Antagonizing EZH2 combined with vitamin D3 exerts a synergistic role in anti-fibrosis through bidirectional effects on hepatocytes and hepatic stellate cells
Background and AimWhether vitamin D3 (VD3) supplementation is associated with improved liver fibrosis is controversial. MethodsLiver fibrosis models were treated with VD3, active VD (1,25-OH2 Vitamin D3), or collaboration with GSK126 (Ezh2 inhibitor), respectively. Hepatic stellate cells (HSCs) were co-cultured with hepatocytes and then stimulated with TGF-beta. Autophagy of hepatocytes was determined after the intervention of 1,25-OH2 Vitamin D3 and GSK126. Also, the active status of HSCs and the mechanism with 1,25-OH2 Vitamin D3 and GSK126 intervention were detected. Results1,25-OH2 Vitamin D3, but not VD3, is involved in anti-fibrosis and partially improves liver function, which might be associated with related enzymes and receptors (especially CYP2R1), leading to decreased of its biotransformation. GSK126 plays a synergistic role in anti-fibrosis. The co-culture system showed increased hepatocyte autophagy after HSCs activation. Supplementation with 1,25-OH2 Vitamin D3 or combined GSK126 reduced these effects. Further studies showed that 1,25-OH2 Vitamin D3 promoted H3K27 methylation of DKK1 promoter through VDR/Ezh2 due to the weakening for HSCs inhibitory signal. ConclusionsVD3 bioactive form 1,25-OH2 Vitamin D3 is responsible for the anti-fibrosis, which might have bidirectional effects on HSCs by regulating histone modification. The inhibitor of Ezh2 plays a synergistic role in this process.
基金：
National Natural Science Foundation of China [81672083, 82070730]; Suzhou Health Youth Backbone Talent of National Mentor System [Qngg2021043]
第一作者机构：[1]Shanghai Jiao Tong Univ, Shanghai Tongren Hosp, Dept Clin Lab, Sch Med, Shanghai 200336, Peoples R China[3]Jiangsu Univ, Kunshan Peoples Hosp 1, Dept Clin Lab, Kunshan, Peoples R China
共同第一作者：
通讯作者：
通讯机构：[1]Shanghai Jiao Tong Univ, Shanghai Tongren Hosp, Dept Clin Lab, Sch Med, Shanghai 200336, Peoples R China[2]Shanghai Jiao Tong Univ, Shanghai Tongren Hosp, Dept Gastroenterol, Sch Med, Shanghai 200336, Peoples R China[*1]Department of Clinical Laboratory, Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200336, China[*2]Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200336, China
推荐引用方式(GB/T 7714)：
Zhang Qinghui,Jia Rongrong,Chen Minjie,et al.Antagonizing EZH2 combined with vitamin D3 exerts a synergistic role in anti-fibrosis through bidirectional effects on hepatocytes and hepatic stellate cells[J].JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY.2023,38(3):441-450.doi:10.1111/jgh.16126.
APA：
Zhang, Qinghui,Jia, Rongrong,Chen, Minjie,Wang, Jianjun,Huang, Feng...&Xu, Ling.(2023).Antagonizing EZH2 combined with vitamin D3 exerts a synergistic role in anti-fibrosis through bidirectional effects on hepatocytes and hepatic stellate cells.JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY,38,(3)
MLA：
Zhang, Qinghui,et al."Antagonizing EZH2 combined with vitamin D3 exerts a synergistic role in anti-fibrosis through bidirectional effects on hepatocytes and hepatic stellate cells".JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 38..3(2023):441-450
