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Excessive fatty acids activate PRMT5/MDM2/Drosha pathway to regulate miRNA biogenesis and lipid metabolism

文献类型：期刊论文

作者Hou, Aijun4,5; Xu, Xiaoding3,5; Zhang, Yu4,5; He, Hongxiu3,5; Feng, Yihan2; Fan, Wenhui3,5; Tan, Rongrong5; Gong, Likun1,4,5; Chen, Jing1,4,5
刊名LIVER INTERNATIONAL
出版日期2024-03-22
页码17
关键词Drosha degradation lipid metabolism miRNA biogenesis NAFLD PRMT5
ISSN号1478-3223
DOI10.1111/liv.15906
通讯作者Gong, Likun(lkgong@simm.ac.cn) ; Chen, Jing(jingchen@simm.ac.cn)
英文摘要BackgroundExcessive fatty acids in the liver lead to the accumulation of lipotoxic lipids and then cellular stress to further evoke the related disease, like non-alcoholic fatty liver disease (NAFLD). As reported, fatty acid stimulation can cause some specific miRNA dysregulation, which caused us to investigate the relationship between miRNA biogenesis and fatty acid overload. MethodsGene expression omnibus (GEO) dataset analysis, miRNA-seq, miRNA cleavage assay, RT-qPCR, western blotting, immunofluorescence and co-immunoprecipitation (co-IP) were used to reveal the change of miRNAs under pathological status and explore the relevant mechanism. High fat, high fructose, high cholesterol (HFHFrHC) diet-fed mice transfected with AAV2/8-shDrosha or AAV2/8-shPRMT5 were established to investigate the in vivo effects of Drosha or PRMT5 on NAFLD phenotype. ResultsWe discovered that the cleavage of miRNAs was inhibited by analysing miRNA contents and detecting some representative pri-miRNAs in multiple mouse and cell models, which was further verified by the reduction of the Microprocessor activity in the presence of palmitic acid (PA). In vitro, PA could induce Drosha, the core RNase III in the Microprocessor complex, degrading through the proteasome-mediated pathway, while in vivo, knockdown of Drosha significantly promoted NAFLD to develop to a more serious stage. Mechanistically, our results demonstrated that PA can increase the methyltransferase activity of PRMT5 to degrade Drosha through MDM2, a ubiquitin E3 ligase for Drosha. The above results indicated that PRMT5 may be a critical regulator in lipid metabolism during NAFLD, which was confirmed by the knocking down of PRMT5 improved aberrant lipid metabolism in vitro and in vivo. ConclusionsWe first demonstrated the relationship between miRNA dosage and NAFLD and proved that PA can activate the PRMT5-MDM2-Drosha signalling pathway to regulate miRNA biogenesis.
WOS关键词ARGININE METHYLTRANSFERASE ; GENE-EXPRESSION ; PRMT5 ; LIVER ; MICRORNA-34A ; PROGRESSION ; DISRUPTION ; RECEPTOR ; DISEASE ; CANCER
资助项目National Natural Science Foundation of China
WOS研究方向Gastroenterology & Hepatology
语种英语
WOS记录号WOS:001189095800001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/310345]  
专题新药研究国家重点实验室
通讯作者Gong, Likun; Chen, Jing
作者单位1.Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, State Key Lab Drug Res, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China
2.Shenyang Pharmaceut Univ, Sch Pharm, Dept Pharmaceut, Shenyang, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
4.Univ Chinese Acad Sci, Sch Pharm, Beijing, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Hou, Aijun,Xu, Xiaoding,Zhang, Yu,et al. Excessive fatty acids activate PRMT5/MDM2/Drosha pathway to regulate miRNA biogenesis and lipid metabolism[J]. LIVER INTERNATIONAL,2024:17.
APA Hou, Aijun.,Xu, Xiaoding.,Zhang, Yu.,He, Hongxiu.,Feng, Yihan.,...&Chen, Jing.(2024).Excessive fatty acids activate PRMT5/MDM2/Drosha pathway to regulate miRNA biogenesis and lipid metabolism.LIVER INTERNATIONAL,17.
MLA Hou, Aijun,et al."Excessive fatty acids activate PRMT5/MDM2/Drosha pathway to regulate miRNA biogenesis and lipid metabolism".LIVER INTERNATIONAL (2024):17.

入库方式： OAI收割

来源：上海药物研究所

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