Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure*
| Autor: | Robert V. Farese, Chad M. Trent, Shi-Lian Hu, William S. Blaner, Ni-Huiping Son, Yuxin Yin, Li Liu, Shunichi Homma, Andrew V. Turnbull, Henry N. Ginsberg, Yunying Hu, Hongfeng Jiang, Xiang Fang, Jan W. Eriksson, Ira J. Goldberg, Li-Shin Huang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Blood Glucose
Male medicine.medical_specialty Ceramide Aging Biology Biochemistry chemistry.chemical_compound Internal medicine medicine Animals Humans Myocytes Cardiac Diacylglycerol O-Acyltransferase Enzyme Inhibitors Molecular Biology Protein kinase C Protein Kinase C Triglycerides Diacylglycerol kinase Heart Failure Mice Knockout Triglyceride Cholesterol Venoms Myocardium Fatty Acids Cell Biology medicine.disease Brain natriuretic peptide Lipids Intestines Mice Inbred C57BL Endocrinology Phenotype Lipotoxicity chemistry Gene Expression Regulation Organ Specificity Heart failure cardiovascular system Exenatide lipids (amino acids peptides and proteins) Peptides Gene Deletion |
| Popis: | Diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final step in triglyceride synthesis, the conversion of diacylglycerol (DAG) to triglyceride. Dgat1(-/-) mice exhibit a number of beneficial metabolic effects including reduced obesity and improved insulin sensitivity and no known cardiac dysfunction. In contrast, failing human hearts have severely reduced DGAT1 expression associated with accumulation of DAGs and ceramides. To test whether DGAT1 loss alone affects heart function, we created cardiomyocyte-specific DGAT1 knock-out (hDgat1(-/-)) mice. hDgat1(-/-) mouse hearts had 95% increased DAG and 85% increased ceramides compared with floxed controls. 50% of these mice died by 9 months of age. The heart failure marker brain natriuretic peptide increased 5-fold in hDgat1(-/-) hearts, and fractional shortening (FS) was reduced. This was associated with increased expression of peroxisome proliferator-activated receptor α and cluster of differentiation 36. We crossed hDgat1(-/-) mice with previously described enterocyte-specific Dgat1 knock-out mice (hiDgat1(-/-)). This corrected the early mortality, improved FS, and reduced cardiac ceramide and DAG content. Treatment of hDgat1(-/-) mice with the glucagon-like peptide 1 receptor agonist exenatide also improved FS and reduced heart DAG and ceramide content. Increased fatty acid uptake into hDgat1(-/-) hearts was normalized by exenatide. Reduced activation of protein kinase Cα (PKCα), which is increased by DAG and ceramides, paralleled the reductions in these lipids. Our mouse studies show that loss of DGAT1 reproduces the lipid abnormalities seen in severe human heart failure. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|