8. Inhibition of fatty acid uptake by TGR5 prevents diabetic cardiomyopathy

Diabetic cardiomyopathy is characterized bymyocardial lipid accumulation and cardiac dysfunction. Bile acid metabolism isknown to play a crucial role in cardiovascular and metabolic diseases. TakedaG-protein-coupled receptor 5 (TGR5), a major bile acid receptor, has beenimplicated in metabolic regulation and myocardial protection. However, theprecise involvement of the bile acid–TGR5 pathway in maintainingcardiometabolic homeostasis remains unclear. Here we show decreased plasma bileacid levels in both male and female participants with diabetic myocardial injury.Additionally, we observe increased myocardial lipid accumulation and cardiac dysfunctionin cardiomyocyte-specific TGR5-deleted mice (both male and female) subjected toa high-fat diet and streptozotocin treatment or bred on the diabetic db/dbgenetic background. Further investigation reveals that TGR5 deletion enhancescardiac fatty acid uptake, resulting in lipid accumulation. Mechanistically,TGR5 deletion promotes localization of CD36 on the plasma membrane through theupregulation of CD36 palmitoylation mediated by the palmitoyl acyltransferaseDHHC4. Our findings indicate that the TGR5-DHHC4 pathway regulates cardiacfatty acid uptake, which highlights the therapeutic potential of targeting TGR5in the management of diabetic cardiomyopathy.