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

Area of Science:

• Hepatology and immunology
• Pharmacology of nuclear receptors
• Gastroenterology

Background:

• Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease causing cholestasis, fibrosis, pruritus, and fatigue.
• Ursodeoxycholic acid (UDCA) is the standard first-line treatment, but many patients have inadequate responses or intolerance.
• Peroxisome proliferator-activated receptor (PPAR) agonists are emerging as potential second-line therapies for PBC.

Purpose of the Study:

• To review the role of PPAR isoforms (PPAR-α, PPAR-δ, PPAR-γ) in PBC pathogenesis.
• To examine the efficacy and safety of PPAR agonists in treating PBC.
• To understand how PPAR isoform selectivity impacts therapeutic outcomes.

Main Methods:

• Literature search of preclinical studies on PPAR agonism in PBC.
• Systematic review of clinical trials involving PPAR agonists for PBC treatment.
• Analysis of PubMed and reference lists for relevant research.

Main Results:

• PPAR-α and PPAR-δ agonism reduce cholestasis by decreasing bile acid synthesis and inflammation.
• PPAR-α enhances bile acid detoxification, while PPAR-δ alleviates pruritus by reducing pruritogenic signals.
• PPAR agonists exhibit varied safety profiles (e.g., PPAR-α: hepatic/muscle; PPAR-γ: fluid retention) and differential effects on pruritus and fatigue.

Conclusions:

• PPAR agonist efficacy and safety are significantly influenced by their isoform selectivity.
• Further research is needed to elucidate isoform-specific mechanisms for symptom relief.
• Investigating agent- and class-specific toxicities is crucial for optimizing PPAR-based therapies in PBC.