The direct peroxisome proliferator-activated receptor target fasting-induced adipose factor (FIAF/PGAR/ANGPTL4) is present in blood plasma as a truncated protein that is increased by fenofibrate treatment.
The fasting-induced adipose factor (FIAF, ANGPTL4, PGAR, HFARP) was previously identified as a novel adipocytokine that was up-regulated by fasting, by peroxisome proliferator-activated receptor agonists, and by hypoxia. To further characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and adipose cell lines as well as in human and mouse plasma. Expression of FIAF mRNA was up-regulated by peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARbeta/delta agonists in rat and human hepatoma cell lines and by PPARgamma and PPARbeta/delta agonists in mouse and human adipocytes. Transactivation, chromatin immunoprecipitation, and gel shift experiments identified a functional PPAR response element within intron 3 of the FIAF gene. At the protein level, in human and mouse blood plasma, FIAF was found to be present both as the native protein and in a truncated form. Differentiation of mouse 3T3-L1 adipocytes was associated with the production of truncated FIAF, whereas in human white adipose tissue and SGBS adipocytes, only native FIAF could be detected. Interestingly, truncated FIAF was produced by human liver. Treatment with fenofibrate, a potent PPARalpha agonist, markedly increased plasma levels of truncated FIAF, but not native FIAF, in humans. Levels of both truncated and native FIAF showed marked interindividual variation but were not associated with body mass index and were not influenced by prolonged semistarvation. Together, these data suggest that FIAF, similar to other adipocytokines such as adiponectin, may partially exert its function via a truncated form.
Mandard
Stéphane
S
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands.
Zandbergen
Fokko
F
Tan
Nguan Soon
NS
Escher
Pascal
P
Patsouris
David
D
Koenig
Wolfgang
W
Kleemann
Robert
R
Bakker
Arjen
A
Veenman
Frank
F
Wahli
Walter
W
Müller
Michael
M
Kersten
Sander
S
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D054392:Adipokines / Q000378:metabolism; D052242:Adiponectin; D000273:Adipose Tissue / Q000378:metabolism; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D011345:Fenofibrate / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D007438:Introns; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D011506:Proteins / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
C474772:ANGPTL4 protein, human; C528241:ANGPTL4 protein, rat; D054392:Adipokines; D052242:Adiponectin; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D002843:Chromatin; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D012313:RNA; D011345:Fenofibrate