title: TLR4 regulates cardiac lipid accumulation and diabetic heart disease in the nonobese diabetic mouse model of type 1 diabetes.
abstract: 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.
authors: Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut, USA.
authors: Baojun
authors: B
authors: Dong
authors: Dake
authors: D
authors: Qi
authors: Long
authors: L
authors: Yang
authors: Yan
authors: Y
authors: Huang
authors: Xiaoyan
authors: X
authors: Xiao
authors: Ningwen
authors: N
authors: Tai
authors: Li
authors: L
authors: Wen
authors: F Susan
authors: FS
authors: Wong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019301:Oleic Acid / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D051381:Rats; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D019301:Oleic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D008071:Lipoprotein Lipase