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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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3T3-L1 Cells
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Adipocytes / drug effects
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Adipocytes / metabolism*
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Aging / metabolism
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Animals
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Calcium Signaling / drug effects
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DNA / metabolism
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Gene Expression Regulation / drug effects
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Histone Deacetylases / metabolism
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Hydroxamic Acids / pharmacology
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Inflammation Mediators / metabolism*
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Mice
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NFATC Transcription Factors / genetics*
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Obesity / genetics
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PPAR alpha / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Phosphatidate Phosphatase
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Promoter Regions, Genetic / genetics
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Protein Binding / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Repressor Proteins / metabolism*
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Trans-Activators / metabolism
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Transcription Factors
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Transcription, Genetic* / drug effects
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Hydroxamic Acids
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Inflammation Mediators
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NFATC Transcription Factors
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Nfatc4 protein, mouse
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Nuclear Proteins
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PPAR alpha
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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RNA, Messenger
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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Tumor Necrosis Factor-alpha
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trichostatin A
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DNA
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Lpin1 protein, mouse
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Phosphatidate Phosphatase
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Histone Deacetylases