title: Folate Protects Hepatocytes of Hyperhomocysteinemia Mice From Apoptosis via Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Activated Endoplasmic Reticulum Stress.
abstract: Folate deficiency is a known risk factor for liver injury; however, the underlying mechanism remains unclear. In this study, we employed a high homocysteine-induced liver injury model of Apolipoprotein E-deficient (ApoE-/-) mice fed high-methionine diet and found that high homocysteine induced endoplasmic reticulum (ER) stress and liver cell apoptosis by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression; observations that were attenuated with supplementation of dietary folate. The regulation on CFTR expression was mediated by CFTR promoter methylation and trimethylation of lysine 27 on histone H3 (H3K27me3). Mechanistically, folate inhibited homocysteine-induced CFTR promoter methylation and H3K27me3, which resulted in upregulation of CFTR expression, and reduced ER stress and liver cell apoptosis. Further study showed that folate inhibited the expression of DNA methyltransferase 1 and enhancer of zeste homolog 2, downregulated the cellular concentrations of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) and upregulated the SAM/SAH ratio, leading to the inhibition of Hcy-induced DNA hypermethylation and H3K27me3 in CFTR promoter. In conclusion, our results provide insight into the protective role of folate in homocysteine-induced ER stress and liver cell apoptosis through the regulation of CFTR expression. J. Cell. Biochem. 118: 2921-2932, 2017. © 2017 Wiley Periodicals, Inc.
  
  
  
  Folate protects hepatocytes of hyperhomocysteinemia mice from apoptosis. Folate alleviates Hcy-induced hepatocyte apoptosis. Folate inhibits Hcy-induced ER stress via upregulation of CFTR expression in hepatocytes. Folate inhibits Hcy-induced methylation of CFTR promotor and H3K27me3.
authors.affiliation: Department of Pathophysiology, West China College of Preclinical and Forensic Medical Sciences, Sichuan University, Chengdu, China.
authors.forename: Anning
authors.initials: A
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
authors.forename: Caiyan
authors.initials: C
authors.lastname: Mao
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
authors.forename: Songhao
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Pathophysiology, West China College of Preclinical and Forensic Medical Sciences, Sichuan University, Chengdu, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Deng
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Ding
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
authors.forename: Minghao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
authors.forename: Shaoju
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
authors.forename: Yideng
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Pathophysiology, West China College of Preclinical and Forensic Medical Sciences, Sichuan University, Chengdu, China.
authors.forename: Ying
authors.identifier: 0000-0002-3517-5527
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D005492:Folic Acid / Q000494:pharmacology*; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005492:Folic Acid
keywords: CFTR; DNA METHYLATION; ENDOPLASMIC RETICULUM STRESS; FOLATE; H3K27ME3; HOMOCYSTEINE