| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Farese, Robert V. Liu, Li Homma, Shunichi Hu, Shi-lian Goldberg, Ira J. Son, Ni-huiping Huang, Li-shin Jiang, Hongfeng Trent, Chad M. Turnbull, Andrew V. Yin, Yu-xin Eriksson, Jan W. Fang, Xiang Blaner, William S. Hu, Yunying Ginsberg, Henry N. |
| Description |
Author Affiliation: Liu L ( From the Divisions of Preventive Medicine and Nutrition and Institute of Systems Biomedicine, Peking University Health Science Center, 100083 Beijing, China.); Trent CM ( From the Divisions of Preventive Medicine and Nutrition and.); Fang X ( From the Divisions of Preventive Medicine and Nutrition and Department of Geriatrics, Affiliated Provincial Hospital, Anhui Medical University, 230001 Hefei, China.); Son NH ( From the Divisions of Preventive Medicine and Nutrition and.); Jiang H ( From the Divisions of Preventive Medicine and Nutrition and.); Blaner WS ( From the Divisions of Preventive Medicine and Nutrition and.); Hu Y ( From the Divisions of Preventive Medicine and Nutrition and.); Yin YX ( Institute of Systems Biomedicine, Peking University Health Science Center, 100083 Beijing, China.); Farese RV ( Gladstone Institute of Cardiovascular Disease and Departments of Medicine and Biochemistry and Biophysics, University of California, San Francisco, California 94158.); Homma S ( Cardiology, Columbia University College of Physicians and Surgeons, New York, New York 10032.); Turnbull AV ( Astra-Zeneca Company, 431 50 Mölndal, Sweden.); Eriksson JW ( Astra-Zeneca Company, 431 50 Mölndal, Sweden, Department of Medical Sciences, Uppsala University, 751 05 Uppsala, Sweden, and.); Hu SL ( Department of Geriatrics, Affiliated Provincial Hospital, Anhui Medical University, 230001 Hefei, China.); Ginsberg HN ( From the Divisions of Preventive Medicine and Nutrition and.); Huang LS ( From the Divisions of Preventive Medicine and Nutrition and.); Goldberg IJ ( From the Divisions of Preventive Medicine and Nutrition and Cardiology, Columbia University College of Physicians and Surgeons, New York, New York 10032, Division of Endocrinology, Diabetes, and Metabolism, New York University Langone School of Medicine, New York, New York 10016 Ira.Goldberg@nyumc.o) |
| Abstract |
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 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 C (PKC ), 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. |
| ISSN |
00219258 |
| e-ISSN |
1083351X |
| Journal |
Journal of Biological Chemistry |
| Issue Number |
43 |
| Volume Number |
289 |
| Language |
English |
| Publisher |
American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date |
2014-10-24 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Heart Failure Blood Enzymology Lipids Myocytes, Cardiac Pathology Aging Animals Blood Glucose Metabolism Cholesterol Diacylglycerol O-Acyltransferase Antagonists & Inhibitors Enzyme Inhibitors Pharmacology Fatty Acids Gene Deletion Gene Expression Regulation Drug Effects Genetics Intestines Mice, Inbred C57BL Mice, Knockout Myocardium Organ Specificity Peptides Phenotype Protein Kinase C Triglycerides Venoms Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Cell Biology Biochemistry Molecular Biology |
