title: Alteration of hepatic nuclear receptor-mediated signaling pathways in hepatitis C virus patients with and without a history of alcohol drinking.
abstract: The current study tests a hypothesis that nuclear receptor signaling is altered in chronic hepatitis C patients and that the altered pattern is specific to alcohol drinking history. The expression of a panel of more than 100 genes encoding nuclear receptors, coregulators, and their direct/indirect targets was studied in human livers. Gene expression pattern was compared between 15 normal donor livers and 23 hepatitis C virus (HCV) genotype 1-positive livers from patients without a drinking history (matched for age, sex, and body mass index). HCV infection increased the expression of nuclear receptors small heterodimer partner and constitutive androstane receptor (CAR) as well as genes involved in fatty acid trafficking, bile acid synthesis and uptake, and inflammatory response. However, the expression of retinoid X receptor (RXR) α, peroxisomal proliferator-activated receptor (PPAR) α and β as well as steroid regulatory element-binding protein (SREBP)-1c was decreased in HCV-infected livers. Gene expression pattern was compared in chronic hepatitis C patients with and without a drinking history. Alcohol drinking increased the expression of genes involved in fatty acid uptake, trafficking, and oxidation, but decreased the expression of genes responsible for gluconeogenesis. These changes were consistent with reduced fasting plasma glucose levels and altered expression of upstream regulators that include RXRα, PPARα, and CAR. The messenger RNA levels of fibroblast growth factor 21, interleukin-10, and fatty acid synthase, which are all regulated by nuclear receptors, showed independent correlation with hepatic HCV RNA levels.
  
  
  CONCLUSIONS
  Our findings suggest that those genes and pathways that showed altered expression could potentially be therapeutic targets for HCV infection and/or alcohol drinking-induced liver injury.
authors: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors: Chuanghong
authors: C
authors: Wu
authors: Richard
authors: R
authors: Gilroy
authors: Ryan
authors: R
authors: Taylor
authors: Mojtaba
authors: M
authors: Olyaee
authors: Bashar
authors: B
authors: Abdulkarim
authors: Jameson
authors: J
authors: Forster
authors: Maura
authors: M
authors: O'Neil
authors: Ivan
authors: I
authors: Damjanov
authors: Yu-Jui Yvonne
authors: YJ
authors: Wan
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000235:genetics* / Q000503:physiopathology; D000090702:Constitutive Androstane Receptor; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000821:virology; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000096:biosynthesis; D012367:RNA, Viral / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D047490:Retinoid X Receptor alpha / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis
chemical_list: D000090702:Constitutive Androstane Receptor; D005227:Fatty Acids; D047493:PPAR alpha; D012367:RNA, Viral; D018160:Receptors, Cytoplasmic and Nuclear; D047490:Retinoid X Receptor alpha; D051780:Sterol Regulatory Element Binding Protein 1