A Murine Model of Isolated Cardiac Steatosis Leads to Cardiomyopathy
- 1 February 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hypertension
- Vol. 57 (2), 216-222
- https://doi.org/10.1161/hypertensionaha.110.160655
Abstract
Lipid accumulation in the heart is associated with obesity and diabetes mellitus and may play an important role in the pathogenesis of heart failure seen in this patient population. Stored triglycerides are synthesized by the enzyme diacylglycerol acyl transferase (DGAT). We hypothesized that forced expression of DGAT1 in the cardiac myocyte would result in increased lipid accumulation and heart dysfunction. A cardiac myocyte–selective DGAT1 transgenic mouse was created and demonstrated increased lipid accumulation in the absence of hyperglycemia, plasma dyslipidemia or differences in body weight. Over time, expression of DGAT1 in the heart resulted in the development of a significant cardiomyopathy. Echocardiography revealed diastolic dysfunction with increased early mitral inflow velocity to late mitral inflow velocity ratio and decreased deceleration time, suggesting a restrictive pattern in the transgenic mice. Moderate systolic dysfunction was also seen at 52 weeks. Histological analysis showed increased cardiac fibrosis and increased expression of procollagen type 1A, matrix metalloproteinase 2, and tissue inhibitor of matrix metalloproteinase 2 in the transgenic mice. Mitochondrial biogenesis was reduced in the transgenic hearts, as was expression of cytochrome c oxidase 1 and cytochrome c . Expression of key transcription factors important in the regulation of mitochondrial biogenesis were reduced. These findings suggest that triglyceride accumulation, in the absence of systemic metabolic derangement, results in cardiac dysfunction and decreased mitochondrial biogenesis.Keywords
This publication has 55 references indexed in Scilit:
- Peroxisome Proliferator-Activated Receptor δ Is an Essential Transcriptional Regulator for Mitochondrial Protection and Biogenesis in Adult HeartCirculation Research, 2010
- DGAT1 Expression Increases Heart Triglyceride Content but Ameliorates LipotoxicityPublished by Elsevier BV ,2009
- PGC-1α and ERRα target gene downregulation is a signature of the failing human heartJournal of Molecular and Cellular Cardiology, 2009
- Minireview: The PGC-1 Coactivator Networks: Chromatin-Remodeling and Mitochondrial Energy MetabolismMolecular Endocrinology, 2009
- Cardiac Remodeling in ObesityPhysiological Reviews, 2008
- Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistanceJCI Insight, 2007
- PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic SteatosisPLoS Biology, 2005
- Mouse models of mitochondrial dysfunction and heart failureJournal of Molecular and Cellular Cardiology, 2005
- Mechanisms of Lipoapoptosis: Implications for Human Heart DiseaseTrends in Cardiovascular Medicine, 2002
- Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1JCI Insight, 2002