Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.

PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle

“…It is tempting to speculate that certain autoimmune myositis disorders such as polymyositis or dermatomyositis, or other forms of musculoskeletal painful diseases could one day be mitigated or treated via an approach that upregulates FoxA2 activity in the muscles. PPARs, as ligand activated nuclear receptors, play crucial biological roles in many health conditions, including metabolic diseases and autoimmune diseases [11]. The use of specific PPARβ/δ agonists in humans could be beneficial to lipid oxidation and could even have an additional benefit by reducing inflammation and painful muscles in these rheumatology conditions.…”

“…The three PPAR isotypes, designated PPARα, PPARβ/δ, and PPARγ, belong to the nuclear hormone receptor superfamily. They are activated by endogenous ligands, such as free fatty acids and their derivatives, and by a variety of synthetic drugs used in the treatment of metabolic syndrome and type 2 diabetes [10,11]. PPARβ/δ is the predominant isotype in skeletal muscle and its activation increases lipid uptake and catabolism via β-oxidation [12], along with a shift towards oxidative fibers, which enhances oxidative capacity and promotes running endurance, leading to an overall reduction in body fat [13][14][15].…”

Pharmacological (or Synthetic) and Nutritional Agonists of PPAR-γ as Candidates for Cytokine Storm Modulation in COVID-19 Disease

“…Therefore, exploring the main activation mechanisms of novel PPAR ligands as well as their pharmacodynamics represents a promising research area, paving the way to more potent and effective therapeutic strategies in many disease fields. A comprehensive overview of PPAR modulators and their current clinical status is reviewed elsewhere [46]. Based on these considerations, PPAR-γ could represent a promising target for treating viral influenza associated with the inflammatory circuit that occurs during the cytokine storm.…”

“…This mechanism is depicted in Figure 3. The wide clinical implications of targeting PPAR-γ encouraged the study and development of a novel class of PPAR-γ agonists, like dual-PPAR and pan-PPAR agonists, called glitazars [46]. Among these, the PPARα/γ dual agonists have been proposed for treatment of type 2 diabetes and dyslipidemia, demonstrating also anti-inflammatory and anti-coagulant effects [10].…”

Dyslipidemia in Kidney Disorders: Perspectives on Mitochondria Homeostasis and Therapeutic Opportunities

“…Fibrates also moderately increase blood HDL cholesterol. Mechanistically, the PPARα agonists activate PPARα, promote peroxisomal and mitochondrial FAO, initiate cellular cascade to upregulate lipoprotein lipase, and ultimately cause more efficient catabolism of VLDL and TAG (Lakhia et al, 2018;Cheng et al, 2019;Yamashita et al, 2020).…”