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

ABSTRACT: ?-Hydroxybutyrate (HB) is a ketone body used as an energy source that has shown anti-inflammatory effects similar to calorie restriction (CR); Here, PGC-1?, an abundantly expressed co-factor in the kidney, was reported to interact with both FoxO1 and NF-?B 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-?B pathway through interactions with PGC-1?. 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-1? selectively interacted with FoxO1, not with NF-?B, 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-1?. This study demonstrates the potential therapeutic role of HB as a CR mimetic, which ameliorates inflammation by a novel mechanism where FoxO1 outcompetes NF-?B by interacting with PGC-1? in aging kidneys.

SUBMITTER: Kim DH

PROVIDER: S-EPMC6402511 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Kim Dae Hyun DH Park Min Hi MH Ha Sugyeong S Bang Eun Jin EJ Lee Yujeong Y Lee A Kyoung AK Lee Jaewon J Yu Byung Pal BP Chung Hae Young HY

Aging 20190201 4

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 exam ...[more]

PMID: 30811347

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Project description:Butyrate and R-?-hydroxybutyrate are two related short chain fatty acids naturally found in mammals. Butyrate, produced by enteric butyric bacteria, is present at millimolar concentrations in the gastrointestinal tract and at lower levels in blood; R-?-hydroxybutyrate, the main ketone body, produced by the liver during fasting can reach millimolar concentrations in the circulation. Both molecules have been shown to be histone deacetylase (HDAC) inhibitors, and their administration has been associated to an improved metabolic profile and better cellular oxidative status, with butyrate inducing PGC1? and fatty acid oxidation and R-?-hydroxybutyrate upregulating oxidative stress resistance factors FOXO3A and MT2 in mouse kidney. Because of the chemical and functional similarity between the two molecules, we compared here their impact on multiple cell types, evaluating i) histone acetylation and hydroxybutyrylation levels by immunoblotting, ii) transcriptional regulation of metabolic and inflammatory genes by quantitative PCR and iii) cytokine secretion profiles using proteome profiling array analysis. We confirm that butyrate is a strong HDAC inhibitor, a characteristic we could not identify in R-?-hydroxybutyrate in vivo nor in vitro. Butyrate had an extensive impact on gene transcription in rat myotubes, upregulating PGC1?, CPT1b, mitochondrial sirtuins (SIRT3-5), and the mitochondrial anti-oxidative genes SOD2 and catalase. In endothelial cells, butyrate suppressed gene expression and LPS-induced secretion of several pro-inflammatory genes, while R-?-hydroxybutyrate acted as a slightly pro-inflammatory molecule. Our observations indicate that butyrate induces transcriptional changes to a higher extent than R-?-hydroxybutyrate in rat myotubes and endothelial cells, in keep with its HDAC inhibitory activity. Also, in contrast with previous reports, R-?-hydroxybutyrate, while inducing histone ?-hydroxybutyrylation, did not display a readily detectable HDAC inhibitor activity and exerted a slight pro-inflammatory action on endothelial cells.

Dataset Information

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

Publications

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

Similar Datasets

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