N-乙酰丝氨酰天门冬酰赖氨酰脯氨酸（AcSDKP）通过 WTAP/mA/Ptch1 轴通过 Hedgehog 通路减轻肝纤维化。

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) mitigates the liver fibrosis via WTAP/mA/Ptch1 axis through Hedgehog pathway.

机构信息

Endoscopy Center, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450008, China.

Department of Gastroenterology, Henan Provincial People's HospitalZhengzhou, Henan 450008, China.

出版信息

Gene. 2022 Mar 1;813:146125. doi: 10.1016/j.gene.2021.146125. Epub 2021 Dec 16.

DOI:10.1016/j.gene.2021.146125

PMID:34921949

Abstract

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous tetrapeptide with potential antifibrotic effect. However, the underlying mechanism in the anti-fibrosis is still unclear. Here, we try to investigate its biofunction and deeplying mechanism in liver fibrosis. Rats were administrated with carbon tetrachloride (CCl4) for liver fibrosis model. The roles of AcSDKP on hepatic stellate cells (HSCs) were detected in vitro using isolated cells treated by TGF-β1. The mA profie of HSCs was screened by methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Results demonstrated that AcSDKP inhibited apoptosis through Hedgehog pathway in the CCl-induced rat HSCs. Moreover, the administration of AcSDKP decreased the N-methyladenosine (mA) methyltransferase WTAP (Wilms' tumour 1-associated protein) expression. Mechanistically, WTAP targeted the 3'-UTR of Ptch1 mRNA, and administration of AcSDKP reduced the stability of Ptch1 mRNA. Thus, these findings revealed an anti-fibrosis axis of AcSDKP/WTAP/mA/Ptch1 in liver fibrosis. Our results identify a novel role of AcSDKP in liver fibrosis via mA modification and Hedgehog pathway, which helps us to shed light on the molecular mechanism in liver fibrosis progression.

摘要

N-乙酰丝氨酰-天冬氨酰-赖氨酰-脯氨酸（AcSDKP）是一种内源性四肽，具有潜在的抗纤维化作用。然而，其抗纤维化的潜在机制尚不清楚。在这里，我们试图研究其在肝纤维化中的生物功能和深入机制。大鼠用四氯化碳（CCl4）处理建立肝纤维化模型。采用 TGF-β1 处理分离的细胞，检测 AcSDKP 对肝星状细胞（HSCs）的作用。采用甲基化 RNA 免疫沉淀测序（MeRIP-Seq）筛选 HSCs 的 mA 谱。结果表明，AcSDKP 通过 Hedgehog 通路抑制 CCl 诱导的大鼠 HSCs 中的细胞凋亡。此外，AcSDKP 的给药降低了 N6-甲基腺苷（mA）甲基转移酶 WTAP（Wilms 肿瘤 1 相关蛋白）的表达。在机制上，WTAP 靶向 Ptch1 mRNA 的 3'-UTR，而 AcSDKP 的给药降低了 Ptch1 mRNA 的稳定性。因此，这些发现揭示了肝纤维化中 AcSDKP/WTAP/mA/Ptch1 的抗纤维化轴。我们的研究结果通过 mA 修饰和 Hedgehog 通路确定了 AcSDKP 在肝纤维化中的新作用，这有助于我们深入了解肝纤维化进展的分子机制。