{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:20:43Z","timestamp":1789996843266,"version":"4.0.1"},"reference-count":28,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T00:00:00Z","timestamp":1683849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["1R01DK131064-01"],"award-info":[{"award-number":["1R01DK131064-01"]}]},{"name":"NIH","award":["1R01 DK117965-01A1"],"award-info":[{"award-number":["1R01 DK117965-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cyp2c70 knockout mice lack the enzyme that produces muricholic acids and show a \u201chuman-like\u201d hydrophobic bile acid pool-induced hepatobiliary injury. In this study, we investigated the potential anti-cholestasis effect of glycine-conjugated \u03b2 muricholic acid (G-\u03b2-MCA) in male Cyp2c70 KO mice based on its hydrophilic physiochemical property and signaling property as an farnesoid X receptor (FXR) antagonist. Our results showed that G-\u03b2-MCA treatment for 5 weeks alleviated ductular reaction and liver fibrosis and improved gut barrier function. Analysis of bile acid metabolism suggested that exogenously administered G-\u03b2-MCA was poorly absorbed in the small intestine and mostly deconjugated in the large intestine and converted to taurine-conjugated MCA (T-MCA) in the liver, leading to T-MCA enrichment in the bile and small intestine. These changes decreased the biliary and intestine bile acid hydrophobicity index. Furthermore, G-\u03b2-MCA treatment decreased intestine bile acid absorption via unknown mechanisms, resulting in increased fecal bile acid excretion and a reduction in total bile acid pool size. In conclusion, G-\u03b2-MCA treatment reduces the bile acid pool size and hydrophobicity and improves liver fibrosis and gut barrier function in Cyp2c70 KO mice.<\/jats:p>","DOI":"10.3390\/cells12101371","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T09:26:13Z","timestamp":1683883573000},"page":"1371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Glycine-\u03b2-Muricholic Acid Improves Liver Fibrosis and Gut Barrier Function by Reducing Bile Acid Pool Size and Hydrophobicity in Male Cyp2c70 Knockout Mice"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4196-0406","authenticated-orcid":false,"given":"Mohammad Nazmul","family":"Hasan","sequence":"first","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianglei","family":"Chen","sequence":"additional","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaiwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhong","family":"Du","sequence":"additional","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung Dai","family":"Clayton","sequence":"additional","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijie","family":"Gu","sequence":"additional","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiangang","family":"Li","sequence":"additional","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1124\/pr.113.008201","article-title":"Bile Acid Signaling in Metabolic Disease and Drug Therapy","volume":"66","author":"Li","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4737","DOI":"10.1021\/bi00135a001","article-title":"Bile acid biosynthesis","volume":"31","author":"Russell","year":"1992","journal-title":"Biochemistry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1126\/science.284.5418.1362","article-title":"Identification of a nuclear receptor for bile acids","volume":"284","author":"Makishima","year":"1999","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9435","DOI":"10.1074\/jbc.M209706200","article-title":"A G protein-coupled receptor responsive to bile acids","volume":"278","author":"Kawamata","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cld.2007.11.010","article-title":"Mechanisms of cholestasis","volume":"12","author":"Zollner","year":"2008","journal-title":"Clin. Liver Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S25","DOI":"10.1016\/j.jhep.2015.02.023","article-title":"New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond","volume":"62","author":"Beuers","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_7","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":"ref_8","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1002\/hep4.1980","article-title":"Maralixibat for the treatment of PFIC: Long-term, IBAT inhibition in an open-label, Phase 2 study","volume":"6","author":"Loomes","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100255","DOI":"10.1016\/j.jhepr.2021.100255","article-title":"Potent suppression of hydrophobic bile acids by aldafermin, an FGF19 analogue, across metabolic and cholestatic liver diseases","volume":"3","author":"Sanyal","year":"2021","journal-title":"JHEP Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.jhep.2018.10.035","article-title":"Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial","volume":"70","author":"Hirschfield","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1002\/hep4.1209","article-title":"NGM282 for Treatment of Patients With Primary Biliary Cholangitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial","volume":"2","author":"Mayo","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1159\/000450988","article-title":"Apical Sodium-Dependent Transporter Inhibitors in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis","volume":"35","author":"Hegade","year":"2017","journal-title":"Dig. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1194\/jlr.M071183","article-title":"Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans","volume":"57","author":"Takahashi","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.cmet.2013.01.003","article-title":"Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist","volume":"17","author":"Sayin","year":"2013","journal-title":"Cell. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1172\/JCI0216309","article-title":"Cholic acid mediates negative feedback regulation of bile acid synthesis in mice","volume":"110","author":"Gafvels","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.bbalip.2005.06.001","article-title":"Cholic acid as key regulator of cholesterol synthesis, intestinal absorption and hepatic storage in mice","volume":"1735","author":"Murphy","year":"2005","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10166","DOI":"10.1038\/ncomms10166","article-title":"Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction","volume":"6","author":"Jiang","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1194\/jlr.RA119000395","article-title":"Regulation of bile acid metabolism in mouse models with hydrophobic bile acid composition","volume":"61","author":"Honda","year":"2020","journal-title":"J. Lipid Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1194\/jlr.RA119000243","article-title":"A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice","volume":"61","author":"Verkade","year":"2020","journal-title":"J. Lipid Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"159163","DOI":"10.1016\/j.bbalip.2022.159163","article-title":"Short-term obeticholic acid treatment does not impact cholangiopathy in Cyp2c70-deficient mice with a human-like bile acid composition","volume":"1867","author":"Li","year":"2022","journal-title":"Biochim. Biophys. Acta Mol. Cell. Biol. Lipids"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.jcmgh.2020.12.004","article-title":"Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid","volume":"11","author":"Palmiotti","year":"2021","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100261","DOI":"10.1016\/j.jlr.2022.100261","article-title":"Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury","volume":"63","author":"Truong","year":"2022","journal-title":"J. Lipid Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100340","DOI":"10.1016\/j.jlr.2023.100340","article-title":"Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice","volume":"64","author":"Hasan","year":"2023","journal-title":"J. Lipid Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/MOG.0000000000000807","article-title":"The gut-liver axis in cholangiopathies: Focus on bile acid based pharmacological treatment","volume":"38","author":"Cariello","year":"2022","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/S0022-2275(20)38331-0","article-title":"Quantitative estimation of the hydrophilic-hydrophobic balance of mixed bile salt solutions","volume":"30","author":"Heuman","year":"1989","journal-title":"J. Lipid Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/2191-219X-3-60","article-title":"Gastrointestinal transit measurements in mice with 99mTc-DTPA-labeled activated charcoal using NanoSPECT-CT","volume":"3","author":"Padmanabhan","year":"2013","journal-title":"EJNMMI Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3348\/kjr.2013.14.1.45","article-title":"Establishment of a protocol for determining gastrointestinal transit time in mice using barium and radiopaque markers","volume":"14","author":"Myagmarjalbuu","year":"2013","journal-title":"Korean J. Radiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1002\/hep.23631","article-title":"Bile acid changes after high-dose ursodeoxycholic acid treatment in primary sclerosing cholangitis: Relation to disease progression","volume":"52","author":"Sinakos","year":"2010","journal-title":"Hepatology"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/10\/1371\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:33:35Z","timestamp":1760124815000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/10\/1371"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,12]]},"references-count":28,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["cells12101371"],"URL":"https:\/\/doi.org\/10.3390\/cells12101371","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,12]]}}}