Anti-angiogenic pigment epithelium-derived factor regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL). J Hepatol 2008 Mar;48(3):471-8
Date
01/15/2008Pubmed ID
18191271DOI
10.1016/j.jhep.2007.10.012Scopus ID
2-s2.0-39149141058 (requires institutional sign-in at Scopus site) 121 CitationsAbstract
BACKGROUND/AIMS: 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.
Author List
Chung C, Doll JA, Gattu AK, Shugrue C, Cornwell M, Fitchev P, Crawford SEAuthor
Jennifer A. Doll PhD Assistant Professor in the Biomedical Sciences department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
AnimalsCarboxylic Ester Hydrolases
Cell Line, Tumor
Cells, Cultured
Eye Proteins
Fatty Liver
Hepatocytes
Homeostasis
Humans
Lipase
Liver
Mice
Mice, Knockout
Naphthalenes
Nerve Growth Factors
Phosphodiesterase Inhibitors
Pyrones
Recombinant Proteins
Serpins
Triglycerides