Cholesterol 25-hydroxylase prevents type 2 diabetes mellitus induced cardiomyopathy by alleviating cardiac lipotoxicity

Jialiang Zhang; Hao Zhou; Fan Lei; Kexin Jiang; Yanbiao Liao; Fangyang Huang; Mao Chen

doi:10.1016/j.bbadis.2024.167158

Cholesterol 25-hydroxylase prevents type 2 diabetes mellitus induced cardiomyopathy by alleviating cardiac lipotoxicity

Biochim Biophys Acta Mol Basis Dis. 2024 Apr 6;1870(5):167158. doi: 10.1016/j.bbadis.2024.167158. Online ahead of print.

Authors

Jialiang Zhang¹, Hao Zhou¹, Fan Lei¹, Kexin Jiang¹, Yanbiao Liao¹, Fangyang Huang², Mao Chen³

Affiliations

¹ Laboratory of Heart Valve Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
² Laboratory of Heart Valve Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: fyhuang1989@126.com.
³ Laboratory of Heart Valve Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: hmaochen@vip.sina.com.

PMID: 38588780
DOI: 10.1016/j.bbadis.2024.167158

Abstract

Objectives: Diabetic cardiomyopathy (DCM) is the leading cause of mortality in type 2 diabetes mellitus (T2DM) patients, with its underlying mechanisms still elusive. This study aims to investigate the role of cholesterol-25-monooxygenase (CH25H) in T2DM induced cardiomyopathy.

Methods: High fat diet combined with streptozotocin (HFD/STZ) were used to establish a T2DM model. CH25H and its product 25-hydroxycholesterol (25HC) were detected in the hearts of T2DM model. Gain- or loss-of-function of CH25H were performed by receiving AAV9-cTNT-CH25H or CH25H knockout (CH25H^-/-) mice with HFD/STZ treatment. Cardiac function was evaluated using echocardiography, and cardiac tissues were collected for immunoblot analysis, histological assessment and quantitative polymerase chain reaction (qPCR). Mitochondrial morphology and function were evaluated using transmission electron microscopy (TEM) and Seahorse XF Cell Mito Stress Test Kit. RNA-sequence analysis was performed to determine the molecular changes associated with CH25H deletion.

Results: CH25H and 25HC were significantly decreased in the hearts of T2DM mice. CH25H^-/- mice treated with HFD/STZ exhibited impaired mitochondrial function and structure, increased lipid accumulation, and aggregated cardiac dysfunction. Conversely, T2DM mice receiving AAV9-CH25H displayed cardioprotective effects. Mechanistically, RNA sequencing and qPCR analysis revealed that CH25H deficiency decreased peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and its target gene expression. Additionally, administration of ZLN005, a potent PGC-1α activator, partially protected against high glucose and palmitic acid induced mitochondria dysfunction and lipid accumulation in vitro.

Conclusion: Our study provides compelling evidence supporting the protective role of CH25H in T2DM-induced cardiomyopathy. Furthermore, the regulation of PGC-1α may be intricately involved in this cardioprotective process.

Keywords: CH25H; Diabetic cardiomyopathy; High fat diet; Lipotoxicity; Type 2 diabetes.