The mitochondrial thiolase ACAT1 regulates monocyte/macrophage type I interferon via epigenetic control.
| العنوان: | The mitochondrial thiolase ACAT1 regulates monocyte/macrophage type I interferon via epigenetic control. |
|---|---|
| المؤلفون: | Wu J; Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Singh K; Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Shing V; Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Gupta AK; Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Huffstutler RD; Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Lee DY; Biochemistry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Sack MN; Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.; Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 31. Date of Electronic Publication: 2024 Jan 31. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Lipid-derived acetyl-CoA is shown to be the major carbon source for histone acetylation. However, there is no direct evidence demonstrating lipid metabolic pathway contribututions to this process. Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) catalyzes the final step of ß-oxidation, the aerobic process catabolizing fatty acids (FA) into acetyl-CoA. To investigate this in the context of immunometabolism, we generated macrophage cell line lacking ACAT1. 13 C-carbon tracing combined with mass spectrometry confirmed incorporation of FA-derived carbons into histone H3 and this incorporation was reduced in ACAT1 KO macrophage cells. RNA-seq identified a subset of genes downregulated in ACAT1 KO cells including STAT1/2 and interferon stimulated genes (ISGs). CHIP analysis demonstrated reduced acetyl-H3 binding to STAT1 promoter/enhancer regions. Increasing histone acetylation rescued STAT1/2 expression in ACAT1 KO cells. Concomitantly, ligand triggered IFNβ release was blunted in ACAT1 KO cells and rescued by reconstitution of ACAT1. Furthermore, ACAT1 promotes FA-mediated histone acetylation in an acetylcarnitine shuttle-dependent manner. In patients with obesity, levels of ACAT1 and histone acetylation are abnormally elevated. Thus, our study identified a novel link between ACAT1 mediated FA metabolism and epigenetic modification on STAT1/2 that uncovers a regulatory role of lipid metabolism in innate immune signaling and opens novel avenues for interventions in human diseases such as obesity. |
| References: | J Immunol. 2024 Jan 1;212(1):7-11. (PMID: 38038390) Semin Immunol. 2005 Feb;17(1):87-94. (PMID: 15582491) Nat Med. 2015 Mar;21(3):263-9. (PMID: 25686106) Science. 2009 May 22;324(5930):1076-80. (PMID: 19461003) Nat Commun. 2020 Jun 2;11(1):2745. (PMID: 32488081) Nat Methods. 2018 Dec;15(12):1067-1073. (PMID: 30478323) Cell Rep. 2016 Nov 1;17(6):1463-1472. (PMID: 27806287) Curr Opin Cell Biol. 2015 Apr;33:125-31. (PMID: 25703630) Mol Cell. 2014 Feb 20;53(4):534-48. (PMID: 24486017) Cell Rep. 2024 Feb 27;43(2):113700. (PMID: 38265935) iScience. 2023 Apr 06;26(5):106578. (PMID: 37128607) Cell Rep. 2023 Jul 25;42(7):112708. (PMID: 37392388) J Clin Invest. 2022 Jan 18;132(2):. (PMID: 35040439) Nature. 2013 Apr 11;496(7444):238-42. (PMID: 23535595) Immunol Rev. 2020 May;295(1):5-14. (PMID: 32320073) Mol Pharmacol. 2014 Jan;85(1):187-97. (PMID: 24170779) J Biol Chem. 2023 Mar;299(3):103005. (PMID: 36775129) Nutrients. 2021 Apr 28;13(5):. (PMID: 33924911) J Clin Invest. 2015 Nov 03;125(12):4592-600. (PMID: 26529255) Immunity. 2021 Jan 12;54(1):19-31. (PMID: 33220233) PLoS Biol. 2020 Nov 30;18(11):e3000981. (PMID: 33253182) Sci Adv. 2023 May 3;9(18):eadf0115. (PMID: 37134161) J Biol Chem. 2001 May 18;276(20):16683-9. (PMID: 11278967) Diabetes Metab Rev. 1989 May;5(3):247-70. (PMID: 2656155) J Leukoc Biol. 2024 Jan 11;:. (PMID: 38207130) J Immunol. 2011 Mar 15;186(6):3299-303. (PMID: 21317389) Nat Rev Immunol. 2016 Sep;16(9):553-65. (PMID: 27396447) Hum Mutat. 2019 Oct;40(10):1641-1663. (PMID: 31268215) Front Immunol. 2014 Oct 27;5:538. (PMID: 25386181) Nature. 2009 Jul 2;460(7251):103-7. (PMID: 19494812) Cell Rep Med. 2023 Sep 19;4(9):101157. (PMID: 37586364) J Biol Chem. 2017 Jul 21;292(29):12153-12164. (PMID: 28584055) Life Sci. 2019 Sep 1;232:116592. (PMID: 31228515) J Clin Invest. 2018 Aug 31;128(9):3651-3661. (PMID: 30059015) Immunity. 2019 Dec 17;51(6):997-1011.e7. (PMID: 31851905) J Clin Invest. 2022 Mar 1;132(5):. (PMID: 35025762) Biomolecules. 2021 Dec 14;11(12):. (PMID: 34944517) Cell Mol Immunol. 2020 Aug;17(8):822-833. (PMID: 32601305) Nat Protoc. 2013 Nov;8(11):2281-2308. (PMID: 24157548) Nat Immunol. 2016 Mar;17(3):277-85. (PMID: 26808230) Nature. 2023 Mar;615(7952):490-498. (PMID: 36890227) EMBO Mol Med. 2021 Aug 9;13(8):e14323. (PMID: 34151532) Annu Rev Immunol. 2020 Apr 26;38:289-313. (PMID: 31986069) Cell. 2016 Oct 6;167(2):457-470.e13. (PMID: 27667687) |
| معلومات مُعتمدة: | ZIA HL005199 United States ImNIH Intramural NIH HHS |
| تواريخ الأحداث: | Date Created: 20240227 Latest Revision: 20240304 |
| رمز التحديث: | 20240304 |
| مُعرف محوري في PubMed: | PMC10896343 |
| DOI: | 10.1101/2024.01.29.577773 |
| PMID: | 38410425 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2024.01.29.577773 |
|---|