title: Ethanol exposure depletes hepatic pigment epithelium-derived factor, a novel lipid regulator.
abstract: OBJECTIVE
  Ethanol abuse can lead to hepatic steatosis and evolve into cirrhosis and hepatocellular carcinoma. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein that is expressed by hepatocytes. Proteomic, experimental, and clinical studies implicate PEDF's role in lipid regulation. Because matrix metalloproteinase (MMP)-2/9 activity regulates PEDF levels, we investigated whether PEDF degradation by MMPs has a permissive role in ethanol-induced hepatic steatosis.
  
  
  METHODS
  PEDF levels were examined in liver biopsy specimens from patients with ethanol-induced steatosis. Hepatic PEDF levels and MMP activity were assessed in 2 animal models of ethanol feeding (rats on an alcohol-containing liquid diet and mice given intragastric infusion of ethanol). The consequences of PEDF depletion in the liver were examined in PEDF-null mice.
  
  
  RESULTS
  Liver biopsy samples from patients with ethanol-induced steatosis had reduced PEDF levels, compared with normal liver samples. Ethanol-fed animals had histologic steatosis and increased liver triglyceride content (P< .05), as well as reduced levels of hepatic PEDF and increased MMP-2/9 activity. Ethanol-exposed hepatic lysates degraded PEDF in a MMP-2/9-dependent manner, and liver sections demonstrated abundant MMP-2/9 activity in situ. Addition of recombinant PEDF to PEDF-null hepatocytes, reduced their triglyceride content.
  
  
  CONCLUSIONS
  Ethanol exposure leads to marked loss of hepatic PEDF in human livers and in 2 animal models of ethanol feeding. Loss of PEDF contributes to the accumulation of lipids in ethanol-induced hepatic steatosis.
authors.affiliation: Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut 06516, USA. chuhan.chung@yale.edu
authors.forename: Chuhan
authors.initials: C
authors.lastname: Chung
authors.forename: Christine
authors.initials: C
authors.lastname: Shugrue
authors.forename: Anil
authors.initials: A
authors.lastname: Nagar
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doll
authors.forename: Mona
authors.initials: M
authors.lastname: Cornwell
authors.forename: Arijeet
authors.initials: A
authors.lastname: Gattu
authors.forename: Tom
authors.initials: T
authors.lastname: Kolodecik
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.forename: Fred
authors.initials: F
authors.lastname: Gorelick
mesh_terms: D000818:Animals; D000431:Ethanol / Q000633:toxicity*; D005136:Eye Proteins / Q000032:analysis* / Q000502:physiology; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000201:enzymology / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000502:physiology; D009414:Nerve Growth Factors / Q000032:analysis* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015843:Serpins / Q000032:analysis* / Q000502:physiology; D014280:Triglycerides / Q000032:analysis; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000431:Ethanol; D005136:Eye Proteins; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009414:Nerve Growth Factors; D015843:Serpins; D014280:Triglycerides; D000099174:Pigment Epithelium-Derived Factor