FoxO1-zDHHC4-CD36 硫酰化轴驱动糖尿病中的代谢功能障碍。

FoxO1-zDHHC4-CD36 S-Acylation Axis Drives Metabolic Dysfunction in Diabetes.

作者信息

Dennis Kaitlyn M J H, Gopal Keshav, Montes Aparicio Claudia N, Zhang Jiashuo Aaron, Castro-Guarda Marcos, Nicol Thomas, Devereux Ríona M, Carter Ryan D, Azizi Saara-Anne, Lan Tong, Purnama Ujang, Carr Carolyn A, Simsek Gul, Gill Eleanor K, Swietach Pawel, Sorop Oana, Heinonen Ilkka H A, Schianchi Francesco, Luiken Joost J F P, Aksentijevic Dunja, Duncker Dirk J, Dickinson Bryan C, De Val Sarah, Ussher John R, Fuller William, Heather Lisa C

机构信息

Department of Physiology, Anatomy and Genetics (K.M.J.H.D., C.N.M.A., J.A.Z., M.C.-G., T.N., R.M.D., R.D.C., U.P., C.A.C., G.S., E.K.G., P.S., S.D.V., L.C.H.), University of Oxford, United Kingdom.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada (K.G., J.R.U.).

出版信息

Circ Res. 2025 Jun 6;136(12):1545-1560. doi: 10.1161/CIRCRESAHA.124.325918. Epub 2025 May 13.

DOI:10.1161/CIRCRESAHA.124.325918

PMID:40357580

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12136392/

Abstract

BACKGROUND

The fatty acid (FA) transporter CD36 (FA translocase/cluster of differentiation 36) is the gatekeeper of cardiac FA metabolism. Preferential localisation of CD36 to the sarcolemma is one of the initiating cellular responses in the development of muscle insulin resistance and in the type 2 diabetic heart. Post-translational S-acylation controls protein trafficking, and in this study we hypothesised that increased CD36 S-acylation may underpin the preferential sarcolemmal localisation of CD36, driving metabolic and contractile dysfunction in diabetes.

METHODS

Type 2 diabetes was induced in the rat using high fat diet and a low dose of streptozotocin. Forkhead box O1 (FoxO1) transcriptional regulation of zDHHC4 (zinc finger DHHC-type palmitoyltransferase 4) and subsequent S-acylation of CD36 was assessed using chromatin immunoprecipitation (ChIP) sequencing, ChIP-quantitative polymerase chain reaction, luciferase assays, siRNA (small interfering RNA) and shRNA silencing.

RESULTS

Type 2 diabetes increased cardiac CD36 S-acylation, CD36 sarcolemmal localisation, FA oxidation rates and triglyceride storage in the diabetic heart. CD36 S-acylation was increased in diabetic rats, mice, diabetic pigs and insulin-resistant human iPSC-derived cardiomyocytes, demonstrating conservation between species. The enzyme responsible for S-acylating CD36, zDHHC4, was transcriptionally upregulated in the diabetic heart, and genetic silencing of zDHHC4 decreased CD36 S-acylation. We identified that expression is under the regulation of the transcription factor FoxO1. Diabetic mice with cardiomyocyte-specific FoxO1 deletion had decreased cardiac expression and decreased CD36 S-acylation, which was further confirmed using diabetic mice treated with the FoxO1 inhibitor AS1842856. Pharmacological inhibition of zDHHC enzymes in diabetic hearts decreased CD36 S-acylation, sarcolemmal CD36 content, FA oxidation rates and triglyceride storage, culminating in improved cardiac function in diabetes. Conversely, inhibiting the de-acylating enzymes in control hearts increased CD36 S-acylation, sarcolemmal CD36 content and FA metabolic rates in control hearts, recapitulating the metabolic phenotype seen in diabetic hearts.

CONCLUSIONS

Activation of the FoxO1-zDHHC4-CD36 S-acylation axis drives metabolic and contractile dysfunction in the type 2 diabetic heart.

摘要

背景

脂肪酸（FA）转运蛋白CD36（FA转位酶/分化簇36）是心脏FA代谢的守门人。CD36在肌膜上的优先定位是肌肉胰岛素抵抗发展和2型糖尿病心脏中最初的细胞反应之一。翻译后S-酰化控制蛋白质运输，在本研究中我们假设CD36 S-酰化增加可能是CD36优先定位于肌膜的基础，从而导致糖尿病中的代谢和收缩功能障碍。

方法

使用高脂饮食和低剂量链脲佐菌素诱导大鼠患2型糖尿病。使用染色质免疫沉淀（ChIP）测序、ChIP定量聚合酶链反应、荧光素酶测定、小干扰RNA（siRNA）和短发夹RNA（shRNA）沉默来评估叉头框O1（FoxO1）对zDHHC4（锌指DHHC型棕榈酰转移酶4）的转录调控以及随后CD36的S-酰化。

结果

2型糖尿病增加了糖尿病心脏中CD36的S-酰化、CD36在肌膜上的定位、FA氧化率和甘油三酯储存。糖尿病大鼠、小鼠、糖尿病猪和胰岛素抵抗的人诱导多能干细胞衍生的心肌细胞中CD36的S-酰化增加，表明种间具有保守性。负责CD36 S-酰化的酶zDHHC4在糖尿病心脏中转录上调，zDHHC4的基因沉默降低了CD36的S-酰化。我们发现其表达受转录因子FoxO1的调控。心肌细胞特异性缺失FoxO1的糖尿病小鼠心脏中其表达降低且CD36的S-酰化减少，使用FoxO1抑制剂AS1842,856处理的糖尿病小鼠进一步证实了这一点。对糖尿病心脏中zDHHC酶的药理学抑制降低了CD36的S-酰化、肌膜CD36含量、FA氧化率和甘油三酯储存，最终改善了糖尿病心脏的功能。相反，抑制对照心脏中的去酰化酶增加了对照心脏中CD36的S-酰化、肌膜CD36含量和FA代谢率，重现了糖尿病心脏中所见的代谢表型。