Lipin 1 represses NFATc4 transcriptional activity in adipocytes to inhibit secretion of inflammatory factors

Lipin 1 is a bifunctional protein that directly regulates gene transcription and, as a Mg2+‐dependent phosphatidic acid phosphatase (PAP), is a key enzyme in the biosynthesis of phospholipids and triacylglycerol. Herein, we describe the functional interaction between lipin 1 and the Nuclear Factor of Activated T‐cells c4 (NFATc4). Lipin 1 represses NFATc4 transcriptional activity through direct protein‐protein interaction at the promoters of NFATc4 transcriptional targets in vivo. The suppression of NFATc4 transcriptional activity is independent of lipin 1 PAP activity, but 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 TNFα, resistin, FABP4 and PPARγ. 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. This work was supported by NIH grants DK28312 and DK52753 (to J.C.L.), DK078187 (to B.N.F.), and a P&F grant from DK063609 (to T.E.H.).