甲状旁腺激素通过抑制去甲基化酶ALKBH5促进非酒精性脂肪性肝纤维化形成中的作用机制研究

There is no effective drug therapy for nonalcoholic steatohepatitis (NASH) at present, especially for patients with liver fibrosis or cirrhosis. Our previous results found that serum parathyroid hormone (PTH) level was positively correlated with the degree of hepatic fibrosis in patients with NASH. Moreover, PTH accelerated the development of hepatic fibrosis in mice, whereas type 1 receptor (PTH1R) knockout suppressed liver fibrosis. Importantly, the stellate cells (HSC) were found to be the main effector of PTH1R signals based on the data of single cell sequencing in human cirrhotic tissues. Further sequencing data of PTH-treated mice and HSC cells showed that demethylase ALKBH5 was an important mediator of PTH action, and m6A modification might be involved in the process of liver fibrosis in NASH. Taken together, we propose the hypothesis that PTH promoted liver fibrosis by inducing m6A demethylase ALKBH5-mediated HSC activation, and PTH1R was a therapeutic target for liver fibrosis in NASH. Using clinical cohort, transgenic mouse models and MeRIP-seq, the study will provide new evidence for m6A modification in liver fibrosis, expand the understanding of the biological role of PTH, and uncover a new therapeutic target for liver fibrosis in NASH.

对非酒精性脂肪性肝炎（NASH）目前尚无有效的药物治疗，尤其针对进展到肝纤维化的患者，未加干预威胁患者生命。我们发现NASH患者甲状旁腺激素（PTH）水平与其肝纤维化程度呈正相关性，PTH可以加速NASH小鼠肝纤维化进展，降低其受体（PTH1R）表达抑制肝纤维化形成。单细胞测序数据显示肝纤维化组织中星状细胞是PTH1R信号的主要效应细胞。进一步对PTH干预的小鼠及细胞测序数据的交叉比对，发现ALKBH5是PTH作用的重要介导者。据此，我们提出：PTH可能通过抑制m6A去甲基化酶ALKBH5诱导星状细胞活化、促进肝纤维化形成，PTH1R是NASH所致肝纤维化的潜在治疗靶标。本研究将依托已建立的肝活检临床队列，利用肝星状细胞敲除PTH1R等小鼠模型，借助MeRIP-seq等方法进行探究，为m6A修饰参与肝纤维化提供新证据，扩展对PTH生物学作用的认识并为NASH肝纤维化提供新的治疗策略。

对非酒精性脂肪性肝炎（NASH）目前尚无有效的药物治疗，尤其针对进展到肝纤维化的患者，未加干预威胁患者生命。甲状旁腺激素（PTH）及其受体（PTH1R）与组织纤维化进程密切相关，但其具体机制尚不明确。依托已建立的肝活检临床队列，我们研究发现甲状旁腺激素1型受体（PTH1R）在NASH肝纤维化组织中显著升高。利用肝星状细胞敲除PTH1R小鼠模型，发现降低PTH1R表达抑制肝纤维化形成，而激活PTH1R可以加速NASH小鼠肝纤维化进展。基于单细胞测序数据提示肝星状细胞（HSCs）是PTH1R信号的主要效应细胞。并且，PTH1R信号激活增加转化生长因子-β（TGFβ）表达水平诱导HSCs活化、促进肝纤维化形成。进一步基因测序分析显示PTH干预能增加环腺苷酸应答元件结合蛋白样蛋白2（Crebl2）表达，从而促进环磷腺苷效应元件结合蛋白（CREB）- Smad同源物3（SMAD3）复合物与TGFβ启动子区结合，升高其转录表达。肝星状细胞敲除Crebl2小鼠模型证实Crebl2是PTH/PTH1R信号活化促进肝纤维化形成的重要介导分子。因此，本研究提出PTH/PTH1R/Crebl2可能是NASH所致肝纤维化的潜在治疗靶标，研究结果扩展了对PTH1R信号生物学作用的认识并为NASH肝纤维化提供新的治疗策略。

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