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Intestinally derived lipopolysaccharides and infused PN phytosterols lead to activation of NF\u03baB, a key factor in PNAC. Our objective was to determine if inhibition of HNF4\u03b1 could interfere with NF\u03baB to alleviate murine PNAC. We showed that HNF4\u03b1 antagonist BI6015 (20\u00a0mg\/kg\/day) in DSS-PN (oral DSS x4d followed by Total PN x14d) mice prevented the increased AST, ALT, bilirubin and bile acids and reversed mRNA suppression of hepatocyte <jats:italic>Abcg5\/8, Abcb11,<\/jats:italic> FXR, SHP and MRP2\u00a0that were present during PNAC. Further, NF\u03baB phosphorylation in hepatocytes and its binding to LRH-1 and BSEP promoters in liver, which are upregulated in DSS-PN mice, were inhibited by BI6015 treatment. BI6015 also prevented the upregulation in liver macrophages of <jats:italic>Adgre1 <\/jats:italic>(F4\/80) and <jats:italic>Itgam<\/jats:italic> (CD11B) that occurs in DSS-PN mice, with concomitant induction of anti-inflammatory genes (<jats:italic>Klf2, Klf4, Clec7a1, Retnla<\/jats:italic>). In conclusion, HNF4\u03b1 antagonism attenuates PNAC by suppressing NF\u03baB activation and signaling while inducing hepatocyte FXR and LRH-1 and their downstream bile and sterol transporters. These data identify HNF4\u03b1 antagonism as a potential therapeutic target for prevention and treatment of PNAC.<\/jats:p>","DOI":"10.1038\/s41598-023-33994-3","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T14:04:13Z","timestamp":1683900253000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pharmacologic inhibition of HNF4\u03b1 prevents parenteral nutrition associated cholestasis in mice"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1902-8025","authenticated-orcid":false,"given":"Swati","family":"Ghosh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0140-8756","authenticated-orcid":false,"given":"Michael W.","family":"Devereaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0417-1400","authenticated-orcid":false,"given":"David J.","family":"Orlicky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7433-4095","authenticated-orcid":false,"given":"Ronald J.","family":"Sokol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,12]]},"reference":[{"key":"33994_CR1","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.cld.2015.08.009","volume":"20","author":"SV Beath","year":"2016","unstructured":"Beath, S. 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