Lipotoxic heart disease in obese rats: implications for human obesity.
To determine the mechanism of the cardiac dilatation and reduced contractility of obese Zucker Diabetic Fatty rats, myocardial triacylglycerol (TG) was assayed chemically and morphologically. TG was high because of underexpression of fatty acid oxidative enzymes and their transcription factor, peroxisome proliferator-activated receptor-alpha. Levels of ceramide, a mediator of apoptosis, were 2-3 times those of controls and inducible nitric oxide synthase levels were 4 times greater than normal. Myocardial DNA laddering, an index of apoptosis, reached 20 times the normal level. Troglitazone therapy lowered myocardial TG and ceramide and completely prevented DNA laddering and loss of cardiac function. In this paper, we conclude that cardiac dysfunction in obesity is caused by lipoapoptosis and is prevented by reducing cardiac lipids.
Zhou
Y T
YT
Gifford Laboratories, Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Grayburn
P
P
Karim
A
A
Shimabukuro
M
M
Higa
M
M
Baetens
D
D
Orci
L
L
Unger
R H
RH
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002839:Chromans / Q000494:pharmacology; D053938:DNA Fragmentation; D004452:Echocardiography; D006331:Heart Diseases / Q000503:physiopathology*; D006801:Humans; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism; D008297:Male; D008854:Microscopy, Electron; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology*; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D000077288:Troglitazone
D001786:Blood Glucose; D002839:Chromans; D007328:Insulin; D012333:RNA, Messenger; D013844:Thiazoles; D045162:Thiazolidinediones; D000077288:Troglitazone