title: The role of hepassocin in the development of non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  While non-alcoholic fatty liver disease (NAFLD) is the most common risk factor of chronic liver disease, the mechanisms that initiate its development are obscure. Hepassocin (HPS) is a hepatokine that has been reported to be involved in liver regeneration. In addition to the mitogenic activity of HPS, HPS expression is decreased in patients with hepatoma. However, the role of HPS in NAFLD is still unknown.
  
  
  METHODS
  A total of 393 subjects with (n=194) or without (n=199) NAFLD were enrolled to evaluate the serum HPS concentration. In order to clarify the causal inference between HPS and NAFLD, we used experimental animal and cell models. Hepatic overexpression or silencing of HPS was achieved by lentiviral vector delivery in mice and lipofectamine transfection in HepG2 cells. Lipogenesis related proteins were detected by Western blots. The expression of inflammatory factors was determined by real-time polymerase chain reaction.
  
  
  RESULTS
  Subjects with NAFLD had a higher serum HPS concentration than those without it. Overexpression of HPS increased hepatic lipid accumulation and NAFLD activity scores (NAS), whereas deletion of HPS improved high fat diet-induced hepatic steatosis and decreased NAS in mice. Additionally, oleic acid, a steatogenic reagent, increased HPS expression in hepatocytes. Furthermore, overexpression of HPS in HepG2 cells induced lipid accumulation through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent pathway, whereas deletion of HPS decreased oleic acid-induced lipid accumulation.
  
  
  CONCLUSIONS
  The present study provides evidence that HPS plays an important role in NAFLD and induces hepatic lipid accumulation through an ERK1/2-dependent pathway.
authors.affiliation: Research Center of Herbal Medicine, New Drugs, and Nutritional Supplements, National Cheng Kung University, Taiwan; Department of Family Medicine, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan.
authors.forename: Hung-Tsung
authors.initials: HT
authors.lastname: Wu
authors.forename: Feng-Hwa
authors.initials: FH
authors.lastname: Lu
authors.forename: Horng-Yih
authors.initials: HY
authors.lastname: Ou
authors.forename: Yu-Chu
authors.initials: YC
authors.lastname: Su
authors.forename: Hao-Chang
authors.initials: HC
authors.lastname: Hung
authors.forename: Jin-Shang
authors.initials: JS
authors.lastname: Wu
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Yang
authors.forename: Chao-Liang
authors.initials: CL
authors.lastname: Wu
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Chang
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005340:Fibrinogen / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood / Q000502:physiology*; D065626:Non-alcoholic Fatty Liver Disease; D019301:Oleic Acid / Q000494:pharmacology
chemical_list: C485894:FGL1 protein, human; C476403:Fgl1 protein, mouse; D009363:Neoplasm Proteins; D019301:Oleic Acid; D005340:Fibrinogen
keywords: ACC-1; ERK1/2; FAS; FFAs; Fatty acids; HCC; HFD; HNF-1; HPS; Hepatic steatosis; Liver; NAFLD; NAFLD activity score; NAS; NASH; OA; Oleic acid; SREBP-1; STAT3; acetyl-CoA carboxylase-1; extracellular signal-regulated kinase 1/2; fatty acid synthase; free fatty acids; hepassocin; hepatocellular carcinoma; hepatocyte nuclear factor-1; high fat diet; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; oleic acid; signal transducer and activator of transcription 3; sterol regulatory element-binding protein-1