title: Lipin 1 represses NFATc4 transcriptional activity in adipocytes to inhibit secretion of inflammatory factors.
abstract: Lipin 1 is a bifunctional protein that regulates gene transcription and, as a Mg(2+)-dependent phosphatidic acid phosphatase (PAP), is a key enzyme in the biosynthesis of phospholipids and triacylglycerol. We describe here the functional interaction between lipin 1 and the nuclear factor of activated T cells c4 (NFATc4). Lipin 1 represses NFATc4 transcriptional activity through protein-protein interaction, and lipin 1 is present at the promoters of NFATc4 transcriptional targets in vivo. Catalytically active and inactive lipin 1 can suppress NFATc4 transcriptional activity, and this suppression may involve recruitment of histone deacetylases to target promoters. In fat pads from mice deficient for lipin 1 (fld mice) and in 3T3-L1 adipocytes depleted of lipin 1 there is increased expression of several NFAT target genes including tumor necrosis factor alpha, resistin, FABP4, and PPARgamma. Finally, both lipin 1 protein and total PAP activity are decreased with increasing adiposity in the visceral, but not subcutaneous, fat pads of ob/ob mice. These observations place lipin 1 as a potentially important link between triacylglycerol synthesis and adipose tissue inflammation.
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Hyun Bae
authors.initials: HB
authors.lastname: Kim
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Lifu
authors.initials: L
authors.lastname: Wang
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Liu
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Keller
authors.forename: John C
authors.initials: JC
authors.lastname: Lawrence
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000375:Aging / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010711:Phosphatidate Phosphatase; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D006877:Hydroxamic Acids; D018836:Inflammation Mediators; D050778:NFATC Transcription Factors; C467907:Nfatc4 protein, mouse; D009687:Nuclear Proteins; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C012589:trichostatin A; D004247:DNA; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; D006655:Histone Deacetylases
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