Nonalcoholic fatty liver disease (NAFLD) is characterized by elevated hepatic lipids caused by nonalcoholic factors, where histone lactylation is lately discovered as a modification driving disease progression. This research aimed to explore the role of histone 3 lysine 18 lactylation (H3K18lac) in NAFLD progression using a high-fat diet (HFD)-treated mouse model and free fatty acids (FFA)-treated L-02 cell lines. Lipids accumulation was screened via Oil Red O staining, real-time quantitative polymerase chain reaction (RT-qPCR), western blotting, and commercially available kits. Similarly, molecular mechanism was analyzed using immunoprecipitation (IP), dual-luciferase reporter assay, and RNA decay assay. Results indicated that FFA upregulated lactate dehydrogenase A (LDHA) and H3K18lac levels in L-02 cells. Besides, LDHA-mediated H3K18lac was enriched on the proximal promoter of methyltransferase 3 (METTL3), translating into an increased expression. Moreover, METTL3 or LDHA knockdown relieved lipid accumulation, decreased total cholesterol (TC) and triglyceride (TG) levels, and downregulated lipogenesis-related proteins in FFA-treated L-02 cell lines, in addition to enhancing the m6A and mRNA levels of stearoyl-coenzyme A desaturase 1 (SCD1). The m6A modification of SCD1 was recognized by YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), resulting in enhanced mRNA stability. LDHA was found to be highly expressed in HFD-treated mice, where knocking down LDHA attenuated HFD-induced hepatic steatosis. These findings demonstrated that LDHA-induced H3K18lac promoted NAFLD progression, where LDHA-induced H3K18lac in METTL3 promoter elevated METTL3 expression, thereby promoting m6A methylation and stabilizing SCD1 via a YTHDF1-dependent manner. Keywords: Nonalcoholic fatty liver disease, LDHA, METTL3, YTHDF1, Histone lactylation.

Shanxi Medical University Yingze District Taiyuan Shanxi China

Zobrazit více v PubMed

Abdelmalek MF. Nonalcoholic fatty liver disease: another leap forward. Nature reviews. Gastroenterol Hepatol. 2021;18:85–86. doi: 10.1038/s41575-020-00406-0. PubMed DOI PMC

Ko E, Yoon EL, Jun DW. Risk factors in nonalcoholic fatty liver disease. Clin Mol Hepatol. 2023;29(Suppl):S79–S85. doi: 10.3350/cmh.2022.0398. PubMed DOI PMC

Makri E, Goulas A, Polyzos SA. Epidemiology, pathogenesis, diagnosis and emerging treatment of nonalcoholic fatty liver disease. Arch Med Res. 2021;52:25–37. doi: 10.1016/j.arcmed.2020.11.010. PubMed DOI

Singh S, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol. 2017;23:6549–6570. doi: 10.3748/wjg.v23.i36.6549. PubMed DOI PMC

Zhang Y, Sun Z, Jia J, Du T, Zhang N, Tang Y, Fang Y, Fang D. Overview of histone modification. 2020;1283:1–16. doi: 10.1007/978-981-15-8104-5_1. First Online: 07 November 2020. PubMed DOI

Andrés M, García-Gomis D, Ponte I, Suau P, Roque A. Histone H1 post-translational modifications: update and future perspectives. International J Mol Sci. 2020;21:5941. doi: 10.3390/ijms21165941. PubMed DOI PMC

Tolsma TO, Hansen JC, Gilbert N, Allan J. Post-translational modifications and chromatin dynamics. Essays Biochem. 2019;63:89–96. doi: 10.1042/EBC20180067. PubMed DOI

Hamam HJ, Palaniyar N. Post-Translational Modifications in NETosis and NETs-Mediated Diseases. Biomolecules. 2019:9. doi: 10.3390/biom9080369. PubMed DOI PMC

Singh G, Singh V, Schneider JS. Post-translational histone modifications and their interaction with sex influence normal brain development and elaboration of neuropsychiatric disorders. Biochim Biophys Acta Mol Basis Dis. 2019;1865:1968–1981. doi: 10.1016/j.bbadis.2018.10.016. PubMed DOI

Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, Liu W, Kim S, Lee S, Perez-Neut M, Ding J, Czyz D, Hu R, Ye Z, He M, Zheng YG, Shuman HA, Dai L, Ren B, Roeder RG, Becker L, Zhao Y. Metabolic regulation of gene expression by histone lactylation. Nature (London) 2019;574(7779):575–580. doi: 10.1038/s41586-019-1678-1. PubMed DOI PMC

Schvartzman JM, Thompson CB, Finley LWS. Metabolic regulation of chromatin modifications and gene expression. J Cell Biol. 2018;217:2247–2259. doi: 10.1083/jcb.201803061. PubMed DOI PMC

Trefely S, Doan MT, Snyder NW. Crosstalk between cellular metabolism and histone acetylation. Methods Enzymol. 2019;626:1–21. doi: 10.1016/bs.mie.2019.07.013. PubMed DOI

Bhagat TD, Von Ahrens D, Dawlaty M, Zou Y, Baddour J, Achreja A, Zhao H, Yang L, Patel B, Kwak C, Choudhary GS, Gordon-Mitchell S, Aluri S, Bhattacharyya S, Sahu S, Bhagat P, Yu Y, Bartenstein M, Giricz O, Suzuki M, Sohal D, Gupta S, Guerrero PA, Batra S, Goggins M, Steidl U, Greally J, Agarwal B, Pradhan K, Banerjee D, Nagrath D, Maitra A, Verma A. Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts. Elife. 2019:8. doi: 10.7554/eLife.50663. PubMed DOI PMC

Yu J, Chai P, Xie M, Ge S, Ruan J, Fan X, Jia R. Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. Genome Biol. 2021;22:85. doi: 10.1186/s13059-021-02308-z. PubMed DOI PMC

Wang T, Chen K, Yao W, Zheng R, He Q, Xia J, Li J, Shao Y, Zhang L, Huang L, Qin L, Xu M, Zhang Z, Pan D, Li Z, Huang F. Acetylation of lactate dehydrogenase B drives NAFLD progression by impairing lactate clearance. J Hepatol. 2021;74:1038–1052. doi: 10.1016/j.jhep.2020.11.028. PubMed DOI

Chen Y, Hong T, Wang S, Mo J, Tian T, Zhou X. Epigenetic modification of nucleic acids: from basic studies to medical applications. Chem Soc Rev. 2017;46:2844–2872. doi: 10.1039/C6CS00599C. PubMed DOI

Zhao LY, Song J, Liu Y, Song CX, Yi C. Mapping the epigenetic modifications of DNA and RNA. Protein Cell. 2020;11:792–808. doi: 10.1007/s13238-020-00733-7. PubMed DOI PMC

Zhong H, Tang HF, Kai Y. N6-methyladenine RNA Modification (m(6)A): An Emerging Regulator of Metabolic Diseases. Curr Drug Targets. 2020;21:1056–1067. doi: 10.2174/1389450121666200210125247. PubMed DOI

Huang W, Chen T, Fang K, Zeng Z, Ye H, Chen Y. N6-methyladenosine methyltransferases: functions, regulation, and clinical potential. J Hematol Oncol. 2021;14:1–117. doi: 10.1186/s13045-021-01129-8. PubMed DOI PMC

Yang J, Chen J, Fei X, Wang X, Wang K. N6-methyladenine RNA modification and cancer. Oncol Lett. 2020;20:1504–1512. doi: 10.3892/ol.2020.11739. PubMed DOI PMC

Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, Liu W, Kim S, Lee S, Perez-Neut M, Ding J, Czyz D, Hu R, Ye Z, He M, Zheng YG, Shuman HA, Dai L, Ren B, Roeder RG, Becker L, Zhao Y. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574(7779):575–580. doi: 10.1038/s41586-019-1678-1. PubMed DOI PMC

Xiong J, He J, Zhu J, Pan J, Liao W, Ye H, Wang H, Song Y, Du Y, Cui B, Xue M, Zheng W, Kong X, Jiang K, Ding K, Lai L, Wang Q. Lactylation-driven METTL3-mediated RNA m(6)A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol Cell. 2022;82:1660–1677. doi: 10.1016/j.molcel.2022.02.033. PubMed DOI

Read JA, Winter VJ, Eszes CM, Sessions RB, Brady RL. Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase. Proteins, structure, function, and bioinformatics. 2001;43:175–185. doi: 10.1002/1097-0134(20010501)43:2<175::AID-PROT1029>3.0.CO;2-#. PubMed DOI

Feng Y, Xiong Y, Qiao T, Li X, Jia L, Han Y. Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy. Cancer Med, 2018;7(12):6124–6136. doi: 10.1002/cam4.1820. PubMed DOI PMC

Jafary F, Ganjalikhany MR, Moradi A, Hemati M, Jafari S. Novel peptide inhibitors for lactate dehydrogenase A (LDHA): A survey to inhibit LDHA activity via disruption of protein-protein interaction. Sci Rep. 2019;9:4686. doi: 10.1038/s41598-019-38854-7. PubMed DOI PMC

Liu Y, Guo JZ, Liu Y, Wang K, Ding W, Wang H, Liu X, Zhou S, Lu XC, Yang HB, Xu C, Gao W, Zhou L, Wang YP, Hu W, Wei Y, Huang C, Lei QY. Nuclear lactate dehydrogenase A senses ROS to produce alpha-hydroxybutyrate for HPV-induced cervical tumor growth. Nat Commun. 2018;9:4429. doi: 10.1038/s41467-018-06841-7. PubMed DOI PMC

Sheppard S, Santosa EK, Lau CM, Violante S, Giovanelli P, Kim H, Cross JR, Li MO, Sun JC. Lactate dehydrogenase A-dependent aerobic glycolysis promotes natural killer cell anti-viral and anti-tumor function. Cell Rep. 2021;35:109210. doi: 10.1016/j.celrep.2021.109210. PubMed DOI PMC

Sun L, Li J, Yan W, Yao Z, Wang R, Zhou X, Wu H, Zhang G, Shi T, Chen W. H19 promotes aerobic glycolysis, proliferation, and immune escape of gastric cancer cells through the microRNA-519d-3p/lactate dehydrogenase A axis. Cancer Sci. 2021;112:2245–2259. doi: 10.1111/cas.14896. PubMed DOI PMC

Nian F, Qian Y, Xu F, Yang M, Wang H, Zhang Z. LDHA promotes osteoblast differentiation through histone lactylation. Biochem Biophys Res Commun, 2022;615:31–35. doi: 10.1016/j.bbrc.2022.05.028. PubMed DOI

Yang W, Wang P, Cao P, Wang S, Yang Y, Su H, Nashun B. Hypoxic in vitro culture reduces histone lactylation and impairs pre-implantation embryonic development in mice. Epigenetics Chromatin, 2021;14:57. doi: 10.1186/s13072-021-00431-6. PubMed DOI PMC

Mezhibovsky E, Knowles KA, He Q, Sui K, Tveter KM, Duran RM, Roopchand DE. Grape polyphenols attenuate diet-induced obesity and hepatic steatosis in mice in association with reduced butyrate and increased markers of intestinal carbohydrate oxidation. Front Nutr. 2021;8:675267. doi: 10.3389/fnut.2021.675267. PubMed DOI PMC

Gao R, Li Y, Xu Z, Zhang F, Xu J, Hu Y, Yin J, Yang K, Sun L, Wang Q, He X, Huang K. Mitochondrial pyruvate carrier 1 regulates fatty acid synthase lactylation and mediates treatment of nonalcoholic fatty liver disease. Hepatology. 2023;78:1800–1815. doi: 10.1097/HEP.0000000000000279. PubMed DOI

Yu J, Chai P, Xie M, Ge S, Ruan J, Fan X, Jia R. Histone lactylation drives oncogenesis by facilitating m 6 A reader protein YTHDF2 expression in ocular melanoma. Genome Biol. 2021;22:85. doi: 10.1186/s13059-021-02308-z. PubMed DOI PMC

Yang Y, Cai J, Yang X, Wang K, Sun K, Yang Z, Zhang L, Yang L, Gu C, Huang X, Wang Z, Zhu X. Dysregulated m6A modification promotes lipogenesis and development of non-alcoholic fatty liver disease and hepatocellular carcinoma. Mol Ther. 2022;30:2342–2353. doi: 10.1016/j.ymthe.2022.02.021. PubMed DOI PMC

Peng Z, Gong Y, Wang X, He W, Wu L, Zhang L, Xiong L, Huang Y, Su L, Shi P, Cao X, Liu R, Li Y, Xiao H. METTL3-m(6)A-Rubicon axis inhibits autophagy in nonalcoholic fatty liver disease. Mol Ther. 2022;30:932–946. doi: 10.1016/j.ymthe.2021.09.016. PubMed DOI PMC

Piccinin E, Cariello M, De Santis S, Ducheix S, Sabbà C, Ntambi JM, Moschetta A. Role of oleic acid in the gut-liver axis: from diet to the regulation of its synthesis via stearoyl-coa desaturase 1 (SCD1) Nutrients. 2019;11:2283. doi: 10.3390/nu11102283. PubMed DOI PMC

Mauvoisin D, Mounier C. Hormonal and nutritional regulation of SCD1 gene expression. Biochimie. 2011;93:78–86. doi: 10.1016/j.biochi.2010.08.001. PubMed DOI

Stoffel W, Schmidt-Soltau I, Jenke B, Binczek E, Hammels I. Hair growth cycle is arrested in SCD1 deficiency by impaired wnt3a-palmitoleoylation and retrieved by the artificial lipid barrier. J Invest Dermatol. 2017;137:1424–1433. doi: 10.1016/j.jid.2017.02.973. PubMed DOI

Shi H, Wei J, He C. Where, When, and How: Context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell. 2019;74:640–650. doi: 10.1016/j.molcel.2019.04.025. PubMed DOI PMC

Liu T, Wei Q, Jin J, Luo Q, Liu Y, Yang Y, Cheng C, Li L, Pi J, Si Y, Xiao H, Li L, Rao S, Wang F, Yu J, Yu J, Zou D, Yi P. The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res. 2020;48:3816–3831. doi: 10.1093/nar/gkaa048. PubMed DOI PMC

Anita R, Paramasivam A, Priyadharsini JV, Chitra S. The m6A readers YTHDF1 and YTHDF3 aberrations associated with metastasis and predict poor prognosis in breast cancer patients. Am J Cancer Res. 2020;10:2546–2554. PubMed PMC

Lin Z, Niu Y, Wan A, Chen D, Liang H, Chen X, Sun L, Zhan S, Chen L, Cheng C, Zhang X, Bu X, He W, Wan G. RNA m(6) A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy. EMBO J. 2020;39:e103181. doi: 10.15252/embj.2019103181. PubMed DOI PMC