Cardiomyocyte-specific loss of diacylglycerol acyltransferase 1 (DGAT1) reproduces the abnormalities in lipids found in severe heart failure.

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 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.

• Authors: Li Liu, Chad M Trent, Xiang Fang, Ni-Huiping Son, HongFeng Jiang, William S Blaner, Yunying Hu, Yu-Xin Yin, Robert V Farese Jr, Shunichi Homma, Andrew V Turnbull, Jan W Eriksson, Shi-Lian Hu, Henry N Ginsberg, Li-Shin Huang, Ira J Goldberg
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 43 Pg. 29881-91 (Oct 24 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25157099 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Blood Glucose
• Enzyme Inhibitors
• Fatty Acids
• Lipids
• Peptides
• Triglycerides
• Venoms
• Cholesterol
• Exenatide
• Diacylglycerol O-Acyltransferase
• Protein Kinase C

Topics

• Aging (pathology)
• Animals
• Blood Glucose (metabolism)
• Cholesterol (blood)
• Diacylglycerol O-Acyltransferase (antagonists & inhibitors, metabolism)
• Enzyme Inhibitors (pharmacology)
• Exenatide
• Fatty Acids (blood)
• Gene Deletion
• Gene Expression Regulation (drug effects)
• Heart Failure (blood, enzymology, genetics)
• Humans
• Intestines (drug effects, pathology)
• Lipids (blood)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Organ Specificity
• Peptides (pharmacology)
• Phenotype
• Protein Kinase C (metabolism)
• Triglycerides (blood)
• Venoms (pharmacology)