Toll-like receptor (TLR)4 regulates inflammation and metabolism and has been 
linked to the pathogenesis of heart disease. TLR4 is upregulated in diabetic 
cardiomyocytes, and we examined the role of TLR4 in modulating cardiac fatty 
acid (FA) metabolism and the pathogenesis of diabetic heart disease in nonobese 
diabetic (NOD) mice. Both wild-type (WT) NOD and TLR4-deficient NOD animals had 
increased plasma triglyceride levels after the onset of diabetes. However, by 
comparison, TLR4-deficient NOD mouse hearts had lower triglyceride accumulation 
in the early stages of diabetes, which was associated with a reduction in 
myeloid differentiation primary response gene (88) (MyD88), phosphorylation of 
p38 MAPK (phospho-p38), lipoprotein lipase (LPL), and JNK levels but increased 
phospho-AMP-activated protein kinase (AMPK). Oleic acid treatment in H9C2 
cardiomyocytes also led to cellular lipid accumulation, which was attenuated by 
TLR4 small interfering RNA. TLR4 deficiency in the cells decreased FA-induced 
augmentation of MyD88, phospho-p38, and LPL, suggesting that TLR4 may modulate 
FA-induced lipid metabolism in cardiomyocytes. In addition, although cardiac 
function was impaired in both diabetic WT NOD and TLR4-deficient NOD animals 
compared with control nondiabetic mice, this deficit was less in the diabetic 
TLR4-deficient NOD mice, which had greater ejection fraction, greater fractional 
shortening, and increased left ventricular developed pressure in the early 
stages after the development of diabetes compared with their diabetic WT NOD 
counterparts. Thus, we conclude that TLR4 plays a role in regulating lipid 
accumulation in cardiac muscle after the onset of type 1 diabetes, which may 
contribute to cardiac dysfunction.