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

Kaitlyn M J H Dennis¹, Keshav Gopal², Claudia N Montes Aparicio¹

¹Department 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.

Circulation Research

|May 13, 2025

Summary

Increased CD36 S-acylation, driven by FoxO1-zDHHC4 signaling, impairs cardiac function in type 2 diabetes. Targeting this pathway improves heart metabolism and contractility in diabetic conditions.

Keywords:

cardiovascular diseases diabetic cardiomyopathies heart failure insulin resistance myocardial infarction

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Area of Science:

Cardiovascular Biology
Metabolic Regulation
Molecular Cardiology

Background:

CD36 is a key fatty acid (FA) transporter in the heart, regulating cardiac FA metabolism.
Preferential CD36 localization to the sarcolemma is an early event in insulin resistance and type 2 diabetic heart disease.
Post-translational S-acylation influences protein trafficking and function.

Purpose of the Study:

To investigate the role of CD36 S-acylation in the development of diabetic cardiomyopathy.
To elucidate the molecular mechanisms regulating CD36 S-acylation in the diabetic heart.
To determine if targeting CD36 S-acylation can ameliorate cardiac dysfunction in type 2 diabetes.

Main Methods:

Type 2 diabetes was induced in rats via high-fat diet and streptozotocin.
Assessed transcriptional regulation of zDHHC4 by FoxO1 using ChIP sequencing and luciferase assays.
Utilized siRNA and shRNA for gene silencing, and pharmacological inhibitors for enzyme modulation.

Main Results:

Type 2 diabetes increased cardiac CD36 S-acylation, sarcolemmal localization, FA oxidation, and triglyceride storage across species.
zDHHC4, the enzyme responsible for CD36 S-acylation, was upregulated by FoxO1 in the diabetic heart.
Inhibition of zDHHC enzymes improved cardiac function in diabetic models by reducing CD36 S-acylation and improving FA metabolism.

Conclusions:

The FoxO1-zDHHC4-CD36 S-acylation axis is activated in the type 2 diabetic heart.
This activation drives metabolic and contractile dysfunction characteristic of diabetic cardiomyopathy.
Targeting this axis offers a potential therapeutic strategy for diabetic heart disease.