Review Article: Targeting Peroxisome Proliferator-Activated Receptors in Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease characterised by cholestasis, progressive fibrosis and symptoms of pruritus and fatigue. Ursodeoxycholic acid (UDCA) is first-line therapy; however, many patients respond inadequately or are intolerant. Peroxisome proliferator-activated receptor (PPAR) agonists have emerged as second-line options.

This review examines PPAR isoform (PPAR-α, PPAR-δ and PPAR-γ) mediated pathways relevant to PBC, and structural, biochemical and clinical efficacy and safety features of PPAR agonists for PBC.

Preclinical studies on therapeutic PPAR agonism and clinical literature on PPAR agonists in PBC were identified through targeted PubMed searches and manual reference screening.

PPAR-α and PPAR-δ agonism improve cholestasis by reducing bile acid synthesis and inflammation. PPAR-α agonism also enhances bile acid detoxification and transport, while PPAR-δ agonism improves cholestatic pruritus by reducing pruritogenic signals. Individual PPAR isoforms are also associated with different safety profiles, with PPAR-α agonism linked to hepatic and muscle signals, and PPAR-γ agonism associated with fluid retention/weight gain. PPAR agonists differ in isoform selectivity. Although all agonists used in PBC reduce alkaline phosphatase levels, their impact on pruritus varies; PPAR-α predominant agonists (off-label fibrates, elafibranor) have a potential anti-pruritic effect, while selective PPAR-δ agonist, seladelpar, has demonstrated statistically significant improvements in pruritus. Fatigue is likely multifactorial, mediated through central nervous system effects and sleep disturbance; PPAR-α and PPAR-δ agents offer possible benefit.

Isoform selectivity contributes to the efficacy and safety profiles of PPAR agonists. Future research should investigate isoform-specific mechanisms, particularly regarding symptom relief and agent- and class-related toxicities.