Chang, Jung‐ChinJung‐ChinChangPanhuis, Wietse In hetWietse In hetPanhuisHsu, Shu‐HaoShu‐HaoHsuDuijst, SuzanneSuzanneDuijstHo‐Mok, Kam S.Kam S.Ho‐Mokvan der Heiden, Jolie F.Jolie F.van der HeidenYing, ZhixiongZhixiongYingErdmann, Joris I.Joris I.ErdmannVogel, Georg F.Georg F.VogelJunge, NormanNormanJungeHartleben, BjörnBjörnHartlebenKoelink, Pim J.Pim J.Koelinkvan Dijk, Sebastian G.Sebastian G.van DijkPeng, Weng ChuanWeng ChuanPengVerhoeven, Arthur J.Arthur J.VerhoevenOude Elferink, Ronald P. J.Ronald P. J.Oude ElferinkHUEY-LING CHENvan de Graaf, Stan F. J.Stan F. J.van de GraafPaulusma, Coen C.Coen C.Paulusma2025-12-302025-12-302025-08-2514783223https://scholars.lib.ntu.edu.tw/handle/123456789/734835Background and aims: Deficiency of the phospholipid transporter ATP8B1 causes infantile-onset progressive familial intrahepatic cholestasis type I (PFIC1). Pre-transplant 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 Atp8b1G308V/G308V mutant mouse, a pre-clinical model of PFIC1. Methods: Atp8b1G308V/G308V and wild-type 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-GCGR). The findings in the mouse model were validated in pre-transplant livers from PFIC1 patients. Results: Atp8b1G308V/G308V mice showed decreased levels of fasting blood glucose, triglycerides and insulin, indicating normal insulin sensitivity and impaired hepatic glucagon response. PMHs from Atp8b1G308V/G308V mice exhibited reduced glucagon-dependent cAMP levels and signalling and had increased expression of Pde4 isoforms. Rolipram-mediated PDE4 inhibition restored glucagon signalling. ATP8B1 knockdown HepG2-GCGR cells also showed increased PDE4D expression and impaired glucagon signalling. Liver tissue from PFIC1 patients exhibited elevated PDE4D and reduced p-CREB levels and very low glycogen content. Conclusions: ATP8B1 deficiency causes upregulation of PDE4D in the liver of Atp8b1G308V/G308V mice and PFIC1 patients. PDE4D-mediated glucagon resistance impairs gluconeogenesis and stimulates compensatory glycogenolysis in Atp8b1G308V/G308V mice and PFIC1 patients. Our study reveals novel metabolic insights of ATP8B1 deficiency in PFIC1 patients.entruecholestasiscyclic adenosine monophosphategluconeogenesisglucose[SDGs]SDG3journal article10.1111/liv.70306408514902-s2.0-105014151671