A novel peptide encoded by circ‐SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac‐mediated CD36 transcription in NAFLD

Author:

Wang Yue1,Tian Xinyao23,Wang Zhecheng1,Liu Deshun4,Zhao Xuzi4,Sun Xin1,Tu Zuoyu1,Li Zekuan3,Zhao Yan1,Zheng Shusen35ORCID,Yao Jihong1ORCID

Affiliation:

1. Department of Pharmacology Dalian Medical University Dalian China

2. Department of Surgery Division of Hepatobiliary and Pancreatic Surgery The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China

3. Department of Surgery Division of Hepatobiliary and Pancreatic Surgery The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou China

4. Department of General Surgery The Second Affiliated Hospital of Dalian Medical University Dalian China

5. Department of Hepatobiliary and Pancreatic Surgery Department of Liver Transplantation Shulan (Hangzhou) Hospital Hangzhou China

Abstract

AbstractBackgroundAs the leading cause of end‐stage liver disease, nonalcoholic fatty liver disease (NAFLD) is mainly induced by lipid dyshomeostasis. The translation of endogenous circular RNAs (circRNAs) is closely related to the progression of various diseases, but the involvement of circRNAs in NAFLD has not been determined.MethodsCombined high‐throughput circRNA profiles were used to identify circRNAs with translational potential. The underlying molecular mechanisms were investigated by RNA sequencing, pull‐down/MS and site‐specific mutagenesis.ResultsIn this study, we focused on circ‐SLC9A6, an abnormally highly expressed circRNA in human and mouse liver tissue during NAFLD development that exacerbates metabolic dyshomeostasis in hepatocytes by encoding a novel peptide called SLC9A6‐126aa in vivo and in vitro. YTHDF2‐mediated degradation of m6A‐modified circ‐SLC9A6 was found to be essential for the regulation of SLC9A6‐126aa expression. We further found that the phosphorylation of SLC9A6‐126aa by AKT was crucial for its cytoplasmic localization and the maintenance of physiological homeostasis, whereas high‐fat stress induced substantial translocation of unphosphorylated SLC9A6‐126aa to the nucleus, resulting in a vicious cycle of lipid metabolic dysfunction. Nuclear SLC9A6‐126aa promotes transcriptional activation of the target gene CD36 and enhances its occupancy of the CD36 promoter locus by regulating MOF‐mediated histone H4K16 acetylation. Hepatic CD36 depletion significantly ameliorated hyperactivated MAPK signalling and lipid disturbance in SLC9A6‐126aa transgenic mice. Clinically, increasing levels of SLC9A6‐126aa were observed during NAFLD progression and were found to be positively correlated with the CD36 and MAPK cascades.ConclusionThis study revealed the role of circ‐SLC9A6‐derived SLC9A6‐126aa in the epigenetic modification‐mediated regulation of lipid metabolism. Our findings may provide promising therapeutic targets for NAFLD and new insights into the pathological mechanisms of metabolic diseases.Highlights Under normal circumstances, driven by m6A modification, YTHDF2 directly recognizes and degrades circ‐SLC9A6, thereby inhibiting the translation of SLC9A6‐126aa. Additionally, AKT1 phosphorylates and inhibits the nuclear translocation of SLC9A6‐126aa. In NAFLD, lipid overload leads to YTHDF2 and AKT1 deficiency, ultimately increasing the expression and nuclear import of SLC9A6‐126aa. Nuclear SLC9A6‐126aa binds directly to the CD36 promoter and initiates CD36 transcription, which induces lipid dyshomeostasis.

Funder

National Natural Science Foundation of China

Publisher

Wiley

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3