PMID- 35347798 OWN - NLM STAT- MEDLINE DCOM- 20220725 LR - 20221015 IS - 1095-8355 (Electronic) IS - 1065-6995 (Print) IS - 1065-6995 (Linking) VI - 46 IP - 8 DP - 2022 Aug TI - Homocysteine facilitates endoplasmic reticulum stress and apoptosis of hepatocytes by suppressing ERO1alpha expression via cooperation between DNMT1 and G9a. PG - 1236-1248 LID - 10.1002/cbin.11805 [doi] AB - Endoplasmic reticulum (ER) stress and apoptosis play a critical role in liver injury. Endoplasmic reticulum oxidoreductase 1alpha (ERO1alpha) is an oxidase that exists in the luminal side of the ER membrane, participating in protein folding and secretion and inhibiting apoptosis, but the underlying mechanism on liver injury induced by homocysteine (Hcy) remains obscure. In this study, hyperhomocysteinemia (HHcy) mice model was established in cbs(+/-) mice by feeding a high-methionine diet for 12 weeks; and cbs(+/-) mice fed with high-methionine diet exhibited more severe liver injury compared to cbs(+/+) mice. Mechanistically, we found that Hcy promoted ER stress and apoptosis of hepatocytes and thereby aggravated liver injury through inhibiting ERO1alpha expression; accordingly, overexpression of ERO1alpha remarkably alleviated ER stress and apoptosis of hepatocytes induced by Hcy. Epigenetic modification analysis revealed that Hcy significantly increased levels of DNA methylation and H3 lysine 9 dimethylation (H3K9me2) on ERO1alpha promoter, which attributed to upregulated DNA methyltransferase 1 (DNMT1) and G9a, respectively. Further study showed that DNMT1 and G9a cooperatively regulated ERO1alpha expression in hepatocytes exposed to Hcy. Taken together, our work demonstrates that Hcy activates ER stress and apoptosis of hepatocytes by downregulating ERO1alpha expression via cooperation between DNMT1 and G9a, which provides new insight into the mechanism of Hcy-induced ER stress and apoptosis of hepatocytes in liver injury. CI - (c) 2022 The Authors. Cell Biology International published by John Wiley & Sons Ltd on behalf of International Federation of Cell Biology. FAU - Shen, Jiangyong AU - Shen J AD - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China. AD - Department of Clinical Medicine, General Hospital of Ningxia Medical University, Yinchuan, China. FAU - Jiao, Yun AU - Jiao Y AD - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China. AD - Department of Infectious Diseases, General Hospital of Ningxia Medical University, Yinchuan, China. FAU - Ding, Ning AU - Ding N AD - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China. FAU - Xie, Lin AU - Xie L AD - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China. FAU - Ma, Shengchao AU - Ma S AD - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China. FAU - Zhang, Hui AU - Zhang H AD - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China. FAU - Yang, Anning AU - Yang A AD - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China. FAU - Zhang, Huiping AU - Zhang H AD - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China. AD - Department of Prenatal Diagnosis Center, General Hospital of Ningxia Medical University, Yinchuan, China. FAU - Jiang, Yideng AU - Jiang Y AUID- ORCID: 0000-0002-4882-5197 AD - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China. LA - eng GR - 2018BEG02004/Key Research and Development Projects in Ningxia Province/ GR - 2019BFG02004/Key Research and Development Projects in Ningxia Province/ GR - 2020BEG03005/Key Research and Development Projects in Ningxia Province/ GR - 2020BFH02003/Key Research and Development Projects in Ningxia Province/ GR - 81870225/National Natural Science Foundation of China/ GR - 81760139/National Natural Science Foundation of China/ GR - 81860555/National Natural Science Foundation of China/ GR - 81870332/National Natural Science Foundation of China/ GR - 82060110/National Natural Science Foundation of China/ GR - 2020AAC02021/Natural Science Foundation of Ningxia Province/ GR - 2020AAC02038/Natural Science Foundation of Ningxia Province/ GR - 2021AAC03337/Natural Science Foundation of Ningxia Province/ PT - Journal Article DEP - 20220414 PL - England TA - Cell Biol Int JT - Cell biology international JID - 9307129 RN - 0LVT1QZ0BA (Homocysteine) RN - AE28F7PNPL (Methionine) RN - EC 1.- (Oxidoreductases) RN - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase 1) RN - EC 2.1.1.37 (Dnmt1 protein, mouse) RN - EC 2.1.1.43 (G9a protein, mouse) RN - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) SB - IM MH - Animals MH - *Apoptosis/genetics/physiology MH - *DNA (Cytosine-5-)-Methyltransferase 1/genetics MH - *Endoplasmic Reticulum Stress/genetics MH - *Hepatocytes/metabolism MH - *Histone-Lysine N-Methyltransferase/genetics MH - *Homocysteine/genetics/metabolism MH - Methionine/metabolism MH - Mice MH - Oxidoreductases/genetics PMC - PMC9543485 OTO - NOTNLM OT - DNMT1 OT - ERO1alpha OT - G9a OT - apoptosis OT - endoplasmic reticulum stress OT - homocysteine COIS- The authors declare no conflicts of interest. EDAT- 2022/03/30 06:00 MHDA- 2022/07/26 06:00 PMCR- 2022/10/07 CRDT- 2022/03/29 05:50 PHST- 2022/03/16 00:00 [revised] PHST- 2021/11/04 00:00 [received] PHST- 2022/03/27 00:00 [accepted] PHST- 2022/03/30 06:00 [pubmed] PHST- 2022/07/26 06:00 [medline] PHST- 2022/03/29 05:50 [entrez] PHST- 2022/10/07 00:00 [pmc-release] AID - CBIN11805 [pii] AID - 10.1002/cbin.11805 [doi] PST - ppublish SO - Cell Biol Int. 2022 Aug;46(8):1236-1248. doi: 10.1002/cbin.11805. Epub 2022 Apr 14.