Zhang Yu-Ting, Yang Xiao-Ming, Jin Quan-Shan, Chen Jia-Yi, Zhu Nan-Bin, Ju Yi, Lin Zi-Yan, Zhi Yang, Dong Yi-Nuo, Li Chun-Min, Mao Yi-Min, Zhi Xiu-Ling, Ma Ming-Yang, Xu Ya-Li, Li Xiao-Bo
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, 750004, China.
Acta Pharmacol Sin. 2025 Aug 5. doi: 10.1038/s41401-025-01622-7.
Acetaminophen (APAP)-induced liver injury (AILI) is a leading cause of acute liver failure, with limited preventive or therapeutic options. The role of betaine-homocysteine methyltransferase (BHMT), a key enzyme in the methionine cycle, remains unclear. We found that BHMT, primarily expressed in hepatocytes, showed reduced expression in the liver but elevated serum levels in the APAP-induced liver injury (AILI) mouse model. GalNAc-mediated targeted knockdown of Bhmt in hepatocytes aggravated AILI in mice. Through RNA-seq screening, we found that Bhmt deficiency dramatically suppressed stearoyl-coenzyme A desaturase 1 (SCD1) expression. Knockdown of Scd1 also exacerbated AILI. Mechanistically, Bhmt knockdown decreased the DNA methylation of BACH1 (BTB and CNC homology 1), a transcriptional factor, leading to upregulated BACH1 expression in primary mouse hepatocytes (PMHs) treated with APAP. BACH1 then bound to the enhancer region of Scd1, transcriptionally repressing SCD1. Lipidomic analysis revealed that Bhmt or Scd1 deficiency reduced levels of intracellular unsaturated fatty acids, particularly oleic acid (OA), whereas SCD1 overexpression increased OA levels and decreased lipid peroxides. OA administration alleviated AILI and mitigated the hepatotoxicity associated with Bhmt or Scd1 knockdown. Our findings indicate that BHMT mitigates AILI via the BACH1-SCD1-OA axis, suggesting that BHMT could serve as a preventive target for AILI, while increasing OA intake may offer dietary benefits for patients.
对乙酰氨基酚（APAP）诱导的肝损伤（AILI）是急性肝衰竭的主要原因，预防或治疗选择有限。甜菜碱-同型半胱氨酸甲基转移酶（BHMT）作为甲硫氨酸循环中的关键酶，其作用仍不清楚。我们发现，主要在肝细胞中表达的BHMT在肝脏中的表达降低，但在APAP诱导的肝损伤（AILI）小鼠模型中血清水平升高。通过GalNAc介导的肝细胞中Bhmt靶向敲低加重了小鼠的AILI。通过RNA测序筛选，我们发现Bhmt缺陷显著抑制硬脂酰辅酶A去饱和酶1（SCD1）的表达。敲低Scd1也会加重AILI。机制上，Bhmt敲低降低了转录因子BACH1（BTB和CNC同源物1）的DNA甲基化，导致在用APAP处理的原代小鼠肝细胞（PMH）中BACH1表达上调。然后，BACH1与Scd1的增强子区域结合，转录抑制SCD1。脂质组学分析显示，Bhmt或Scd1缺陷降低了细胞内不饱和脂肪酸的水平，尤其是油酸（OA），而SCD1过表达增加了OA水平并降低了脂质过氧化物。给予OA可减轻AILI，并减轻与Bhmt或Scd1敲低相关的肝毒性。我们的研究结果表明，BHMT通过BACH1-SCD1-OA轴减轻AILI，这表明BHMT可作为AILI的预防靶点，而增加OA摄入量可能对患者有饮食益处。
