Molecular actions of PPARα in lipid metabolism and inflammation

Nadia Bougarne, Basiel Weyers, Sofie J Desmet, Julie Deckers, David W Ray, Bart Staels, Karolien De Bosscher
2018 Endocrine reviews  
29 Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor of 30 clinical interest as a drug target in various metabolic disorders. PPARα also exhibits 31 marked anti-inflammatory capacities. The first generation PPARα agonists, the 32 fibrates, have however been hampered by drug-drug interaction issues, statin drop-in 33 and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the 34 molecular mechanisms by which PPARα works will enable control
more » ... of its activities as 35 a drug target for metabolic diseases with an underlying inflammatory component. 36 Given its role in reshaping the immune system, the full potential of this nuclear 37 receptor subtype as a versatile drug target with high plasticity becomes increasingly 38 clear, and a novel generation of agonists may pave the way for novel fields of 39 applications. 40 41 42 43 44 45 46 47 48 49 3 Outline 50 I. Introduction to PPAR family members 51 II. PPARα expression profile, gene and protein 52 structure 53 III. Modulating factors of PPARα activity 54 PPAR gene and protein expression 55 PPAR cofactors 56 PPAR post-translational modifications 57 IV. PPARα natural and synthetic ligands 58 PPAR natural ligands 59 PPAR synthetic ligands 60 Selective PPAR modulators (SPPARMs) 61 V. PPARα target genes and their function 62 PPAR target genes in liver 63 PPAR target genes in heart 64 PPAR target genes in lipid metabolism 65 PPAR target gene expression in immune cells 66 PPAR targets linked to the rodent-only hepatocarcinoma side effect 67 VI. PPAR agonists in a clinical setting 68 PPAR agonists and effects on liver in humans 69 PPAR agonists and effects on lipid and lipoprotein metabolism in 70 humans 71 PPAR agonists and effects on the cardiovascular system in humans 72 Human clinical trials and clinical trial endpoints 73 Selective PPAR modulators (SPPARMs) in humans 74 VII. Inflammation-priming and inflammation-resolving 75 molecular actions of PPARα 76 Effector cells mediating the anti-inflammatory activity of PPAR 77 Interactions between PPAR and other transcription factors 78 Cooperation between PPAR and other anti-inflammatory nuclear 79 receptors 80 Regulation of MAPK and PKC kinase activities by PPAR 81 Anti-inflammatory activity of PPAR in a PPRE-dependent manner 82 PPAR in the metabolic syndrome as an inflammatory disease 83 PPAR in age-related inflammation 84 PPAR in inflammatory bowel disease 85 PPAR in inflammatory skin disease 86 PPAR in other inflammatory diseases 87 The paradox of PPAR as a pro-inflammatory mediator 88 VIII. Future perspectives 89 90 91 92 93 5
doi:10.1210/er.2018-00064 pmid:30020428 fatcat:wjvef6lm4ngtjgwxmq65gca4bu