Anti-angiogenic pigment epithelium-derived factor regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL).
OBJECTIVE
Anti-angiogenic pigment epithelium-derived factor (PEDF) is a 50 kDa secreted glycoprotein that is highly expressed in hepatocytes. Adipose triglyceride lipase (ATGL), a novel lipase critical for triglyceride metabolism, is a receptor for PEDF. We postulated that hepatocyte triglyceride metabolism was dependent on interactions between PEDF and ATGL, and loss of PEDF would impair mobilization of triglycerides in the liver.


METHODS
Immunoprecipitation studies were performed in PEDF null and control hepatocytes with recombinant PEDF (rPEDF) as bait. Immunofluorescent microscopy was used to localize ATGL. Triglyceride content was analyzed in hepatocytes and in whole liver with and without rPEDF. ATGL was blocked using an inhibitor, (R)-bromoenol lactone.


RESULTS
PEDF co-immunoprecipitated with ATGL in hepatic and HCC lysates. All PEDF deficient livers demonstrated steatosis. Triglyceride content was significantly increased in PEDF null livers compared to wildtype (p<0.05) and in isolated hepatocytes (p<0.01). Treatment of PEDF null hepatocytes with rPEDF decreased TG content (p<0.05) and this activity was dependent on ATGL.


CONCLUSIONS
Our results identify a novel role for PEDF in hepatic triglyceride homeostasis through binding to ATGL and demonstrate that rPEDF and ATGL localize to adiposomes in hepatocytes. Dysregulation of this pathway may be one mechanism underlying fatty liver disease.
Chung
Chuhan
C
Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.
Doll
Jennifer A
JA
Gattu
Arijeet K
AK
Shugrue
Christine
C
Cornwell
Mona
M
Fitchev
Philip
P
Crawford
Susan E
SE
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005136:Eye Proteins / Q000378:metabolism* / Q000494:pharmacology; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015843:Serpins / Q000378:metabolism* / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor; D000217:Acyltransferases
D002265:Carboxylic Ester Hydrolases; D005136:Eye Proteins; D008049:Lipase; D009281:Naphthalenes; D009414:Nerve Growth Factors; D010726:Phosphodiesterase Inhibitors; D011753:Pyrones; D011994:Recombinant Proteins; D015843:Serpins; D014280:Triglycerides; D000099174:Pigment Epithelium-Derived Factor; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; C494794:PNPLA2 protein, human; D000217:Acyltransferases; C494445:PNPLA2 protein, mouse