Lipotoxic Heart Disease in Obese Rats: Implications for Human Obesity

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2000 Mar 4

PMID 10677535

Citations 426

Authors

Y T Zhou

P Grayburn

A Karim

M Shimabukuro

M Higa

D Baetens

L Orci

R H Unger

Affiliations

Soon will be listed here.

Abstract

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.

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References

Unger R, Zhou Y, Orci L . Regulation of fatty acid homeostasis in cells: novel role of leptin. Proc Natl Acad Sci U S A. 1999; 96(5):2327-32. PMC: 26783. DOI: 10.1073/pnas.96.5.2327. View

Mokdad A, Serdula M, Dietz W, Bowman B, Marks J, Koplan J . The spread of the obesity epidemic in the United States, 1991-1998. JAMA. 1999; 282(16):1519-22. DOI: 10.1001/jama.282.16.1519. View

Phillips M, Liu Q, HAMMOND H, Dugan V, Hey P, Caskey C . Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet. 1996; 13(1):18-9. DOI: 10.1038/ng0596-18. View

Bielawska A, Shapiro J, Jiang L, Melkonyan H, Piot C, Wolfe C . Ceramide is involved in triggering of cardiomyocyte apoptosis induced by ischemia and reperfusion. Am J Pathol. 1997; 151(5):1257-63. PMC: 1858093. View

Shimabukuro M, Zhou Y, Levi M, Unger R . Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci U S A. 1998; 95(5):2498-502. PMC: 19389. DOI: 10.1073/pnas.95.5.2498. View

Zhou Y, Shimabukuro M, Lee Y, Koyama K, Higa M, Ferguson T . Enhanced de novo lipogenesis in the leptin-unresponsive pancreatic islets of prediabetic Zucker diabetic fatty rats: role in the pathogenesis of lipotoxic diabetes. Diabetes. 1998; 47(12):1904-8. DOI: 10.2337/diabetes.47.12.1904. View

Tandler B . Improved uranyl acetate staining for electron microscopy. J Electron Microsc Tech. 1990; 16(1):81-2. DOI: 10.1002/jemt.1060160110. View

Lee Y, Hirose H, Ohneda M, Johnson J, McGarry J, Unger R . Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci U S A. 1994; 91(23):10878-82. PMC: 45129. DOI: 10.1073/pnas.91.23.10878. View

Higa M, Zhou Y, Ravazzola M, Baetens D, Orci L, Unger R . Troglitazone prevents mitochondrial alterations, beta cell destruction, and diabetes in obese prediabetic rats. Proc Natl Acad Sci U S A. 1999; 96(20):11513-8. PMC: 18065. DOI: 10.1073/pnas.96.20.11513. View

10.

Alpert M, Terry B, Mulekar M, Cohen M, Massey C, Fan T . Cardiac morphology and left ventricular function in normotensive morbidly obese patients with and without congestive heart failure, and effect of weight loss. Am J Cardiol. 1997; 80(6):736-40. DOI: 10.1016/s0002-9149(97)00505-5. View

11.

Zhou Y, Wang Z, Higa M, Newgard C, Unger R . Reversing adipocyte differentiation: implications for treatment of obesity. Proc Natl Acad Sci U S A. 1999; 96(5):2391-5. PMC: 26794. DOI: 10.1073/pnas.96.5.2391. View

12.

Zhou Y, Shimabukuro M, Wang M, Lee Y, Higa M, Milburn J . Role of peroxisome proliferator-activated receptor alpha in disease of pancreatic beta cells. Proc Natl Acad Sci U S A. 1998; 95(15):8898-903. PMC: 21174. DOI: 10.1073/pnas.95.15.8898. View

13.

Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W . Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci U S A. 1993; 90(6):2160-4. PMC: 46045. DOI: 10.1073/pnas.90.6.2160. View

14.

Iida M, Murakami T, Ishida K, Mizuno A, Kuwajima M, Shima K . Substitution at codon 269 (glutamine --> proline) of the leptin receptor (OB-R) cDNA is the only mutation found in the Zucker fatty (fa/fa) rat. Biochem Biophys Res Commun. 1996; 224(2):597-604. DOI: 10.1006/bbrc.1996.1070. View

15.

Perry D, Hannun Y . The use of diglyceride kinase for quantifying ceramide. Trends Biochem Sci. 1999; 24(6):226-7. DOI: 10.1016/s0968-0004(99)01407-3. View

16.

DANNO H, Jincho Y, Budiyanto S, Furukawa Y, Kimura S . A simple enzymatic quantitative analysis of triglycerides in tissues. J Nutr Sci Vitaminol (Tokyo). 1992; 38(5):517-21. DOI: 10.3177/jnsv.38.517. View

17.

Yip J, Facchini F, Reaven G . Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease. J Clin Endocrinol Metab. 1998; 83(8):2773-6. DOI: 10.1210/jcem.83.8.5005. View

18.

Shimabukuro M, Ohneda M, Lee Y, Unger R . Role of nitric oxide in obesity-induced beta cell disease. J Clin Invest. 1997; 100(2):290-5. PMC: 508191. DOI: 10.1172/JCI119534. View