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Store-Operated Calcium Channel and Inositol Triphosphate Receptor Calcium Channel Hyperactivation Inhibits Hepatocyte Autophagy to Promote Nonalcoholic Fatty Liver Disease

  • CELL BIOLOGY
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Abstract

Previously, we demonstrated that store-operated calcium channel (SOCC) and inositol triphosphate receptor (IP3R) calcium channel upregulation inhibits autophagy via (TRPC1/IP3R)/ERK/(FOXO/mTORC1) signaling pathways to promote nonalcoholic fatty liver disease (NAFLD) in vitro; however, it remains unclear whether this mechanism exists in vivo. In this study, We observed that Lee’s Index, body mass index, plasma lipid indices, and hepatic triglyceride and total cholesterol content were increased in high-fat diet(HFD)-fed mice compared to normal diet(ND)-fed mice, whereas hepatocytes from HFD-fed mice showed macrovesicular steatosis and hepatocellular ballooning. The levels of SOCC and IP3R channel proteins such as calcium release-activated calcium channel protein 1, stromal interaction molecule 1, transient receptor potential canonical 1 (TRPC1) and IP3R were markedly increased in hepatocytes from HFD-fed mice compared to those from ND-fed mice, suggesting calcium channels over-activation. The levels of key proteins such as extracellular regulated protein kinases 1/2 (ERK1/2), phosphorylated(p)-forkhead/winged helix O 3 (FOXO3), p-tuberous sclerosis 2, p-ribosomal protein S6, and p-Unc-51 like autophagy activating kinase 1 in (TRPC1/IP3R)/ERK/(FOXO/mTORC1) signaling pathways were increased in HFD-fed mice, whereas autophagy-related gene 12 (ATG12) expression was downregulated, indicating FOXO signaling inhibition and mTORC1 signaling activation. Furthermore, the levels of autophagy-related proteins such as microtubule-associated protein 1-light chain 3 B and Yeast ATG 6 homolog were decreased in HFD-fed mice, suggesting autophagy inhibition. Importantly calcium channel blockers (CCBs) reversed HFD-induced abnormal changes in mice fed with HFD + CCB. Taken together, these results indicated that SOCC and IP3R upregulation and subsequent increased cytoplasmic calcium signaling inhibit hepatocyte autophagy via (TRPC1/IP3R)/ERK/(FOXO/mTORC1) signaling, thus leading to lipid droplet accumulation and NAFLD in vivo.

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DATA AVAILABILITY STATEMENT

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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ACKNOWLEDGMENTS

We thank Elsevier Language Editing Services for their linguistic assistance during the preparation of this manuscript.

Funding

This work was supported by the Department of Health of Zhejiang Province, China (grant no. 2022KY911); the Young and Middle-Aged Research Innovation Foundation of the Zhejiang Chinese Medical University, China (grant no. KC201921); and the Scientific Research and Cultivation Project of College of Life Sciences, Zhejiang Chinese Medical University, China (grant no. 2022BJ001).

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Authors and Affiliations

  1. College of Life Science/Institute of Molecular Medicine, Zhejiang Chinese Medical University, 310053, Hangzhou, Zhejiang Province, China

    Ruirui Yang, Zhelan Zhao, Yesang Li, Hui Chai, Xiaobing Dou & Lin Zhang

  2. College of Life Science, Zhejiang University, 310058, Hangzhou, Zhejiang Province, China

    Yuanqing Jiang

Authors
  1. Ruirui Yang
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  2. Zhelan Zhao
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  3. Yesang Li
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  4. Yuanqing Jiang
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  5. Hui Chai
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  6. Xiaobing Dou
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  7. Lin Zhang
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Contributions

Ruirui Yang and Zhelan Zhao contributed equally to this work and should be considered co-first authors. Lin Zhang developed the idea and obtained the fund. Lin Zhang, Ruirui Yang, Zhelan Zhao, and Yesang Li designed the study, executed the experiments, analyzed the data, and drafted and wrote the manuscript. Yuanqing Jiang provided support and assistance in the writing of the manuscript. Hui Chai and Xiaobing Dou provided experimental resources and critically evaluated the manuscript.

Corresponding author

Correspondence to Lin Zhang.

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Conflict of interest. The authors declare that they have no conflict of interest.

Statement on the welfare of animals. All procedures and experiments were performed in accordance with all relevant guidelines and regulations including a protocol approved by the Animal Ethical and Welfare Committee of Zhejiang Chinese Medical University (ZCMU), Hangzhou, China (approval no. IACUC-20200608-05 of January 18, 2021) and in accordance with the ARRIVE guidelines (https://www.arriveguidelines.org).

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Ruirui Yang, Zhao, Z., Li, Y. et al. Store-Operated Calcium Channel and Inositol Triphosphate Receptor Calcium Channel Hyperactivation Inhibits Hepatocyte Autophagy to Promote Nonalcoholic Fatty Liver Disease. Biol Bull Russ Acad Sci 50, 1093–1105 (2023). https://doi.org/10.1134/S1062359023600514

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  • DOI: https://doi.org/10.1134/S1062359023600514

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