title: 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.affiliation: From the Divisions of Preventive Medicine and Nutrition and Institute of Systems Biomedicine, Peking University Health Science Center, 100083 Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: From the Divisions of Preventive Medicine and Nutrition and.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Trent
authors.affiliation: From the Divisions of Preventive Medicine and Nutrition and Department of Geriatrics, Affiliated Provincial Hospital, Anhui Medical University, 230001 Hefei, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Fang
authors.affiliation: From the Divisions of Preventive Medicine and Nutrition and.
authors.forename: Ni-Huiping
authors.initials: NH
authors.lastname: Son
authors.affiliation: From the Divisions of Preventive Medicine and Nutrition and.
authors.forename: HongFeng
authors.initials: H
authors.lastname: Jiang
authors.affiliation: From the Divisions of Preventive Medicine and Nutrition and.
authors.forename: William S
authors.initials: WS
authors.lastname: Blaner
authors.affiliation: From the Divisions of Preventive Medicine and Nutrition and.
authors.forename: Yunying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Institute of Systems Biomedicine, Peking University Health Science Center, 100083 Beijing, China.
authors.forename: Yu-Xin
authors.initials: YX
authors.lastname: Yin
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Departments of Medicine and Biochemistry and Biophysics, University of California, San Francisco, California 94158.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.affiliation: Cardiology, Columbia University College of Physicians and Surgeons, New York, New York 10032.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.affiliation: Astra-Zeneca Company, 431 50 Mölndal, Sweden.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Turnbull
authors.affiliation: Astra-Zeneca Company, 431 50 Mölndal, Sweden, Department of Medical Sciences, Uppsala University, 751 05 Uppsala, Sweden, and.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Eriksson
authors.affiliation: Department of Geriatrics, Affiliated Provincial Hospital, Anhui Medical University, 230001 Hefei, China.
authors.forename: Shi-Lian
authors.initials: SL
authors.lastname: Hu
authors.affiliation: From the Divisions of Preventive Medicine and Nutrition and.
authors.forename: Henry N
authors.initials: HN
authors.lastname: Ginsberg
authors.affiliation: From the Divisions of Preventive Medicine and Nutrition and.
authors.forename: Li-Shin
authors.initials: LS
authors.lastname: Huang
authors.affiliation: 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.org.
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077270:Exenatide; D005227:Fatty Acids / Q000097:blood; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000097:blood* / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008055:Lipids / Q000097:blood*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D009928:Organ Specificity; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014688:Venoms / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D008055:Lipids; D010455:Peptides; D014280:Triglycerides; D014688:Venoms; D002784:Cholesterol; D000077270:Exenatide; D051048:Diacylglycerol O-Acyltransferase; D011493:Protein Kinase C
keywords: Animal Model; Cardiac Metabolism; Ceramide; Diacylglycerol; Heart Failure; Lipid; Lipotoxicity; Metabolism; Signal Transduction