Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors activated by natural fatty acid derivatives and synthetic agonists. Their regulation of whole-body inflammation, as well as lipid and glucose metabolism, allows PPAR family members, including isotypes PPARα, PPARβ and PPARγ, to modulate target tissue transcriptomic profiles according to changing nutritional, metabolic, and inflammatory environments. As such, PPARs regulate several pathways implicated in NASH pathogenesis.
This review aimed to explore existing evidence supporting PPAR-modulating drugs’ anti-NASH activity in preclinical models and clinical trials.
The excessive lipid accumulation underpinning NAFLD triggers mitochondrial damage, hepatocytic ballooning, pro-inflammatory cytokine activation and pro-fibrogenic factor release affecting hepatic stellate cells. Exposure of the liver to microbiota-derived pathogen- and damage-associated molecular patterns combined with dysregulations in adipokine and myokine secretion all contribute to NASH development. According to pre-clinical and clinical data, these intra- and extra-hepatic vascular processes can be modulated by PPARs. Moreover, pre-clinical and clinical testing of PPAR-modulating drugs for NASH suggests that pan-PPAR agonism may be necessary to achieve significant results on histological endpoints. Results from the phase 2b NATIVE trial of lanifibranor, a pan-PPAR agonist, support this: 24 weeks of treatment with the compound revealed dose-dependent effects on primary and composite endpoints. These findings also emphasise the importance of developing PPAR-modulating compounds with the ability to target NASH’s extra-hepatic metabolo-inflammatory drivers and its intra-hepatic disease mechanisms to maximise the chances of therapeutic success.