Inhibition of cardiac lipoprotein utilization by transgenic overexpression of Angptl4 in the heart.
To investigate the role of Angptl4, an inhibitor of lipoprotein lipase that is induced by >3-fold in the heart after rosiglitazone treatment, we generated transgenic mice that overexpress Angptl4 in the heart (MHC-Angptl4). We show that MHC-Angptl4 mice exhibit cardiac-restricted expression of the transgene and inhibition of cardiac lipoprotein lipase (LPL) activity. However, LPL activities in other tissues or that released into plasma by heparin are not affected. In addition, MHC-Angptl4 mice also exhibit hypertriglyceridemia after 6 h of fasting. We use echocardiography to show that MHC-Angptl4 mice develop left-ventricular dysfunction. Comparison of the metabolic profiles of isolated working hearts demonstrates that cardiac impairment in MHC-Angptl4 mice is positively associated with decreased triglyceride (TG) utilization. When bred to transgenic mice that overexpress acyl-CoA synthetase in the heart, a strain that exhibits elevated cardiac TG accumulation, cardiac TG content in double transgenic mice is reversed to that of wild-type mice. Taken together, our data support the hypothesis that induction of Angptl4 in the heart inhibits lipoprotein-derived fatty acid delivery. This mouse model will be useful to elucidate the role of reduced fatty acid supply in the pathogenesis of heart failure and related disorders.
Yu
Xinxin
X
Department of Physiology, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Burgess
Shawn C
SC
Ge
Hongfei
H
Wong
Kenny K
KK
Nassem
R Haris
RH
Garry
Daniel J
DJ
Sherry
A Dean
AD
Malloy
Craig R
CR
Berger
Joel P
JP
Li
Cai
C
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D000818:Animals; D001798:Blood Proteins / Q000235:genetics / Q000502:physiology*; D009202:Cardiomyopathies / Q000235:genetics / Q000503:physiopathology; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D008071:Lipoprotein Lipase / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D001798:Blood Proteins; D008074:Lipoproteins; D008071:Lipoprotein Lipase