Treating NASH by targeting peroxisome proliferator-activated receptors

Abstract

The pathophysiology of non-alcoholic steatohepatitis (NASH) encompasses a complex set of intra- and extrahepatic driving mechanisms, involving numerous metabolic, inflammatory, vascular and fibrogenic pathways. The peroxisome proliferator-activated receptors (PPARs) α, β/δ and γ belong to the nuclear receptor family of ligand-activated transcription factors. Activated PPARs modulate target tissue transcriptomic profiles, enabling the body's adaptation to changing nutritional, metabolic and inflammatory environments. PPARs hence regulate several pathways involved in NASH pathogenesis. Whereas single PPAR agonists exert robust anti-NASH activity in several preclinical models, their clinical effects on histological endpoints of NASH resolution and fibrosis regression appear more modest. Simultaneous activation of several PPAR isotypes across different organs and within-organ cell types, resulting in pleiotropic actions, enhances the therapeutic potential of PPAR agonists as pharmacological agents for NASH and NASH-related hepatic and extrahepatic morbidity, with some compounds having already shown clinical efficacy on histological endpoints.