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Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure*
- Publication Year :
- 2014
- Publisher :
- American Society for Biochemistry and Molecular Biology, 2014.
-
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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....7723e96c628316d2eef422c90c7cf4bc