Obesity-induced metabolic imbalance allosterically modulates CtBP2 to inhibit PPAR-alpha transcriptional activity.

The Journal of biological chemistry 2023 Jul

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Maintenance of metabolic homeostasis is secured by metabolite-sensing systems, which can be overwhelmed by constant macronutrient surplus in obesity. Not only the uptake processes but also the consumption of energy substrates determine the cellular metabolic burden. We herein describe a novel transcriptional system in this context comprised of peroxisome proliferator-activated receptor alpha (PPARα), a master regulator for fatty acid oxidation, and C-terminal binding protein 2 (CtBP2), a metabolite-sensing transcriptional corepressor. CtBP2 interacts with PPARα to repress its activity, and the interaction is enhanced upon binding to malonyl-CoA, a metabolic intermediate increased in tissues in obesity and reported to suppress fatty acid oxidation through inhibition of carnitine palmitoyltransferase 1. In line with our preceding observations that CtBP2 adopts a monomeric configuration upon binding to acyl-CoAs, we determined that mutations in CtBP2 that shift the conformational equilibrium toward monomers increase the interaction between CtBP2 and PPARα. In contrast, metabolic manipulations that reduce malonyl-CoA decreased the formation of the CtBP2-PPARα complex. Consistent with these in vitro findings, we found that the CtBP2-PPARα interaction is accelerated in obese livers while genetic deletion of CtBP2 in the liver causes derepression of PPARα target genes. These findings support our model where CtBP2 exists primarily as a monomer in the metabolic milieu of obesity to repress PPARα, representing a liability in metabolic diseases that can be exploited to develop therapeutic approaches. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Kenji Saito, Motohiro Sekiya, Kenta Kainoh, Ryunosuke Yoshino, Akio Hayashi, Song-Iee Han, Masaya Araki, Hiroshi Ohno, Yoshinori Takeuchi, Tomomi Tsuyuzaki, Daichi Yamazaki, Chen Wanpei, Lisa Hada, Sho Watanabe, Putu Indah Paramita Adi Putri, Yuki Murayama, Yoko Sugano, Yoshinori Osaki, Hitoshi Iwasaki, Naoya Yahagi, Hiroaki Suzuki, Takafumi Miyamoto, Takashi Matsuzaka, Hitoshi Shimano. Obesity-induced metabolic imbalance allosterically modulates CtBP2 to inhibit PPAR-alpha transcriptional activity. The Journal of biological chemistry. 2023 Jul;299(7):104890