WTAP boosts lipid oxidation and induces diabetic cardiac fibrosis by enhancing AR methylation

Kai Song; He Sun; Bin Tu; Yang Zhou; Li-Chan Lin; Zhi-Yan Liu; Rui Li; Jing-Jing Yang; Ye Zhang; Jian-Yuan Zhao; Hui Tao

doi:10.1016/j.isci.2023.107931

WTAP boosts lipid oxidation and induces diabetic cardiac fibrosis by enhancing AR methylation

iScience. 2023 Sep 15;26(10):107931. doi: 10.1016/j.isci.2023.107931. eCollection 2023 Oct 20.

Authors

Kai Song¹, He Sun¹, Bin Tu¹, Yang Zhou¹, Li-Chan Lin², Zhi-Yan Liu², Rui Li², Jing-Jing Yang³, Ye Zhang², Jian-Yuan Zhao⁴, Hui Tao^{1

2}

Affiliations

¹ Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
² Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
³ Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
⁴ Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Childrens Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.

Abstract

Dysregulated lipid metabolism occurs in pathological processes characterized by cell proliferation and migration. Nonetheless, the mechanism of increased mitochondrial lipid oxidation is poorly appreciated in diabetic cardiac fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. Herein, increased WTAP expression promotes cardiac fibroblast proliferation and migration, contributing to diabetic cardiac fibrosis. Knockdown of WTAP suppresses mitochondrial lipid oxidation, fibroblast proliferation and migration to ameliorate diabetic cardiac fibrosis. Mechanistically, WTAP-mediated m6A methylation of AR induced its degradation, dependent on YTHDF2. Additionally, AR directly interacts with mitochondrial lipid oxidation enzyme Decr1; overexpression of AR-suppressed Decr1-mediates mitochondrial lipid oxidation, inhibiting cardiac fibroblast proliferation and migration. Knockdown of AR produced the opposite effect. Clinically, increased WTAP and YTHDF2 levels correlate with decreased AR expression in human DCM heart tissue. We describe a mechanism wherein WTAP boosts higher mitochondrial lipid oxidation, cardiac fibroblast proliferation, and migration by enhancing AR methylation in a YTHDF2-dependent manner.

Keywords: Biological sciences; Cell biology; Molecular biology.