Ethanol exposure depletes hepatic pigment epithelium-derived factor, a novel lipid regulator.
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.
Chung
Chuhan
C
Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut 06516, USA. chuhan.chung@yale.edu
Shugrue
Christine
C
Nagar
Anil
A
Doll
Jennifer A
JA
Cornwell
Mona
M
Gattu
Arijeet
A
Kolodecik
Tom
T
Pandol
Stephen J
SJ
Gorelick
Fred
F
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
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