controls, whereas profibrotic factors were increased. Pharmacological AMPK activation recovered SHP expression, and Ad-SHP inhibited HCV-induced fibrotic gene expression. This finding was accompanied by inhibition of HCV-stimulated nuclear factor-kappa B, an inducer of TGF-β. Moreover, CytoSelect invasion assay revealed that enhanced activity and invasiveness of hepatic stellate cells induced by CM.
  
  
  CONCLUSIONS
  These results demonstrate that overexpression of SHP and activation of AMPK reverses profibrogenic features of HCV-infected cells by decreasing TGF-β and fibrotic gene expression. These findings provide a rationale for SHP as a possible therapeutic target against HCV-induced hepatic fibrosis.
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Gwon-Soo
authors.initials: GS
authors.lastname: Jung
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Jae-Han
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Yeon-Kyung
authors.initials: YK
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Se Young
authors.initials: SY
authors.lastname: Jang
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors.forename: Eui-Cheol
authors.initials: EC
authors.lastname: Shin
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: Department of Pathology, Keimyung University School of Medicine, Daegu, Korea.
authors.forename: Yu Na
authors.initials: YN
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D005943:Gluconeogenesis / Q000187:drug effects; D016174:Hepacivirus; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008687:Metformin / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000494:pharmacology*; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D012265:Ribonucleotides; D016212:Transforming Growth Factor beta; C099713:nuclear receptor subfamily 0, group B, member 2; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: AMP-activated protein kinase; hepatitis C virus; liver fibrosis; small heterodimer partner