Targeting PPAR-Regulated Pathways to Treat Cholestatic Liver Diseases: Novel Applications of Liquid Biopsies

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are chronic cholestatic liver diseases with limited therapeutic options. First-line therapy for PBC is ursodeoxycholic acid, although up to 40% of patients respond incompletely, and there is no effective therapy for PSC. Newer peroxisome proliferator-activated receptor (PPAR) agonists, e.g., seladelpar and elafibranor, received accelerated FDA approval as second-line treatments for PBC, and additional studies of PPAR agonists for PSC are underway. PPAR agonists have varying affinities for the PPAR isoforms (α, δ, γ), and the functional effects of isoform activation in humans are less known. Interindividual PPAR isoform expression varies across diseases and traditionally required invasive tissue biopsies for evaluation. Newer experimental approaches, such as extracellular vesicles (EVs) from liquid biopsies, can be used to characterize individual gene expression as an alternative (to tissue biopsy). The transcriptomic profiling of EVs uniquely allows for the quantification of coding and non-coding RNA transcripts, which may be used to study pathways relevant to PPAR expression and regulation and to identify biomarkers of treatment response to PPAR agonists in cholestasis. This review explores the application(s) of liquid biopsy-derived EVs for the identification of PPAR regulated pathways and its potential role in the treatment of PBC and PSC.