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Loss of G protein pathway suppressor 2 in human adipocytes triggers lipid remodeling by upregulating ATP binding cassette subfamily G member 1.

Loss of G protein pathway suppressor 2 in human adipocytes triggers lipid remodeling by upregulating ATP binding cassette subfamily G member 1.

Authors :
Barilla, Serena
Liang, Ning
Mileti, Enrichetta
Ballaire, Raphaëlle
Lhomme, Marie
Ponnaiah, Maharajah
Lemoine, Sophie
Soprani, Antoine
Gautier, Jean-Francois
Amri, Ez-Zoubir
Le Goff, Wilfried
Venteclef, Nicolas
Treuter, Eckardt
Source :
Molecular Metabolism; Dec2020, Vol. 42, pN.PAG-N.PAG, 1p
Publication Year :
2020

Abstract

Adipogenesis is critical for adipose tissue remodeling during the development of obesity. While the role of transcription factors in the orchestration of adipogenic pathways is already established, the involvement of coregulators that transduce regulatory signals into epigenome alterations and transcriptional responses remains poorly understood. The aim of our study was to investigate which pathways are controlled by G protein pathway suppressor 2 (GPS2) during the differentiation of human adipocytes. We generated a unique loss-of-function model by RNAi depletion of GPS2 in human multipotent adipose-derived stem (hMADS) cells. We thoroughly characterized the coregulator depletion-dependent pathway alterations during adipocyte differentiation at the level of transcriptome (RNA-seq), epigenome (ChIP-seq H3K27ac), cistrome (ChIP-seq GPS2), and lipidome. We validated the in vivo relevance of the identified pathways in non-diabetic and diabetic obese patients. The loss of GPS2 triggers the reprogramming of cellular processes related to adipocyte differentiation by increasing the responses to the adipogenic cocktail. In particular, GPS2 depletion increases the expression of BMP4 , an important trigger for the commitment of fibroblast-like progenitors toward the adipogenic lineage and increases the expression of inflammatory and metabolic genes. GPS2-depleted human adipocytes are characterized by hypertrophy, triglyceride and phospholipid accumulation, and sphingomyelin depletion. These changes are likely a consequence of the increased expression of ATP-binding cassette subfamily G member 1 (ABCG1) that mediates sphingomyelin efflux from adipocytes and modulates lipoprotein lipase (LPL) activity. We identify ABCG1 as a direct transcriptional target, as GPS2 depletion leads to coordinated changes of transcription and H3K27 acetylation at promoters and enhancers that are occupied by GPS2 in wild-type adipocytes. We find that in omental adipose tissue of obese humans, GPS2 levels correlate with ABCG1 levels, type 2 diabetic status, and lipid metabolic status, supporting the in vivo relevance of the hMADS cell-derived in vitro data. Our study reveals a dual regulatory role of GPS2 in epigenetically modulating the chromatin landscape and gene expression during human adipocyte differentiation and identifies a hitherto unknown GPS2-ABCG1 pathway potentially linked to adipocyte hypertrophy in humans. • GPS2 depletion in human adipose-derived mesenchymal stem cells increases expression of adipogenic genes, including BMP4. • Loss of GPS2 leads to coordinated changes of epigenome and transcriptome during human adipocyte differentiation. • Loss of GPS2 upregulates ABCG1 and LPL and induces lipidome remodeling including sphingomyelin depletion. • The GPS2-ABCG1 pathway contributes to adipocyte hypertrophy. • GPS2 and ABCG1 levels in omental adipose tissue inversely correlate with type 2 diabetes in obese humans. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
22128778
Volume :
42
Database :
Supplemental Index
Journal :
Molecular Metabolism
Publication Type :
Academic Journal
Accession number :
147295683
Full Text :
https://doi.org/10.1016/j.molmet.2020.101066