The Role of PPAR-δ in Metabolism, Inflammation, and Cancer: Many Characters of a Critical Transcription Factor

Abstract

Peroxisome proliferator-activated receptor-delta (PPAR-δ), one of three members of the PPAR group in the nuclear receptor superfamily, is a ligand-activated transcription factor. PPAR-δ regulates important cellular metabolic functions that contribute to maintaining energy balance. PPAR-δ is especially important in regulating fatty acid uptake, transport, and β-oxidation as well as insulin secretion and sensitivity. These salutary PPAR-δ functions in normal cells are thought to protect against metabolic-syndrome-related diseases, such as obesity, dyslipidemia, insulin resistance/type 2 diabetes, hepatosteatosis, and atherosclerosis. Given the high clinical burden these diseases pose, highly selective synthetic activating ligands of PPAR-δ were developed as potential preventive/therapeutic agents. Some of these compounds showed some efficacy in clinical trials focused on metabolic-syndrome-related conditions. However, the clinical development of PPAR-δ agonists was halted because various lines of evidence demonstrated that cancer cells upregulated PPAR-δ expression/activity as a defense mechanism against nutritional deprivation and energy stresses, improving their survival and promoting cancer progression. This review discusses the complex relationship between PPAR-δ in health and disease and highlights our current knowledge regarding the different roles that PPAR-δ plays in metabolism, inflammation, and cancer.

PPAR Beta/Delta and the Hallmarks of Cancer

“…Many studies using different cell models have been published afterwards. Several aspects of PPARβ/δ function with relevance for cancer growth have been reviewed recently [1,5,6,[9][10][11].…”

Endogenous hydrogen sulfide improves vascular remodeling through PPARδ/SOCS3 signaling

“…PPARδ inhibits VSMCs proliferation through suppressing cyclin D1 and cyclin-dependent kinase 4, and inducing cyclin-dependent kinase inhibitor p21 and p27 [44] . PPARδ contributes to anti-inflammation and anti-apoptosis effects and suppresses cellular migration in metabolic diseases by inhibiting IL1β [45] . In diabetic mice, the phosphorylation of STAT3 is suppressed by PPARδ or its agonist GW501516 which blocks inflammation in adipocytes and hepatocytes [46] .…”

Alisol A Alleviates Arterial Plaque by Activating AMPK/SIRT1 Signaling Pathway in apoE-Deficient Mice

“…PPARd is an unsaturated fatty acid receptor, expresses in most cells including skeletal muscle and macrophages, and acts as a critical regulator of cellular energy expenditure. Its activation can suppress inflammation, reduce lipase activity, and inhibit low density lipoprotein production (Liu et al, 2018). It has been reported that PPARd regulated fatty acid transport, b-oxidation, and mitochondrial respiration (Wang et al, 2003).…”