G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide‐induced ATP‐binding cassette transporter A1 expression in macrophages

Abstract

Macrophages play important roles in linking alterations of cholesterol metabolism and inflammation to the development of atherosclerosis. Previous studies have identified several positive and negative crosstalk mechanisms that connect cholesterol efflux and inflammation at the transcriptional level. Of particular relevance is that the expression of ATP‐binding cassette transporter A1 (Abca1), a main regulator of cholesterol efflux, can be induced by oxysterol receptor LXR agonists but also by bacterial endotoxins, such as LPS, that activate TLR4 signaling. However, the extent to which these pathways influence each other has remained incompletely understood. We investigated the possible role of the transcriptional coregulator G protein pathway suppressor 2 (GPS2) in LPS‐induced Abca1 expression and cholesterol efflux in mouse and human macrophages. To activate Abca1, GPS2 cooperates with the LPS‐inducible NF‐κB subunit p65, but not with LXRs nor with corepressor complex subunits that otherwise cooperate with GPS2 to repress proinflammatory gene expression. Overall, our work identifies a regulatory chromatin component of crosstalk mechanisms between cholesterol efflux and inflammation that specifically affects ABCA1. Because GPS2 expression is down‐regulated in some humans with obese and type 2 diabetes, the macrophage GPS‐2/ABC‐A1 pathway could be altered and contribute to atherogenesis.—Huang, Z., Liang, N., Damdimopoulos, A., Fan, R., Treuter, E. G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide‐induced ATP‐binding cassette transporter A1 expression in macrophages. FASEB J. 33, 1631–1643 (2019). http://www.fasebj.org

The impact of ATP-binding cassette transporters on metabolic diseases

“…ABCA1 also plays an important role in responding to abnormal cholesterol metabolism-related conditions, such as inflammation. Cholesterol efflux is relevant to inflammation at the transcription level [ 40 ]. ABCA1 has been reported to exert anti-inflammatory effects by inhibiting the production of some inflammatory cytokines in macrophages [ 13 ].…”

“…ABCA1 transcription can be regulated by obligate heterodimers of liver X receptors (LXRs) and retinoid X receptors (RXRs), bacterial endotoxins such as LPS and peroxisome proliferator-activated receptors (PPARs) [ 40 , 44 , 45 ]. LXR is a transcription factor for ABCA1 [ 46 ].…”

“…Unsaturated fatty acids can suppress ABCA1 expression post transcriptionally via LXR and can facilitate ABCA1 degradation. LPS activates ABCA1 by inducing the cooperation of NF-κB subunit p65 and the transcriptional coregulator G protein pathway suppressor 2 (GPS2) [ 40 ]. In addition, endocytosis is able to regulate ABCA1 expression, which is mediated by the ADP-ribosylation factor 6 (ARF6)-dependent pathway [ 34 ].…”

“…In addition, these mice without adipocyte-specific ABCA1 also showed decreased levels of the most active form of adiponectin and high-molecular-weight adiponectin [ 38 ]. Furthermore, GPS2 has been found to be downregulated in obese and T2DM subjects, providing additional evidence for the repression of ABCA1 in obesity and T2DM [ 40 ]. There are two single nucleotide polymorphisms (SNPs) of the ABCA1 gene, R219K and I883M, that have been found to have a close relationship with susceptibility to obesity.…”

“…The macrophage-mediated cholesterol uptake and metabolism is associated with the initiation and progression of AS in focal areas of the arterial subendothelial space [ 40 ]. The formation of lipid-laden macrophages, also known as foam cells, is the initial step of AS.…”