Fatty-acyl-CoA thioesters inhibit recruitment of steroid receptor co-activator 1 to α and γ isoforms of peroxisome-proliferator-activated receptors by competing with agonists

Abstract

Peroxisome-proliferator-activated receptors (PPARs) alpha and gamma are ligand-dependent transcription factors that are key regulators of lipid and carbohydrate homoeostasis. Fatty acids bind to the ligand-binding domains (LBDs) of PPARalpha and PPARgamma and activate these receptors. To clarify whether fatty-acyl-CoAs interact directly with the LBDs of PPARalpha and PPARgamma, we performed a competition binding assay with radiolabelled KRP-297, a known dual agonist for these receptors. We show here that fatty-acyl-CoAs bind directly to PPARalpha and PPARgamma. Interestingly, fatty-acyl-CoAs, unlike fatty acids, failed to recruit steroid receptor co-activator 1 (SRC-1), on the basis of conformational changes in the LBDs of PPARalpha and PPARgamma. Moreover, fatty-acyl-CoAs also markedly inhibited agonist-induced recruitment of SRC-1. These findings demonstrate that fatty-acyl-CoAs have a novel function in the signalling pathways of PPARalpha and PPARgamma.

Opposing Effects of Fatty Acids and Acyl‐CoA Esters on Conformation and Cofactor Recruitment of Peroxisome Proliferator‐Activated Receptors

“…This ligand also decreased the sensitivity of PPARγ to chymotrypsin; in contrast, though, to the other PPARγ ligands, GW9662 only enhanced protection of the 32‐kDa fragment. In conclusion, addition of S ‐hexadecyl‐CoA did not alter the sensitivity of PPARγ to chymotrypsin and, thus, if S ‐hexadecyl‐CoA does bind to PPARγ, as would be expected from competition experiments using normal acyl‐CoA esters,15 the effect of binding on conformation is distinct from that observed for PPARα and PPARδ.…”

“…It was initially observed that overexpression of an acyl‐CoA synthetase blunted fatty acid‐induced PPARα activation and it was suggested that this simply reflected the reduced abundance of the activating free fatty acids 13. However, recently, we and others presented evidence that acyl‐CoA esters directly bind to PPARα and PPARγ and affect DNA binding, conformation, and cofactor recruitment in a manner suggesting that acyl‐CoA esters may, in fact, function as PPAR antagonists 14,15. Thus, we showed that a nonhydrolyzable acyl‐CoA analogue, S ‐hexadecyl‐CoA, prevented agonist‐induced recruitment of SRC‐1 to PPARα, but enhanced interaction with the corepressor NCoR 14.…”

Steroid receptor coactivators: servants and masters for control of systems metabolism

“…The counterbalance of SRC regulation may be a consequence of SRC-1 and SRC-2 both competing for binding to peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1αa regulator of mitochondrial biogenesis and function, and PPARγ, a NR that controls adipogenesis and regulates fatty acid storage and glucose metabolism. Fatty acids serve as ligands for the PPARs and stimulate complex formation with SRC-1; however, fatty-acyl-CoAs inhibit recruitment of SRC-1 to the ligand binding domain (LBD) of PPARγ and its activation, thus possibly shutting down lipolysis and adipogenic programs in adipose cells [14]. In the BAT of mice on a HFD, SRC-2 decreases the stability of the PGC1α/PPARγ complex thereby reducing adaptive thermogenesis while increasing energy storage and adiposity.…”

Peroxisome proliferator‐activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle

“…Recent studies (Elholm et al. 2001, Murakami et al. 2001) indicate that long‐chain acyl‐CoA esters also interact with PPAR α .…”