Importantly, endothelial dysfunction may cause portal hypertension and its ensuing complications, thereby conferring affected patients with higher risks of morbidity and mortality. Despite this, pharmacotherapies for vascular dysfunction in NASH remain an unmet need. Peroxisome proliferator‐activated receptors (PPARs) are nuclear receptors functioning as ligand‐activated transcription factors. The three PPAR isoforms (PPARα, PPARβ/δ and PPARγ) are major regulators of key physiological functions, including glucose metabolism, inflammation, endothelial function and fibrosis. Interestingly, the severity of NASH in humans has been found to inversely correlate with hepatic PPARα and PPARγ expression, supporting their clinical investigation for vascular dysfunction in chronic liver disease.
This review aimed to summarise the state of research into PPARs for NAFLD and NASH, with a focus on their hepatic (notably vascular) and cardiovascular effects.
PPAR activation in the liver is vasoprotective and anticoagulant: it improves endothelial dysfunction and regulates vascular tone. Moreover, PPARs attenuate hepatic inflammation by releasing anti-inflammatory mediators and preventing immune cell recruitment and activation. In this vein, PPARs play a central role in countering the NAFLD-to-NASH transition. These powerful hepatic effects have been confirmed in vivo: in NASH clinical trials, lanifibranor, a pan-PPAR agonist, achieved both fibrosis improvement and NASH resolution endpoints. To date, it remains the only compound to do so. Importantly, PPARs affect the heart: they improve cardiovascular outcomes by mediating hepatokine activity, which may indirectly attenuate liver disease. This warrants the incorporation of cardiovascular function assessments in clinical trials for NASH, both for safety and efficacy purposes.