{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:36:19Z","timestamp":1790739379445,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>\n                      Deficiency of the phospholipid transporter ATP8B1 causes infantile\u2010onset progressive familial intrahepatic cholestasis type I (PFIC1). Pre\u2010transplant PFIC1 patients often present with mild dyslipidaemia. This raises the possibility that PFIC1 patients, besides cholestasis, may also experience defects in glucose and lipid metabolism. In this study, we aimed to investigate the role of ATP8B1 in hepatic glucose and lipid metabolism using the\n                      <jats:italic>Atp8b1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>G308V\/G308V<\/jats:italic>\n                      <\/jats:sup>\n                      mutant mouse, a pre\u2010clinical model of PFIC1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Atp8b1<\/jats:italic>\n                      <jats:sup>G308V\/G308V<\/jats:sup>\n                      and wild\u2010type mice on normal chow were examined. Hepatic glucose metabolism was evaluated by oral glucose tolerance testing, quantification of fasting plasma glucose, insulin and lipids. Mechanistic studies were conducted in primary mouse hepatocytes (PMHs) and HepG2 cells overexpressing glucagon receptor (HepG2\u2010GCGR). The findings in the mouse model were validated in pre\u2010transplant livers from PFIC1 patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Atp8b1<\/jats:italic>\n                      <jats:sup>G308V\/G308V<\/jats:sup>\n                      mice showed decreased levels of fasting blood glucose, triglycerides and insulin, indicating normal insulin sensitivity and impaired hepatic glucagon response. PMHs from\n                      <jats:italic>Atp8b1<\/jats:italic>\n                      <jats:sup>G308V\/G308V<\/jats:sup>\n                      mice exhibited reduced glucagon\u2010dependent cAMP levels and signalling and had increased expression of\n                      <jats:italic>Pde4<\/jats:italic>\n                      isoforms. Rolipram\u2010mediated PDE4 inhibition restored glucagon signalling. ATP8B1 knockdown HepG2\u2010GCGR cells also showed increased PDE4D expression and impaired glucagon signalling. Liver tissue from PFIC1 patients exhibited elevated PDE4D and reduced p\u2010CREB levels and very low glycogen content.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      ATP8B1 deficiency causes upregulation of PDE4D in the liver of\n                      <jats:italic>Atp8b1<\/jats:italic>\n                      <jats:sup>G308V\/G308V<\/jats:sup>\n                      mice and PFIC1 patients. PDE4D\u2010mediated glucagon resistance impairs gluconeogenesis and stimulates compensatory glycogenolysis in\n                      <jats:italic>Atp8b1<\/jats:italic>\n                      <jats:sup>G308V\/G308V<\/jats:sup>\n                      mice and PFIC1 patients. Our study reveals novel metabolic insights of ATP8B1 deficiency in PFIC1 patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.70306","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T08:07:19Z","timestamp":1756109239000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["ATP8B1 Deficiency Causes Phosphodiesterase 4\u2010Mediated Glucagon Resistance and Impaired Gluconeogenesis in Mouse and Human Liver"],"prefix":"10.1111","volume":"45","author":[{"given":"Jung\u2010Chin","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Biomolecular Health Sciences Faculty of Veterinary Medicine, Utrecht University  Utrecht the Netherlands"},{"name":"Tytgat Institute for Liver and Intestinal Research Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4394-6387","authenticated-orcid":false,"given":"Wietse In het","family":"Panhuis","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu\u2010Hao","family":"Hsu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Anatomy and Cell Biology National Taiwan University College of Medicine  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Duijst","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kam S.","family":"Ho\u2010Mok","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8845-5625","authenticated-orcid":false,"given":"Jolie F.","family":"van der Heiden","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixiong","family":"Ying","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joris I.","family":"Erdmann","sequence":"additional","affiliation":[{"name":"Department of Surgery, Cancer Center Amsterdam Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2515-4490","authenticated-orcid":false,"given":"Georg F.","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Pediatrics I Medical University of Innsbruck  Innsbruck Austria"},{"name":"Institute of Cell Biology, Biocenter Medical University of Innsbruck  Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3099-2667","authenticated-orcid":false,"given":"Norman","family":"Junge","sequence":"additional","affiliation":[{"name":"Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic Diseases Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Hartleben","sequence":"additional","affiliation":[{"name":"Institute of Pathology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pim J.","family":"Koelink","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research 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Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1779-0833","authenticated-orcid":false,"given":"Ronald P. J.","family":"Oude Elferink","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4074-5838","authenticated-orcid":false,"given":"Huey\u2010Ling","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics National Taiwan University Children's Hospital  Taipei Taiwan"},{"name":"Department and Graduate Institute of Medical Education and Bioethics National Taiwan University College of Medicine  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4238-4359","authenticated-orcid":false,"given":"Stan F. 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