title: A murine model of isolated cardiac steatosis leads to cardiomyopathy.
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.
authors.affiliation: Department of Medicine and Diabetes Center, University of California at San Francisco, San Francisco, CA 94143-0540, USA. dglenn@diabetes.ucsf.edu
authors.forename: Denis J
authors.initials: DJ
authors.lastname: Glenn
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Minobu
authors.initials: M
authors.lastname: Nishimoto
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Cruz
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uchida
authors.forename: Walter M
authors.initials: WM
authors.lastname: Holleran
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yerem
authors.initials: Y
authors.lastname: Yeghiazarians
authors.forename: David G
authors.initials: DG
authors.lastname: Gardner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D014280:Triglycerides; D045304:Cytochromes c; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase