Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Cardiomyocyte-restricted peroxisome proliferator-activated receptor-δ deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy

Nature Medicine volume 10, pages 1245–1250 (2004)Cite this article

Abstract

Fatty acid oxidation (FAO) is a primary energy source for meeting the heart's energy requirements1,2,3. Peroxisome proliferator-activated receptor-δ (PPAR-δ) may have important roles in FAO4,5,6,7,8. But it remains unclear whether PPAR-δ is required for maintaining basal myocardial FAO. We show that cre-loxP-mediated cardiomyocyte-restricted deletion of PPAR-δ in mice downregulates constitutive expression of key FAO genes and decreases basal myocardial FAO. These mice have cardiac dysfunction, progressive myocardial lipid accumulation, cardiac hypertrophy and congestive heart failure with reduced survival. Thus, chronic myocardial PPAR-δ deficiency leads to lipotoxic cardiomyopathy. Together, our data show that PPAR-δ is a crucial determinant of constitutive myocardial FAO and is necessary to maintain energy balance and normal cardiac function. We suggest that PPAR-δ is a potential therapeutic target in treating lipotoxic cardiomyopathy and other heart diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: PPAR-δ and FAO gene expression, palmitate oxidation and glucose uptake rates.
Figure 2: Myocardial lipid accumulation and lipogenesis.
Figure 3: Cardiac hypertrophy and dilated cardiomyopathy in hearts from adult CR-Ppard−/− mice.
Figure 4: Isolated working heart function in CR-Ppard−/− and α-MyHC-Cre mice.

Similar content being viewed by others

References

  1. van der Vusse, G.J., Glatz, J.F., Stam, H.C. & Reneman, R.S. Fatty acid homeostasis in the normoxic and ischemic heart. Physiol. Rev. 72, 881–940 (1992).

    Article  CAS  Google Scholar 

  2. Vary, T.C., Reibel, D.K. & Neely, J.R. Control of energy metabolism of heart muscle. Annu. Rev. Physiol. 43, 419–430 (1981).

    Article  CAS  Google Scholar 

  3. Neely, J.R., Rovetto, M.J. & Oram, J.F. Myocardial utilization of carbohydrate and lipids. Prog. Cardiovasc. Dis. 15, 289–329 (1972).

    Article  CAS  Google Scholar 

  4. Wang, Y.X. et al. Peroxisome proliferator activated receptor δ activates fat metabolism to prevent obesity. Cell 113, 159–170 (2003).

    Article  CAS  Google Scholar 

  5. Tanaka, T. et al. Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc. Natl. Acad. Sci. USA 100, 15924–15929 (2003).

    Article  CAS  Google Scholar 

  6. Dressel, U. et al. The peroxisome proliferator-activated receptor β/δ agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol. Endocrinol. 17, 2477–2493 (2003).

    Article  CAS  Google Scholar 

  7. Gilde, A.J. et al. Peroxisome proliferator-activated receptor (PPAR) α and PPARβ/δ, but not PPARγ, modulate the expression of genes involved in cardiac lipid metabolism. Circ. Res. 92, 518–524 (2003).

    Article  CAS  Google Scholar 

  8. Cheng, L. et al. Peroxisome proliferator-activated receptor δ activates fatty acid oxidation in cultured neonatal and adult cardiomyocytes. Biochem. Biophys. Res. Commun. 313, 277–286 (2004).

    Article  CAS  Google Scholar 

  9. Barak, Y. et al. Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer. Proc. Natl. Acad. Sci. USA 99, 303–308 (2002).

    Article  CAS  Google Scholar 

  10. Peters, J.M. et al. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor β(δ). Mol. Cell Biol. 20, 5119–5128 (2000).

    Article  CAS  Google Scholar 

  11. Agah, R. et al. Gene recombination in postmitotic cells. Targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo. J. Clin. Invest. 100, 169–179 (1997).

    Article  CAS  Google Scholar 

  12. Gutstein, D.E. et al. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ. Res. 88, 333–339 (2001).

    Article  CAS  Google Scholar 

  13. Watanabe, K. et al. Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor α associated with age-dependent cardiac toxicity. J. Biol. Chem. 275, 22293–22299 (2000).

    Article  CAS  Google Scholar 

  14. Kersten, S. et al. Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting. J. Clin. Invest. 103, 1489–1498 (1999).

    Article  CAS  Google Scholar 

  15. Lee, Y. et al. Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM. Diabetes 46, 408–413 (1997).

    Article  CAS  Google Scholar 

  16. Chiu, H.C. et al. A novel mouse model of lipotoxic cardiomyopathy. J. Clin. Invest. 107, 813–822 (2001).

    Article  CAS  Google Scholar 

  17. Yagyu, H. et al. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J. Clin. Invest. 111, 419–426 (2003).

    Article  Google Scholar 

  18. Zhou, Y.T. et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc. Natl. Acad. Sci. USA 97, 1784–1789 (2000).

    Article  CAS  Google Scholar 

  19. Regan, T.J. & Weisse, A.B. Diabetic cardiomyopathy. J. Am. Coll. Cardiol. 19, 1165–1166 (1992).

    Article  CAS  Google Scholar 

  20. Zoneraich, S. & Mollura, J.L. Diabetes and the heart: state of the art in the 1990s. Can. J. Cardiol. 9, 293–299 (1993).

    CAS  Google Scholar 

  21. Szczepaniak, L.S. et al. Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am. J. Physiol. 276, E977–E989 (1999).

    CAS  Google Scholar 

  22. Chatham, J.C., Gao, Z.P. & Forder, J.R. Impact of 1 wk of diabetes on the regulation of myocardial carbohydrate and fatty acid oxidation. Am. J. Physiol. 277, E342–E351 (1999).

    CAS  Google Scholar 

  23. Shindo, Y., Osumi, T. & Hashimoto, T. Effects of administration of di-(2-ethylhexyl)phthalate on rat liver mitochondria. Biochem. Pharmacol. 27, 2683–2688 (1978).

    Article  CAS  Google Scholar 

  24. King, M.T. & Reiss, P.D. Separation and measurement of short-chain coenzyme-A compounds in rat liver by reversed-phase high-performance liquid chromatography. Anal. Biochem. 146, 173–179 (1985).

    Article  CAS  Google Scholar 

  25. Saddik, M., Gamble, J., Witters, L.A. & Lopaschuk, G.D. Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J. Biol. Chem. 268, 25836–25845 (1993).

    CAS  Google Scholar 

  26. Coven, D.L. et al. Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. Am. J. Physiol. Endocrinol. Metab. 285, E629–E636 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Chatham and G.H. Gibbons for reading of the manuscript. This work was partially supported by a starting grant from Morehouse Cardiovascular Research Institute (Enhancement of Cardiovascular and Related Research Areas, NIH/NHLBI 5 UH1 HL03676-02), grants from the US National Institutes of Health (MBRS S06GM08248 and G12-RR03034) and a scientist development award from the American Heart Association national center.

Author information

Authors and Affiliations

  1. Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, 30310, Georgia, USA

    Lihong Cheng, Guoliang Ding, Qianhong Qin, Yao Huang, Florence A Brako, Yan Xiao, Yuqing E Chen & Qinglin Yang

  2. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, 30322, Georgia, USA

    William Lewis

  3. Department of Pharmacology, Morehouse School of Medicine, Atlanta, 30310, Georgia, USA

    Nu He

  4. Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Ronald M Evans

  5. Center for Cardiovascular Development, Baylor College of Medicine, Houston, 77030, Texas, USA

    Michael D Schneider

Authors
  1. Lihong Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guoliang Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qianhong Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. William Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nu He
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ronald M Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael D Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Florence A Brako
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yan Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yuqing E Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qinglin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qinglin Yang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Generation of CR-PPAR-δ−/− mice. (PDF 76 kb)

Supplementary Fig. 2

Transcript levels of PPAR-α and PPAR-γ. (PDF 120 kb)

Supplementary Fig. 3

Relative protein levels of PGC-1α. (PDF 92 kb)

Supplementary Fig. 4

Heart weight to tibia length ratios. (PDF 78 kb)

Supplementary Fig. 5

Transcript levels of FAO genes. (PDF 120 kb)

Supplementary Methods (PDF 22 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, L., Ding, G., Qin, Q. et al. Cardiomyocyte-restricted peroxisome proliferator-activated receptor-δ deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med 10, 1245–1250 (2004). https://doi.org/10.1038/nm1116

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1116

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing