Dataset Information

Lipin1 regulates PPAR? transcriptional activity.

ABSTRACT: PPAR? (peroxisome-proliferator-activated receptor ?) is a master transcription factor involved in adipogenesis through regulating adipocyte-specific gene expression. Recently, lipin1 was found to act as a key factor for adipocyte maturation and maintenance by modulating the C/EBP? (CCAAT/enhancer-binding protein ?) and PPAR? network; however, the precise mechanism by which lipin1 affects the transcriptional activity of PPAR? is largely unknown. The results of the present study show that lipin1 activates PPAR? by releasing co-repressors, NCoR1 (nuclear receptor co-repressor 1) and SMRT (silencing mediator of retinoid and thyroid hormone receptor), from PPAR? in the absence of the ligand rosiglitazone. We also identified a novel lipin1 TAD (transcriptional activation domain), between residues 217 and 399, which is critical for the activation of PPAR?, but not PPAR?. Furthermore, this TAD is unique to lipin1 since this region does not show any homology with the other lipin isoforms, lipin2 and lipin3. The activity of the lipin1 TAD is enhanced by p300 and SRC-1 (steroid receptor co-activator 1), but not by PCAF (p300/CBP-associated factor) and PGC-1? (PPAR co-activator 1?). The physical interaction between lipin1 and PPAR? occurs at the lipin1 C-terminal region from residues 825 to 926, and the VXXLL motif at residue 885 is critical for binding with and the activation of PPAR?. The action of lipin1 as a co-activator of PPAR? enhanced adipocyte differentiation; the TAD and VXXLL motif played critical roles, but the catalytic activity of lipin1 was not directly involved. Collectively, these data suggest that lipin1 functions as a key regulator of PPAR? activity through its ability to release co-repressors and recruit co-activators via a mechanism other than PPAR? activation.

SUBMITTER: Kim HE

PROVIDER: S-EPMC3690191 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lipin1 regulates PPARγ transcriptional activity.

Kim Hee Eun HE Bae Eunju E Jeong Deok-Yoon DY Kim Min-Ji MJ Jin Won-Ji WJ Park Sahng-Wook SW Han Gil-Soo GS Carman George M GM Koh Eunjin E Kim Kyung-Sup KS

The Biochemical journal 20130701 1

PPARγ (peroxisome-proliferator-activated receptor γ) is a master transcription factor involved in adipogenesis through regulating adipocyte-specific gene expression. Recently, lipin1 was found to act as a key factor for adipocyte maturation and maintenance by modulating the C/EBPα (CCAAT/enhancer-binding protein α) and PPARγ network; however, the precise mechanism by which lipin1 affects the transcriptional activity of PPARγ is largely unknown. The results of the present study show that lipin1 a ...[more]

PMID: 23627357

Similar Datasets

Project description:BackgroundPPARs (?,?,?) are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL), an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown.Methods/principal findingsUsing PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (>HDL?LDL, IDL) to activate PPAR? preferentially over PPAR? or PPAR?, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPAR? in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPAR? target genes, including adipocyte differentiation related protein (ADRP), angiopoietin like protein 4 and pyruvate dehydrogenase kinase-4. HL/VLDL regulated ADRP through a PPRE in the promoter region of this gene. In vivo, adenoviral-mediated hepatic HL expression in C57BL/6 mice increased hepatic ADRP mRNA levels by 30%. In ob/ob mice, a model with higher triglycerides than C57BL/6 mice, HL overexpression increased ADRP expression by 70%, demonstrating the importance of triglyceride substrate for HL-mediated PPAR? activation. Global metabolite profiling identified HL/VLDL released fatty acids including oleic acid and palmitoleic acid that were capable of recapitulating PPAR? activation and ADRP gene regulation in vitro.ConclusionsThese data define a novel pathway involving HL hydrolysis of VLDL that activates PPAR? through generation of specific monounsaturated fatty acids. These data also demonstrate how integrating cell biology with metabolomic approaches provides insight into specific lipid mediators and pathways of lipid metabolism that regulate transcription.

Dataset Information

Lipin1 regulates PPAR? transcriptional activity.

Publications

Lipin1 regulates PPARγ transcriptional activity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets