biostudies-literatureDennis KMJHBritish Heart FoundationDutch Research Council (NWO)Wellcome Trust1545-1560https://www.ebi.ac.uk/biostudies/studies/S-EPMC12136392biostudies-literatureUnknown136(12)<h4>Background</h4>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.<h4>Methods</h4>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 subseCirculation researchFoxO1-zDHHC4-CD36 S-Acylation Axis Drives Metabolic Dysfunction in Diabetes.PMC12136392221604218514ALWOP.367FS/19/61/34900FS/17/58/33072Carr CANicol TCastro-Guarda MSorop ODickinson BCMontes Aparicio CNHeinonen IHAAksentijevic DDevereux RMAzizi SADuncker DJDe Val SSimsek GUssher JRGopal KLuiken JJFPSwietach PDennis KMJHSchianchi FFuller WGill EKLan TCarter RDPurnama UHeather LCZhang JAfalseFoxO1-zDHHC4-CD36 S-Acylation Axis Drives Metabolic Dysfunction in Diabetes.<h4>Background</h4>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.<h4>Methods</h4>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 subse2025-01-01T00:00:00Z2025 Jun2026-07-15T05:58:49.255Z2026-06-30T03:20:21.153ZS-EPMC121363924035758010.1161/CIRCRESAHA.124.325918