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PPAR control of metabolism and cardiovascular functions

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From Nature Reviews Cardiology

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Abstract

Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.

Key points

  • Peroxisome proliferator-activated receptors (PPARs) are fatty acid sensors that regulate whole-body metabolism.

  • Activation of PPARγ (for example, by glitazones) improves the management of diabetes mellitus by increasing insulin sensitivity.

  • Activation of PPARα (for example, by fibrates) normalizes atherogenic dyslipidaemia, thereby lowering the risk of cardiovascular disease.

  • PPARs are expressed in the heart, where they modulate lipid and glucose metabolism.

  • Failing or stressed hearts switch from the preferential use of fatty acids as energy substrates to glucose oxidation, with repression of the PPARα and PPARδ pathways.

  • Rescuing PPARδ or both PPARα and PPARδ signalling, particularly in early stages of cardiac remodelling, might be a promising therapeutic strategy for heart failure.

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Fig. 1: Metabolic switches driven by the PPAR and HIF–mTOR pathways during heart failure.
Fig. 2: PPAR regulation of cardiomyocyte metabolism.

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Acknowledgements

The authors are supported by grants from the French Agence Nationale de la Recherche (ANR-16-RHUS-0006-PreciNASH; European Genomic Institute for Diabetes ANR-10-LABX-0046 and ANR-16-IDEX-0004 ULNE; ANR TOMIS-Leukocyte ANR-CE14-0003-01 and ANR CALMOS ANR-18-CE17-0003-02), the Leducq Foundation LEAN Network 16CVD01 and the French National Center for Precision Diabetic Medicine — PreciDIAB (ANR-18-IBHU-0001; 20001891/NP0025517; 2019_ESR_11). B.S. is a recipient of an ERC Advanced Grant (694717).

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B.S. is a consultant for Genfit. D.M. and L.B. declare no competing interests.

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Nature Reviews Cardiology thanks K. Drosatos, D. Kelly, A. Murray and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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The authors have focused on original research articles published after 2017 covering the topics of cardiovascular risk factors, metabolism and new mechanisms of regulation by PPARs, because exhaustive reviews on PPAR functions covering the period before 2017 have been published previously. For the section on the role of PPARs in heart metabolism, they focus on studies showing the function of the PPARs in the heart.

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Montaigne, D., Butruille, L. & Staels, B. PPAR control of metabolism and cardiovascular functions. Nat Rev Cardiol 18, 809–823 (2021). https://doi.org/10.1038/s41569-021-00569-6

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