Butyrate enhances CPT1A activity to promote fatty acid oxidation and iTreg differentiation

Abstract

Inducible regulatory T (iTreg) cells play a crucial role in immune suppression and are important for the maintenance of immune homeostasis. Mounting evidence has demonstrated connections between iTreg differentiation and metabolic reprogramming, especially rewiring in fatty acid oxidation (FAO). Previous work showed that butyrate, a specific type of short-chain fatty acid (SCFA) readily produced from fiber-rich diets through microbial fermentation, was critical for the maintenance of intestinal homeostasis and capable of promoting iTreg generation by up-regulating histone acetylation for gene expression as an HDAC inhibitor. Here, we revealed that butyrate could also accelerate FAO to facilitate iTreg differentiation. Moreover, butyrate was converted, by acyl-CoA synthetase short-chain family member 2 (ACSS2), into butyryl-CoA (BCoA), which up-regulated CPT1A activity through antagonizing the association of malonyl-CoA (MCoA), the best known metabolic intermediate inhibiting CPT1A, to promote FAO and thereby iTreg differentiation. Mutation of CPT1A at Arg243, a reported amino acid required for MCoA association, impaired both MCoA and BCoA binding, indicating that Arg243 is probably the responsible site for MCoA and BCoA association. Furthermore, blocking BCoA formation by ACSS2 inhibitor compromised butyrate-mediated iTreg generation and mitigation of mouse colitis. Together, we unveil a previously unappreciated role for butyrate in iTreg differentiation and illustrate butyrate–BCoA–CPT1A axis for the regulation of immune homeostasis.

ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation

“… Raud et al, 2018 found that naive CD4 + T cells isolated from mice with CPT1 deletion in T cells (TCPT1 mice) did not seem to have any defect in iTreg differentiation and proposed that the phenotypes induced by high-dose CPT1 inhibitor, etomoxir (>100 μM), were due to the off-target effect. However, we found that siRNA-mediated Cpt1 knockdown or low-dose etomoxir (5 μM), which inhibits CPT1 without introducing off-target effects, impaired iTreg differentiation in vitro ( Hao et al, 2021 ; O'Connor et al, 2018 ; Figure 2F , Figure 2—figure supplement 5B ). Of note, TCPT1 mice reported in Raud et al, 2018 survived from the lack of CPT1.…”

Fatty acids role in multiple sclerosis as “metabokines”

“…Butyrate and propionate facilitate the extrathymic differentiation of Treg cells by promoting the acetylation of Foxp3 promotor locus and FOXP3 protein, to enhance FOXP3 transcription and protein stability, as well as its TF function [77]. Apart from acting as an HDAC inhibitor, butyrate can be transformed into butyryl-CoA with the help of acyl-CoA synthetase shortchain family member 2 (ACSS2), to antagonize the inhibitory effect of malonyl-CoA on CPT, thus by upregulating CPT1A activity promotes FAO, and facilitates iTreg differentiation [104] (Fig. 2c).…”

Association Between Gut Microbiota and Osteoarthritis: A Review of Evidence for Potential Mechanisms and Therapeutics

“…For example, vitamin B9, the synthesis of which depend on Bifidobacterium and Lactobacillus, is a survival factor for Treg cells ( Kunisawa et al., 2012 ) ( Figure 5 , III ). Butyrate derived from gut microbiota is conducive to shaping the intestinal immune homeostasis by inducing the differentiation of colonic inducible Treg cells ( Furusawa et al., 2013 ) through enhancing fatty acid oxidation dependent on carnitine palmitoyl transferase 1A (CPT1A) ( Hao et al., 2021 ). Butyrate also promotes the generation of Treg cells by upregulating gene expression of histone acetylation ( Arpaia et al., 2015 ) ( Figure 5 , IV ).…”

“…III Vitamin B9 contributed to the survival of Treg cells ( Kunisawa et al., 2012 ). IV Butyrate modulated the generation and differentiation of Treg cells by up regulating histone acetylation ( Arpaia et al., 2015 ) and enhancing fatty acid oxidation dependent on carnitine palmitoyl transferase 1A (CPT1A) ( Hao et al., 2021 ). IFN, interferon.…”