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

Wilson’s disease (WD) is a copper metabolic disorder caused by a defective ATP7B function. Conventional therapies cause severe side effects and significant variation in efficacy, according to cohort studies. Thus, exploring new therapeutic approaches to prevent progression to liver failure is urgent...

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Autores principales: Song, Dan, Takahashi, Gou, Zheng, Yun-Wen, Matsuo-Takasaki, Mami, Li, Jingyue, Takami, Miho, An, Yuri, Hemmi, Yasuko, Miharada, Natsumi, Fujioka, Tsuyoshi, Noguchi, Michiya, Nakajima, Takashi, Saito, Megumu K, Nakamura, Yukio, Oda, Tatsuya, Miyaoka, Yuichiro, Hayashi, Yohei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9616579/
https://www.ncbi.nlm.nih.gov/pubmed/35388883
http://dx.doi.org/10.1093/hmg/ddac080
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author Song, Dan
Takahashi, Gou
Zheng, Yun-Wen
Matsuo-Takasaki, Mami
Li, Jingyue
Takami, Miho
An, Yuri
Hemmi, Yasuko
Miharada, Natsumi
Fujioka, Tsuyoshi
Noguchi, Michiya
Nakajima, Takashi
Saito, Megumu K
Nakamura, Yukio
Oda, Tatsuya
Miyaoka, Yuichiro
Hayashi, Yohei
author_facet Song, Dan
Takahashi, Gou
Zheng, Yun-Wen
Matsuo-Takasaki, Mami
Li, Jingyue
Takami, Miho
An, Yuri
Hemmi, Yasuko
Miharada, Natsumi
Fujioka, Tsuyoshi
Noguchi, Michiya
Nakajima, Takashi
Saito, Megumu K
Nakamura, Yukio
Oda, Tatsuya
Miyaoka, Yuichiro
Hayashi, Yohei
author_sort Song, Dan
collection PubMed
description Wilson’s disease (WD) is a copper metabolic disorder caused by a defective ATP7B function. Conventional therapies cause severe side effects and significant variation in efficacy, according to cohort studies. Thus, exploring new therapeutic approaches to prevent progression to liver failure is urgent. To study the physiology and pathology of WD, immortalized cell lines and rodent WD models have been used conventionally; however, a large gap remains among different species as well as in genetic backgrounds among individuals. We generated induced pluripotent stem cells (iPSCs) from four WD patients carrying compound heterozygous mutations in the ATP7B gene. 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. Although the expression of ATP7B protein varied among WD-specific hepatocytes differentiated from these iPSCs, the expression and secretion of ceruloplasmin (Cp), a downstream copper carrier in plasma, were consistently decreased in WD patient-derived and ATP7B-deficient hepatocytes. A transcriptome analysis detected abnormalities in the retinoid signaling pathway and lipid metabolism in WD-specific hepatocytes. Drug screening using WD patient-derived hepatocytes identified retinoids as promising candidates for rescuing Cp secretion. All-trans retinoic acid also alleviates reactive oxygen species production induced by lipid accumulation in WD-specific hepatocytes treated with oleic acid. These patient-derived iPSC-based hepatic models function as effective platforms for the development of potential therapeutics for hepatic steatosis in WD and other fatty liver diseases.
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spelling pubmed-96165792022-11-01 Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes Song, Dan Takahashi, Gou Zheng, Yun-Wen Matsuo-Takasaki, Mami Li, Jingyue Takami, Miho An, Yuri Hemmi, Yasuko Miharada, Natsumi Fujioka, Tsuyoshi Noguchi, Michiya Nakajima, Takashi Saito, Megumu K Nakamura, Yukio Oda, Tatsuya Miyaoka, Yuichiro Hayashi, Yohei Hum Mol Genet Original Article Wilson’s disease (WD) is a copper metabolic disorder caused by a defective ATP7B function. Conventional therapies cause severe side effects and significant variation in efficacy, according to cohort studies. Thus, exploring new therapeutic approaches to prevent progression to liver failure is urgent. To study the physiology and pathology of WD, immortalized cell lines and rodent WD models have been used conventionally; however, a large gap remains among different species as well as in genetic backgrounds among individuals. We generated induced pluripotent stem cells (iPSCs) from four WD patients carrying compound heterozygous mutations in the ATP7B gene. 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. Although the expression of ATP7B protein varied among WD-specific hepatocytes differentiated from these iPSCs, the expression and secretion of ceruloplasmin (Cp), a downstream copper carrier in plasma, were consistently decreased in WD patient-derived and ATP7B-deficient hepatocytes. A transcriptome analysis detected abnormalities in the retinoid signaling pathway and lipid metabolism in WD-specific hepatocytes. Drug screening using WD patient-derived hepatocytes identified retinoids as promising candidates for rescuing Cp secretion. All-trans retinoic acid also alleviates reactive oxygen species production induced by lipid accumulation in WD-specific hepatocytes treated with oleic acid. These patient-derived iPSC-based hepatic models function as effective platforms for the development of potential therapeutics for hepatic steatosis in WD and other fatty liver diseases. Oxford University Press 2022-04-07 /pmc/articles/PMC9616579/ /pubmed/35388883 http://dx.doi.org/10.1093/hmg/ddac080 Text en © The Author(s) 2022. Published by Oxford University Press. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Song, Dan
Takahashi, Gou
Zheng, Yun-Wen
Matsuo-Takasaki, Mami
Li, Jingyue
Takami, Miho
An, Yuri
Hemmi, Yasuko
Miharada, Natsumi
Fujioka, Tsuyoshi
Noguchi, Michiya
Nakajima, Takashi
Saito, Megumu K
Nakamura, Yukio
Oda, Tatsuya
Miyaoka, Yuichiro
Hayashi, Yohei
Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes
title Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes
title_full Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes
title_fullStr Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes
title_full_unstemmed Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes
title_short Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes
title_sort retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in wilson’s disease-specific hepatocytes
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9616579/
https://www.ncbi.nlm.nih.gov/pubmed/35388883
http://dx.doi.org/10.1093/hmg/ddac080
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