PPARα, β/δ and γ isotypes are regulators of signalling pathways involved in non-alcoholic steatohepatitis (NASH), modulating fatty acid oxidation, lipid storage, insulin sensitivity, and glucose metabolism. Importantly, as these PPAR family members are differentially expressed within and between organs, they exhibit complementary activities in steatotic and fibrotic cellular processes. Moreover, as these isotypes are variably expressed in disparate immune cells, they further exert control over NASH-associated hepatic and systemic inflammatory responses.
This review aimed to underscore lessons learned regarding PPARs and emphasise their promise as pharmacological targets for NASH therapeutics.
Individual PPAR agonists are chemically, and thus pharmacokinetically and pharmacodynamically, distinct from one another. As such, disparate PPAR agonists elicit diverse drug-specific responses and thus require individual safety and efficacy assessments. While certain single (PPARα and PPARγ) and dual PPAR agonists have exhibited efficacy on histological parameters, pre-clinical and clinical observations underscore the importance of comprehensive pan-PPAR agonism to attain significant improvements in histological endpoints. Alongside liver histology and function, these pan-PPAR agonists also have the potential to improve NASH’s metabolic features, and may thus prevent the development of comorbid extrahepatic diseases, e.g. type 2 diabetes and obesity. Notably, such histological and metabolic improvements have been achieved with the pan-PPAR agonist lanifibranor, whose promising efficacy in phase 2 trials has spurred its advancement into phase 3.