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Recent work has demonstrated that mutations in\n                    <jats:italic>ANKS6<\/jats:italic>\n                    can cause CHF due to its role in bile duct development. Here, we report a novel\n                    <jats:italic>ANKS6<\/jats:italic>\n                    mutation, which was identified in an infant presenting with neonatal jaundice due to underlying biliary abnormalities and liver fibrosis. Molecular analysis revealed that\n                    <jats:italic>ANKS6<\/jats:italic>\n                    liver pathology is associated with the infiltration of inflammatory macrophages to the periportal fibrotic tissue and ductal epithelium. To further investigate the role of macrophages in CHF pathophysiology, we generated a novel liver\u2010specific\n                    <jats:italic>Anks6<\/jats:italic>\n                    knockout mouse model. The mutant mice develop biliary abnormalities and rapidly progressing periportal fibrosis reminiscent of human CHF. The development of portal fibrosis in\n                    <jats:italic>Anks6<\/jats:italic>\n                    KO mice coincided with the accumulation of inflammatory monocytes and macrophages in the mutant liver. Gene expression and flow cytometric analysis demonstrated the preponderance of M1\u2010 over M2\u2010like macrophages at the onset of fibrosis. A critical role for macrophages in promoting peribiliary fibrosis was demonstrated by depleting the macrophages with clodronate liposomes which effectively reduced inflammatory gene expression and fibrosis, and ameliorated tissue histology and biliary function in\n                    <jats:italic>Anks6<\/jats:italic>\n                    KO livers. Together, this study demonstrates that macrophages play an important role in the initiation of liver fibrosis in\n                    <jats:italic>ANKS6<\/jats:italic>\n                    \u2010deficient livers and their therapeutic elimination may provide an avenue to mitigate CHF in patients.\n                  <\/jats:p>","DOI":"10.1096\/fj.202101387r","type":"journal-article","created":{"date-parts":[[2022,1,15]],"date-time":"2022-01-15T12:25:17Z","timestamp":1642249517000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Mitigation of portal fibrosis and cholestatic liver disease in\n                    <i>ANKS6<\/i>\n                    \u2010deficient livers by macrophage depletion"],"prefix":"10.1096","volume":"36","author":[{"given":"Merlin","family":"Airik","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Pediatrics University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blake","family":"McCourt","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Pediatrics University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tugba Tastemel","family":"Ozturk","sequence":"additional","affiliation":[{"name":"Division of Pediatric Nephrology, Department of Pediatrics Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy B.","family":"Huynh","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Pediatrics University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin T.","family":"Tometich","sequence":"additional","affiliation":[{"name":"R.K. Mellon Institute for Pediatric Research, Department of Pediatrics, Division of Infectious Disease UPMC Children\u2019s Hospital of Pittsburgh, University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rezan","family":"Topaloglu","sequence":"additional","affiliation":[{"name":"Division of Pediatric Nephrology, Department of Pediatrics Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasan","family":"Ozen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Pediatrics Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diclehan","family":"Orhan","sequence":"additional","affiliation":[{"name":"Pediatric Pathology Unit, Department of Pediatrics Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari","family":"Nejak\u2010Bowen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center The University of Pittsburgh and University of Pittsburgh Medical Center  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satdarshan P.","family":"Monga","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center The University of Pittsburgh and University of Pittsburgh Medical Center  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy W.","family":"Hand","sequence":"additional","affiliation":[{"name":"R.K. Mellon Institute for Pediatric Research, Department of Pediatrics, Division of Infectious Disease UPMC Children\u2019s Hospital of Pittsburgh, University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatih","family":"Ozaltin","sequence":"additional","affiliation":[{"name":"Division of Pediatric Nephrology, Department of Pediatrics Hacettepe University  Ankara Turkey"},{"name":"Nephrogenetics Laboratory, Division of Pediatric Nephrology, Department of Pediatrics Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7055-6325","authenticated-orcid":false,"given":"Rannar","family":"Airik","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Pediatrics University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Developmental Biology University of Pittsburgh  Pittsburgh Pennsylvania 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