Activation of HIF-1 signaling ameliorates liver steatosis in zebrafish atp7b deficiency (Wilson's disease) models.

Xiaoxiao Mi, Zhihui Li, Jian Yan, Yingniang Li, Jun Zheng, Zhenjie Zhuang, Wenjun Yang, Ling Gong, Junping Shi

Biochimica et biophysica acta. Molecular basis of disease 2020 Oct 01

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Wilson's disease is an autosomal recessive disease characterized by excess copper accumulated in the liver and brain. It is caused by mutations in the copper transporter gene ATP7B. However, based on the poor understanding of the transcriptional program involved in the pathogenesis of Wilson's disease and the lack of more safe and efficient therapies, the identification of novel pathways and the establishment of complementary model systems of Wilson's disease are urgently needed. Herein, we generated two zebrafish atp7b-mutant lines using the CRISPR/Cas9 editing system, and the mutants developed hepatic and behavioral deficits similar to those observed in humans with Wilson's disease. Interestingly, we found that atp7b-deficient zebrafish embryos developed liver steatosis under low-dose Cu exposure, and behavioral deficits appeared under high-dose Cu exposure. Analyses of publicly available transcriptomic data from ATP7B-knockout HepG2 cells demonstrated that the HIF-1 signaling pathway is downregulated in ATP7B-knockout HepG2 cells compared with wildtype cells following Cu exposure. The HIF-1 signaling pathway was also downregulated in our atp7b-deficient zebrafish mutants following Cu exposure. Furthermore, we demonstrate that activation of the HIF-1 signaling pathway with the chemical compound FG-4592 or DMOG ameliorates liver steatosis and reduces accumulated Cu levels in zebrafish atp7b deficiency models. These findings introduce a novel prospect that modulation of the HIF-1 signaling pathway should be explored as a novel strategy to reduce copper toxicity in Wilson's disease patients. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Xiaoxiao Mi, Zhihui Li, Jian Yan, Yingniang Li, Jun Zheng, Zhenjie Zhuang, Wenjun Yang, Ling Gong, Junping Shi. Activation of HIF-1 signaling ameliorates liver steatosis in zebrafish atp7b deficiency (Wilson's disease) models. Biochimica et biophysica acta. Molecular basis of disease. 2020 Oct 01;1866(10):165842