Loss of G protein pathway suppressor 2 in human adipocytes triggers lipid remodeling through upregulation of ATP binding cassette subfamily G member 1
Here we demonstrate that the loss of GPS2 triggers the reprogramming of cellular processes related to adipocyte differentiation by increasing the responses to the adipogenic cocktail. Moreover, 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 promoter and enhancers which are occupied by GPS2 in wild-type adipocytes. Finally, we find that in omental adipose tissue of obese humans GPS2 levels correlate with ABCG1 levels, type 2 diabetic status, and lipid metabolic status. Overall design: Transcriptome signature of GPS2-regulated genes between shGFP and shGPS2 during adipognesis was assessed through RNAseq analysis. Epigenomic status of shGFP and shGPS2 preadipocytes and adipocytes was analyzed using histone marker H3K27ac ChIPseq. GPS2 cistrome was analyzed in hMADS cells at day 0 and day 14 of differentiation. Transcriptome signature of non-diabetic and diabetic obese patients was assessed through RNAseq.