{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T16:53:16Z","timestamp":1755795196158,"version":"3.44.0"},"reference-count":61,"publisher":"Portland Press Ltd.","issue":"16","license":[{"start":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T00:00:00Z","timestamp":1753228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,8,21]]},"abstract":"<jats:p>Obeticholic acid (OCA) is the second-line therapy for primary biliary cholangitis. While efficient in promoting bile acid (BA) detoxification and limiting liver fibrosis, its clinical use is restricted by severe dose-dependent side effects. We tested the hypothesis that adding n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids to OCA may improve the therapeutic effect of the low drug dosage. Several liver cell lines were exposed to vehicle, low or high OCA dose (1\u201320 \u03bcM) in the presence or absence of EPA\/DHA for 24 h. To induce ER stress, apoptosis, and fibrosis, HepG2 cells were exposed to a 400 \u03bcM BA mixture or to 2 ng\/ml transforming growth factor-\u03b2 (TGF-\u03b2). For inflammation analyses, THP-1 cells were activated with 100 ng\/ml lipopolysaccharides (LPS). The impact of OCA+EPA\/DHA was assessed using transcriptomic (qRT-PCR), proteomic (ELISA, caspase-3), and metabolomic (LC-MS\/MS) approaches. The addition of EPA\/DHA reinforced the ability of low OCA dose to down-regulate the expression of genes involved in BA synthesis (CYP7A1 and CYP8B1) and uptake (NTCP) and to up-regulate the expression of MRP2 and 3 genes. EPA\/DHA also enhanced the anti-inflammatory response of the drug by reducing the expression of the LPS-induced cytokines: tumor necrosis factor \u03b1 (TNF\u03b1), interleukin (IL)-6, IL-1\u03b2, and monocyte chemoattractant protein-1 in THP-1 macrophages. OCA+EPA\/DHA decreased the expression of BIP, CHOP, and COL1A1 genes and the caspase-3 activity. EPA+DHA potentiate the response to low OCA doses on BA toxicity and provide additional benefits on ER stress, apoptosis, inflammation, and fibrosis. These observations support the idea that adding n-3 PUFAs to the drug may reduce the risk of dose-related side effects in patients treated with OCA.<\/jats:p>","DOI":"10.1042\/bcj20253113","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T16:23:03Z","timestamp":1753287783000},"page":"1145-1161","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmaco-nutraceutical improvement of the response to obeticholic acid with omega-3 polyunsaturated fatty acids"],"prefix":"10.1042","volume":"482","author":[{"given":"Audrey-Anne","family":"Lavoie","sequence":"first","affiliation":[{"name":"1Laboratory of Molecular Pharmacology, Endocrinology-Nephrology, CHU de Qu\u00e9bec Research Center, Qu\u00e9bec, QC G1V 4G2, Canada"},{"name":"2Faculty of Pharmacy, Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"},{"name":"3Centre Nutrition, sant\u00e9 et soci\u00e9t\u00e9 (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariane","family":"Th\u00e9rien","sequence":"additional","affiliation":[{"name":"1Laboratory of Molecular Pharmacology, Endocrinology-Nephrology, CHU de Qu\u00e9bec Research Center, Qu\u00e9bec, QC G1V 4G2, Canada"},{"name":"2Faculty of Pharmacy, Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"},{"name":"3Centre Nutrition, sant\u00e9 et soci\u00e9t\u00e9 (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anisia","family":"Silva","sequence":"additional","affiliation":[{"name":"2Faculty of Pharmacy, Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"},{"name":"4Quebec Heart and Lung Institute, Quebec City, QC G1V 4G5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuel","family":"Par\u00e9","sequence":"additional","affiliation":[{"name":"5CHU de Qu\u00e9bec Research Center, Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 4G5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Cie\u0161lak","sequence":"additional","affiliation":[{"name":"1Laboratory of Molecular Pharmacology, Endocrinology-Nephrology, CHU de Qu\u00e9bec Research Center, Qu\u00e9bec, QC G1V 4G2, Canada"},{"name":"2Faculty of Pharmacy, Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"},{"name":"3Centre Nutrition, sant\u00e9 et soci\u00e9t\u00e9 (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Gagnon","sequence":"additional","affiliation":[{"name":"1Laboratory of Molecular Pharmacology, Endocrinology-Nephrology, CHU de Qu\u00e9bec Research Center, Qu\u00e9bec, QC G1V 4G2, Canada"},{"name":"2Faculty of Pharmacy, Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"},{"name":"3Centre Nutrition, sant\u00e9 et soci\u00e9t\u00e9 (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cl\u00e9mence","family":"Desjardins","sequence":"additional","affiliation":[{"name":"1Laboratory of Molecular Pharmacology, Endocrinology-Nephrology, CHU de Qu\u00e9bec Research Center, Qu\u00e9bec, QC G1V 4G2, Canada"},{"name":"2Faculty of Pharmacy, Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"},{"name":"3Centre Nutrition, sant\u00e9 et soci\u00e9t\u00e9 (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00e9lanie","family":"Verreault","sequence":"additional","affiliation":[{"name":"1Laboratory of Molecular Pharmacology, Endocrinology-Nephrology, CHU de Qu\u00e9bec Research Center, Qu\u00e9bec, QC G1V 4G2, Canada"},{"name":"2Faculty of Pharmacy, Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jocelyn","family":"Trottier","sequence":"additional","affiliation":[{"name":"1Laboratory of Molecular Pharmacology, Endocrinology-Nephrology, CHU de Qu\u00e9bec Research Center, Qu\u00e9bec, QC G1V 4G2, Canada"},{"name":"3Centre Nutrition, sant\u00e9 et soci\u00e9t\u00e9 (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie-Claude","family":"Vohl","sequence":"additional","affiliation":[{"name":"3Centre Nutrition, sant\u00e9 et soci\u00e9t\u00e9 (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Philippe","family":"Drouin-Chartier","sequence":"additional","affiliation":[{"name":"3Centre Nutrition, sant\u00e9 et soci\u00e9t\u00e9 (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacques","family":"Corbeil","sequence":"additional","affiliation":[{"name":"5CHU de Qu\u00e9bec Research Center, Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 4G5, Canada"},{"name":"6Faculty of Medicine, Qu\u00e9bec, QC G1V 0A6, Universit\u00e9 Laval, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandre","family":"Caron","sequence":"additional","affiliation":[{"name":"2Faculty of Pharmacy, Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"},{"name":"4Quebec Heart and Lung Institute, Quebec City, QC G1V 4G5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3067-1134","authenticated-orcid":false,"given":"Olivier","family":"Barbier","sequence":"additional","affiliation":[{"name":"1Laboratory of Molecular Pharmacology, Endocrinology-Nephrology, CHU de Qu\u00e9bec Research Center, Qu\u00e9bec, QC G1V 4G2, Canada"},{"name":"2Faculty of Pharmacy, Universit\u00e9 Laval, Qu\u00e9bec, QC G1V 0A6, Canada"},{"name":"4Quebec Heart and Lung Institute, Quebec City, QC G1V 4G5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"key":"2025082112011198100_BCJ-2025-3113C1","unstructured":"Krupa, K.N., Nguyen, H. and Parmar, M. 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Liver Physiol."},{"key":"2025082112011198100_BCJ-2025-3113C5","doi-asserted-by":"crossref","first-page":"115606","DOI":"10.1016\/j.biopha.2023.115606","article-title":"The regulation of tissue-specific farnesoid X receptor on genes and diseases involved in bile acid homeostasis","volume":"168","author":"Xiang","year":"2023","journal-title":"Biomed. Pharmacother"},{"key":"2025082112011198100_BCJ-2025-3113C6","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1016\/S0016-5085(03)00388-3","article-title":"FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity","volume":"124","author":"Barbier","year":"2003","journal-title":"Gastroenterology"},{"key":"2025082112011198100_BCJ-2025-3113C7","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1751-2980.2010.00427.x","article-title":"Pharmacotherapy of cholestatic liver diseases","volume":"11","author":"Paumgartner","year":"2010","journal-title":"J. Dig. Dis."},{"key":"2025082112011198100_BCJ-2025-3113C8","article-title":"Studies on the mechanisms of bile acid initiated hepatic inflammation in cholestatic liver injury","volume":"4","author":"Cai","year":"2017","journal-title":"Inflamm. Cell Signal."},{"key":"2025082112011198100_BCJ-2025-3113C9","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.1021\/jm025529g","article-title":"6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity","volume":"45","author":"Pellicciari","year":"2002","journal-title":"J. Med. Chem."},{"key":"2025082112011198100_BCJ-2025-3113C10","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1080\/17474124.2016.1216784","article-title":"Obeticholic acid for the treatment of primary biliary cirrhosis","volume":"10","author":"Jones","year":"2016","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"2025082112011198100_BCJ-2025-3113C11","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1093\/bmb\/ldaa006","article-title":"Obeticholic acid-a new therapy in PBC and NASH","volume":"133","author":"Chapman","year":"2020","journal-title":"Br. Med. Bull."},{"key":"2025082112011198100_BCJ-2025-3113C12","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.jhep.2020.02.033","article-title":"A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis","volume":"73","author":"Kowdley","year":"2020","journal-title":"J. Hepatol."},{"key":"2025082112011198100_BCJ-2025-3113C13","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.dld.2021.04.028","article-title":"Treatment of primary sclerosing cholangitis","volume":"53","author":"Floreani","year":"2021","journal-title":"Dig. Liver Dis."},{"key":"2025082112011198100_BCJ-2025-3113C14","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/hep.32405","article-title":"Mechanisms and molecules: What are the treatment targets for primary biliary cholangitis?","volume":"76","author":"Mayo","year":"2022","journal-title":"Hepatology"},{"key":"2025082112011198100_BCJ-2025-3113C15","first-page":"66","article-title":"Primary biliary cirrhosis and liver transplantation","volume":"1","author":"Akamatsu","year":"2012","journal-title":"Intractable Rare Dis. 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(Bartlesville)."},{"key":"2025082112011198100_BCJ-2025-3113C18","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1053\/j.gastro.2014.12.005","article-title":"Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid","volume":"148","author":"Hirschfield","year":"2015","journal-title":"Gastroenterology"},{"key":"2025082112011198100_BCJ-2025-3113C19","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1002\/hep.29569","article-title":"A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis","volume":"67","author":"Kowdley","year":"2018","journal-title":"Hepatology"},{"key":"2025082112011198100_BCJ-2025-3113C20","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/S0140-6736(24)01303-5","article-title":"Primary biliary cholangitis","volume":"404","author":"Tanaka","year":"2024","journal-title":"Lancet"},{"key":"2025082112011198100_BCJ-2025-3113C21","doi-asserted-by":"crossref","first-page":"390","DOI":"10.14309\/ajg.0000000000003029","article-title":"COBALT: A confirmatory trial of obeticholic acid in primary biliary cholangitis with placebo and external controls","volume":"120","author":"Kowdley","year":"2025","journal-title":"Am. J. Gastroenterol."},{"key":"2025082112011198100_BCJ-2025-3113C22","doi-asserted-by":"crossref","DOI":"10.1097\/HC9.0000000000000005","article-title":"Safety and tolerability of obeticholic acid in chronic liver disease: a pooled analysis of 1878 individuals","volume":"7","author":"Ng","year":"2023","journal-title":"Hepatol. Commun."},{"key":"2025082112011198100_BCJ-2025-3113C23","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1097\/HEP.0000000000000864","article-title":"Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?","volume":"80","author":"Jones","year":"2024","journal-title":"Hepatology"},{"key":"2025082112011198100_BCJ-2025-3113C24","first-page":"6031074","article-title":"N-3 Polyunsaturated fatty acids stimulate bile acid detoxification in human cell models","author":"Cieslak","year":"2018","journal-title":"Can. J. Gastroenterol. 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Hepatol."},{"key":"2025082112011198100_BCJ-2025-3113C27","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1177\/0148607111409588","article-title":"Eicosapentaenoic acid and docosahexaenoic acid synergistically attenuate bile acid-induced hepatocellular apoptosis","volume":"36","author":"Tillman","year":"2012","journal-title":"JPEN J. Parenter. 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Sci."},{"key":"2025082112011198100_BCJ-2025-3113C30","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.jhep.2008.10.031","article-title":"Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice","volume":"50","author":"Ishii","year":"2009","journal-title":"J. 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