Review article: targeting peroxisome proliferator-activated receptors in primary biliary cholangitis
Schattenberg, Jörn M Banales, Jesus M Hirschfield, Gideon Trivedi, Palak Cable, Edward E McWherter, Charles A Billin, Andrew N Crittenden, Daria B Budas, Grant
Schattenberg, Jörn M
Banales, Jesus M
Hirschfield, Gideon
Trivedi, Palak
Cable, Edward E
McWherter, Charles A
Billin, Andrew N
Crittenden, Daria B
Budas, Grant
Abstract
Background: 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.
Aims: 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.
Methods: Preclinical studies on therapeutic PPAR agonism and clinical literature on PPAR agonists in PBC were identified through targeted PubMed searches and manual reference screening.
Results: 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.
Conclusions: 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.
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Date
2026-03-29
Type
Article
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Citation
Schattenberg JM, Banales JM, Hirschfield G, Trivedi P, Cable EE, McWherter CA, Billin AN, Crittenden DB, Budas G. Review Article: Targeting Peroxisome Proliferator-Activated Receptors in Primary Biliary Cholangitis. Aliment Pharmacol Ther. 2026 May;63(9):1215-1235. doi: 10.1111/apt.70598. Epub 2026 Mar 29