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DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity
Li Liu1, XiaoJing Shi1, Kalyani G Bharadwaj1
1Department of Medicine, Division of Preventive Medicine and Metabolism, Columbia University College of Physicians and Surgeons, New York, New York 10032.
The Journal of Biological Chemistry
|September 26, 2009
Summary
Triglyceride (TG) accumulation in the heart is not directly toxic but may protect against lipotoxicity. Overexpressing the TG-synthesizing enzyme diacylglycerol acyltransferase 1 (DGAT1) improved heart function and survival in mice.
Area of Science:
- Cardiology
- Molecular Biology
- Metabolic Diseases
Background:
- Intracellular lipid accumulation in the heart is linked to cardiomyopathy.
- The specific role of triglyceride (TG) in cardiac health and disease remains poorly understood.
- Physiologic cardiac hypertrophy, induced by exercise, is associated with increased TG stores and diacylglycerol acyltransferase 1 (DGAT1) expression.
Purpose of the Study:
- To investigate the role of triglyceride (TG) synthesis via diacylglycerol acyltransferase 1 (DGAT1) in cardiac function and lipid metabolism.
- To determine if enhancing DGAT1 activity can mitigate lipotoxic cardiomyopathy.
- To assess the impact of DGAT1 overexpression on cardiac lipid profiles, function, and survival.
Main Methods:
- Generated transgenic mice overexpressing DGAT1 in cardiomyocytes using the alpha-myosin heavy chain (MHC) promoter.
- Crossed MHC-DGAT1 mice with MHC-ACS mice, which exhibit lipotoxic cardiomyopathy.
- Assessed cardiac function using echocardiography and cardiac catheterization, measured lipid levels, and evaluated cardiomyocyte apoptosis and fatty acid oxidation.
Main Results:
- DGAT1 overexpression doubled cardiac DGAT activity and TG content, while reducing ceramide, DAG, and free fatty acid levels, without affecting baseline cardiac function.
- Double transgenic MHC-DGAT1xMHC-ACS mice showed significantly improved cardiac function (74% increase in fractional shortening) and diastolic function compared to MHC-ACS mice.
- Improved cardiac function correlated with reduced cardiac DAG and ceramide, decreased cardiomyocyte apoptosis, and increased fatty acid oxidation, leading to enhanced survival.
Conclusions:
- Triglyceride (TG) is likely not a toxic lipid species but rather a component of physiologic hypertrophy and may play a cytoprotective role during lipid overload.
- Induction of DGAT1 may offer a therapeutic strategy to ameliorate cardiac dysfunction in conditions of excess toxic lipid accumulation.
- Targeting DGAT1 could be beneficial in managing lipotoxic cardiomyopathy by modulating cardiac lipid metabolism and reducing cellular stress.
