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Farnesoid X receptor (FXR) controls bile acid homeostasis and modulates the progression of various liver diseases. Although global FXR deficiency in mice enhances APAP intoxication, the mechanism remains elusive. In this study, an increased sensitivity to APAP-induced toxicity was found in global Fxr-null (Fxr\u2212\/\u2212) mice, but was not observed in hepatocyte-specific or macrophage-specific Fxr-null mice, suggesting that global FXR deficiency enhances APAP hepatotoxicity via disruption of systematic bile acid homeostasis. Indeed, more bile acid accumulation was found in global Fxr\u2212\/\u2212 mice, while 2% cholestyramine diet feeding decreased serum bile acids and alleviated APAP hepatotoxicity in global Fxr\u2212\/\u2212 mice, suggesting that bile acid accumulation contributes to APAP toxicity. Bile acids were suspected to induce macrophage to release tumor necrosis factor-\u03b1 (TNF-\u03b1), which is known to enhance the APAP hepatotoxicity. In vitro, deoxycholic acid (DCA), a secondary bile acid metabolite, significantly induced Tnfa mRNA and dose-dependently enhanced TNF-\u03b1 release from macrophage, while the same dose of DCA did not directly potentiate APAP toxicity in cultured primary hepatocytes. In vivo, DCA enhanced TNF-\u03b1 release and potentiated APAP toxicity, both of which were abolished by the specific TNF-\u03b1 antagonist infliximab. These results reveal an FXR-DCA-TNF-\u03b1 axis that potentiates APAP hepatotoxicity, which could guide the clinical safe use of APAP.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab027","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T17:45:41Z","timestamp":1614275141000},"page":"273-284","source":"Crossref","is-referenced-by-count":31,"title":["FXR-Deoxycholic Acid-TNF-\u03b1 Axis Modulates Acetaminophen-Induced Hepatotoxicity"],"prefix":"10.1093","volume":"181","author":[{"given":"Tingting","family":"Yan","sequence":"first","affiliation":[{"name":"Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Yan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Yagai","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, China"},{"name":"Department of Metabolic Bioregulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Luo","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shogo","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher W","family":"Krausz","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangji","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiping","family":"Hao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,2,28]]},"reference":[{"key":"2021052817014415600_kfab027-B1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/0016-5085(93)90846-5","article-title":"Increased serum deoxycholic acid levels in men with colorectal adenomas","volume":"104","author":"Bayerdorffer","year":"1993","journal-title":"Gastroenterology"},{"key":"2021052817014415600_kfab027-B2","doi-asserted-by":"crossref","first-page":"G283","DOI":"10.1152\/ajpgi.00205.2016","article-title":"Hepatocyte-specific PPARA expression exclusively promotes agonist-induced cell proliferation without influence from nonparenchymal cells","volume":"312","author":"Brocker","year":"2017","journal-title":"Am. 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