{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:49:26Z","timestamp":1790704166777,"version":"4.1.0"},"reference-count":82,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T00:00:00Z","timestamp":1722470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients respond incompletely to UDCA, and advanced cases do not respond. UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. Left untreated, these diseases can progress to fibrosis and cirrhosis, resulting in liver failure and the need for transplantation. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience an incomplete response to UDCA. PPAR\u03b1 is predominantly expressed in the liver, and it plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5\u2019-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPAR\u03b1 agonists, e.g., fenofibrate, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC, and elafibranor, the first PPAR (dual \u03b1, \u03b2\/\u03b4) agonist, has been FDA-approved for the second-line treatment of PBC. Additionally, newer PPAR agonists that target various PPAR isoforms (\u03b2\/\u03b4, \u03b3) are under development as an adjunct therapy for PBC or PSC, although their impact on glucuronidation pathways are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC.<\/jats:p>","DOI":"10.3390\/cells13151296","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T08:14:46Z","timestamp":1722500086000},"page":"1296","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["PPAR-Mediated Bile Acid Glucuronidation: Therapeutic Targets for the Treatment of Cholestatic Liver Diseases"],"prefix":"10.3390","volume":"13","author":[{"given":"Gina M.","family":"Gallucci","sequence":"first","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen M.","family":"Hayes","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8959-6036","authenticated-orcid":false,"given":"James L.","family":"Boyer","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3067-1134","authenticated-orcid":false,"given":"Olivier","family":"Barbier","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Laval University, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Assis","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4724-0576","authenticated-orcid":false,"given":"Nisanne S.","family":"Ghonem","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1002\/cphy.c120027","article-title":"Bile formation and secretion","volume":"3","author":"Boyer","year":"2013","journal-title":"Compr. 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