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Cardiac Metabolism and Mechanics are Altered by Genetic Loss of Lipoprotein Triglyceride Lipolysis

Abstract

Introduction

Most circulating fatty acids are contained in lipoprotein triglycerides. For the heart to acquire these lipids, they must be broken down into free fatty acids via the enzyme lipoprotein lipase (LpL). Although it has long been known that hearts primarily use esterified fatty acids as fuel, different sources of fatty acids were thought to be interchangeable.

Materials and methods

By creating mice with neonatal and acute LpL deletion we showed that lipoprotein-derived fatty acids could not be replaced by albumin-associated free fatty acids. Loss of cardiac LpL forces the heart to increase its uptake of glucose, reduce fatty acid oxidation, and eventually leads to cardiac dysfunction. In contrast, cardiomyocyte specific overexpression of an anchored form of LpL leads to excess lipid uptake, induction of fatty acid oxidation genes, and dilated cardiomyopathy.

Conclusion

Increasing lipid secretion from the heart or redirecting lipids to adipose tissue can alleviate this lipotoxic situation.

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References

  1. Ballard FB, Danforth WH, Naegle S, Bing RJ. Myocardial metabolism of fatty acids. J Clin Invest 1960;39:717–23.

    PubMed  CAS  Article  Google Scholar 

  2. Srinivasan M, Herrero P, McGill JB, Bennik J, Heere B, Lesniak D, et al. The effects of plasma insulin and glucose on myocardial blood flow in patients with type 1 diabetes mellitus. J Am Coll Cardiol 2005;46:42–8.

    PubMed  Article  CAS  Google Scholar 

  3. Pillutla P, Hwang YC, Augustus A, Yokoyama M, Yagyu H, Johnston TP et al. Perfusion of hearts with triglyceride-rich particles reproduces the metabolic abnormalities in lipotoxic cardiomyopathy. Am J Physiol Endocrinol Metab 2005;288:E1229–35.

    PubMed  Article  CAS  Google Scholar 

  4. Augustus A, Yagyu H, Haemmerle G, Bensadoun A, Vikramadithyan RK, Park SY, et al. Cardiac-specific knock-out of lipoprotein lipase alters plasma lipoprotein triglyceride metabolism and cardiac gene expression. J Biol Chem 2004;279:25050–7.

    PubMed  Article  CAS  Google Scholar 

  5. Levak-Frank S, Hofmann W, Weinstock PH, Radner H, Sattler W, Breslow JL, et al. Induced mutant mouse lines that express lipoprotein lipase in cardiac muscle, but not in skeletal muscle and adipose tissue, have normal plasma triglyceride and high-density lipoprotein-cholesterol levels. Proc Natl Acad Sci USA 1999;96:3165–70.

    PubMed  Article  CAS  Google Scholar 

  6. Herrero P, Peterson LR, McGill JB, Matthew S, Lesniak D, Dence C, et al. Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J Am Coll Cardiol 2006;47:598–604.

    PubMed  Article  CAS  Google Scholar 

  7. Augustus AS, Buchanan J, Park TS, Hirata K, Noh HL, Sun J, et al. Loss of lipoprotein lipase-derived fatty acids leads to increased cardiac glucose metabolism and heart dysfunction. J Biol Chem 2006;281:8716–23.

    PubMed  Article  CAS  Google Scholar 

  8. Noh HL, Okajima K, Molkentin JD, Homma S, Goldberg IJ. Acute lipoprotein lipase deletion in adult mice leads to dyslipidemia and cardiac dysfunction. Am J Physiol Endocrinol Metab 2006;291:E755–60.

    PubMed  Article  CAS  Google Scholar 

  9. Petrich BG, Molkentin JD, Wang Y. Temporal activation of c-Jun N-terminal kinase in adult transgenic heart via cre–loxP-mediated DNA recombination. Faseb J 2003;17:749–51.

    PubMed  CAS  Google Scholar 

  10. Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y, et al. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest 2003;111:419–26.

    PubMed  Article  Google Scholar 

  11. Yokoyama M, Yagyu H, Hu Y, Seo T, Hirata K, Homma S, et al. Apolipoprotein B production reduces lipotoxic cardiomyopathy: studies in heart-specific lipoprotein lipase transgenic mouse. J Biol Chem 2004;279:4204–11.

    PubMed  Article  CAS  Google Scholar 

  12. Vikramadithyan RK, Hirata K, Yagyu H, Hu, Y, Augustus A, Homma S, et al. Peroxisome proliferator-activated receptor agonists modulate heart function in transgenic mice with lipotoxic cardiomyopathy. J Pharmacol Exp Ther 2005;313:586–93.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Ira J. Goldberg.

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Noh, HL., Yamashita, H. & Goldberg, I.J. Cardiac Metabolism and Mechanics are Altered by Genetic Loss of Lipoprotein Triglyceride Lipolysis. Cardiovasc Drugs Ther 20, 441–444 (2006). https://doi.org/10.1007/s10557-006-0633-1

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  • DOI: https://doi.org/10.1007/s10557-006-0633-1

Key words

  • cardiac metabolism
  • cardiomyocyte
  • lipid secretion