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 Mg2؉ -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 PPAR␥. 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.

Fat-specific protein 27 modulates nuclear factor of activated T cells 5 and the cellular response to stress

“…Interestingly, similar to the current observations with FSP27 and NFAT5, lipin, a protein important in TAG synthesis and LD formation and which is known to interact with several nuclear proteins ( 38 ), has been reported to interact with NFATc4 and to repress infl ammatory genes ( 39 ).…”

Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice

“…Lipin 2 antibody has been previously described ( 21 DNA-bound transcription factors to regulate their activity ( 14 ). Lipin 1 coactivates the PPARs ( 14-16 ) and hepatic nuclear receptor 4 ␣ (HNF4 ␣ ) ( 17 ) nuclear receptors but represses nuclear factor of activated T-cells 4c ( 18 ) and the sterol-response element binding protein 1 [SREBP1; ( 19 )]. As a general rule, the transcriptional regulatory effects of lipin 1 do not require intact PAP catalytic activity and are mechanistically separable.…”

Endoplasmic reticulum stress suppresses lipin-1 expression in 3T3-L1 adipocytes

“…PPAR- or co-activator protein (PPAR- coactivator-1) [6]. Last, lipin-1 regulates inflammation in adipocyte by acting as a co-repressor to suppress the expression of pro-inflammatory cytokines [7]. Taken together, these findings establish lipin-1 as a multiple regulator of metabolism.…”

“…Recently, we and the other group have showed that reduced adipose lipin-1 has been induced the expression of cytokines, MCP-1 and TNF-, suggesting adipose lipin-1 regulates inflammation [7,15]. Recovering the reduced lipin-1 expression in adipocytes could improve overall glucose metabolism, at least in part, by reducing these pro-inflammatory cytokines.…”

“…The significance of depleted adipose lipin-1 expression in obesity has been partially determined. Kim et al reported the forced depletion of lipin-1 in adipocytes induces TNF- production [7]. We previously have reported that the knockdown of lipin-1 in 3T3-L1 adipocytes resulted in the induction of monocyte chemoattractant protein-1 [15].…”