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Research Paper|Volume 11, Issue 4|pp 1283—1304

Anti-inflammatory action of β-hydroxybutyrate via modulation of PGC-1α and FoxO1, mimicking calorie restriction

Dae Hyun Kim1, Min Hi Park1,3, Sugyeong Ha1, Eun Jin Bang1, Yujeong Lee1, A Kyoung Lee1, Jaewon Lee1, Byung Pal Yu2, Hae Young Chung1
  • 1Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Korea
  • 2Department of Physiology, The University of Texas Health Science Center at San Antonio, TX, 78229, USA
  • 3Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX, 77843, USA
Received: November 11, 2018Accepted: February 17, 2019Published: February 27, 2019
https://doi.org/10.18632/aging.101838

Copyright: © 2019 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

β-Hydroxybutyrate (HB) is a ketone body used as an energy source that has shown anti-inflammatory effects similar to calorie restriction (CR); Here, PGC-1α, an abundantly expressed co-factor in the kidney, was reported to interact with both FoxO1 and NF-κB although the definitive interactive mechanism has not yet been reported. In this study, we investigated whether renal aging-related inflammation is modulated by HB. We compared aged rats administered with HB to calorie restricted rats and examined the modulation of FoxO1 and the NF-κB pathway through interactions with PGC-1α. We found that in aged rats treated with HB, pro-inflammatory signaling changes were reversed and showed effects comparable to CR. As FoxO1 and its target genes catalase/MnSOD were upregulated by HB treatment and PGC-1α selectively interacted with FoxO1, not with NF-κB, and ameliorated the renal inflammatory response. These findings were further confirmed using FoxO1 overexpression and siRNA transfection in vitro. Our findings suggest that HB suppressed aging-related inflammation as a CR mimetic by enabling the co-activation and selective interaction between FoxO1 and PGC-1α. This study demonstrates the potential therapeutic role of HB as a CR mimetic, which ameliorates inflammation by a novel mechanism where FoxO1 outcompetes NF-κB by interacting with PGC-1α in aging kidneys.