RT Journal Article
SR Electronic
T1 Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.10.455792
DO 10.1101/2021.08.10.455792
A1 Dan Song
A1 Gou Takahashi
A1 Yun-Wen Zheng
A1 Mami Matsuo-Takasaki
A1 Jingyue Li
A1 Miho Takami
A1 Yuri An
A1 Yasuko Hemmi
A1 Natsumi Miharada
A1 Tsuyoshi Fujioka
A1 Michiya Noguchi
A1 Takashi Nakajima
A1 Megumu K. Saito
A1 Yukio Nakamura
A1 Tatsuya Oda
A1 Yuichiro Miyaoka
A1 Yohei Hayashi
YR 2021
UL http://biorxiv.org/content/early/2021/08/10/2021.08.10.455792.abstract
AB Wilson’s disease (WD) is a copper metabolic disorder, which is caused by defective ATP7B function. Here, we have generated induced pluripotent stem cells (iPSCs) from WD patients carrying compound heterozygous mutations on ATP7B. ATP7B loss- and gain-of-functions were further manifested with ATP7B-deficient iPSCs and heterozygously-corrected R778L WD patient-derived iPSCs using CRISPR-Cas9-based gene editing. Transcriptome analysis identified abnormalities of retinoid signaling pathway and lipid metabolism in WD-specific hepatocytes. Although the expression level of ATP7B protein was variable among WD-specific hepatocytes, the expression and secretion of ceruloplasmin (Cp), which is a downstream copper carrier in plasma, were consistently decreased. Cp secretion-based drug screening identified all-trans retinoic acid (ATRA) as promising candidates for rescuing Cp secretion. ATRA also alleviated reactive oxygen species (ROS) production induced by lipid accumulation in WD-specific hepatocytes. Our patient-derived iPSC-based hepatic models provide potential therapeutics for liver steatosis in WD and other fatty liver diseases.