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

Song, D.; Takahashi, G.; Zheng, Y.-W.; Matsuo-Takasaki, M.; Li, J.; Takami, M.; An, Y.; Hemmi, Y.; Miharada, N.; Fujioka, T.; Noguchi, M.; Nakajima, T.; Saito, m. K.; Nakamura, Y.; Oda, T.; MIyaoka, Y.; Hayashi, Y.

doi:10.1101/2021.08.10.455792

bioRxiv · 10.1101/2021.08.10.455792

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

Song, D.·Takahashi, G.·Zheng, Y.-W.·Matsuo-Takasaki, M.·Li, J.·Takami, M.·An, Y.·Hemmi, Y.·Miharada, N.·Fujioka, T.·Noguchi, M.·Nakajima, T.·Saito, m. K.·Nakamura, Y.·Oda, T.·MIyaoka, Y.·Hayashi, Y.

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Abstract

Wilsons 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.

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Song, D., Takahashi, G., Zheng, Y.-W., Matsuo-Takasaki, M., Li, J., Takami, M., An, Y., Hemmi, Y., Miharada, N., Fujioka, T., Noguchi, M., Nakajima, T., Saito, m. K., Nakamura, Y., Oda, T., MIyaoka, Y., Hayashi, Y.. 2021-08-10. Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson's disease-specific hepatocytes. https://doi.org/10.1101/2021.08.10.455792

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