論文

2021年8月10日

Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes

bioRxiv
  • Dan Song
  • ,
  • Gou Takahashi
  • ,
  • Yun-Wen Zheng
  • ,
  • Mami Matsuo-Takasaki
  • ,
  • Jingyue Li
  • ,
  • Miho Takami
  • ,
  • Yuri An
  • ,
  • Yasuko Hemmi
  • ,
  • Natsumi Miharada
  • ,
  • Tsuyoshi Fujioka
  • ,
  • Michiya Noguchi
  • ,
  • Takashi Nakajima
  • ,
  • Megumu K. Saito
  • ,
  • Yukio Nakamura
  • ,
  • Tatsuya Oda
  • ,
  • Yuichiro Miyaoka
  • ,
  • Yohei Hayashi

DOI
10.1101/2021.08.10.455792
出版者・発行元
Cold Spring Harbor Laboratory

<title>Summary</title>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 <italic>ATP7B</italic>. 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.

リンク情報
DOI
https://doi.org/10.1101/2021.08.10.455792
URL
https://syndication.highwire.org/content/doi/10.1101/2021.08.10.455792
ID情報
  • DOI : 10.1101/2021.08.10.455792

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