2. Academic Validation
  3. KIRA8 attenuates non-alcoholic steatohepatitis through inhibition of the IRE1α/XBP1 signalling pathway

KIRA8 attenuates non-alcoholic steatohepatitis through inhibition of the IRE1α/XBP1 signalling pathway

  • Biochem Biophys Res Commun. 2022 Sep 29;632:158-164. doi: 10.1016/j.bbrc.2022.09.098.
Shiting Zhao 1,  Xiaomin Liu 2,  Lei Li 3,  Xinyu Kong 3,  Wei Sun 2,  Kerry Loomes 4,  Tao Nie 5,  Xiaoyan Hui 6,  Donghai Wu 7
Affiliations

Affiliations

  • 1 Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Guangzhou Medical University, Guangzhou, 511436, China; University of Chinese Academy of Sciences, Beijing, 100049, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, 510530, China.
  • 2 Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, 510530, China.
  • 3 Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; University of Chinese Academy of Sciences, Beijing, 100049, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, 510530, China.
  • 4 School of Biological Sciences and Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.
  • 5 School of Basic Medicine, Hubei University of Arts and Science, China. Electronic address: [email protected].
  • 6 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: [email protected].
  • 7 Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, 510530, China. Electronic address: [email protected].
PMID: 36209584 DOI: 10.1016/j.bbrc.2022.09.098
Abstract

Endoplasmic reticulum (ER) stress is enhanced in non-alcoholic steatohepatitis (NASH). Among three signalling pathways, the IRE1α/XBP1 signalling pathway is strongly implicated in the pathogenesis of NASH but its significance is still largely uncharacterised. In this report, we constructed a hepatocyte-specific XBP1-Luciferase knock-in mouse model that allows in vivo monitoring of the IRE1α/XBP1 activity in hepatocytes. Using this mouse model, we found that IRE1α/XBP1 was activated within hepatocytes during the pathogenesis of NASH. Significantly, a specific IRE1α kinase-inhibiting RNase attenuator, KIRA8, attenuated NASH in mice. In conclusion, our hepatocyte-specific XBP1 splicing reporter mouse represents a valid model for research and drug development of NASH, which showed that the IRE1α-induced XBP splicing is potentiated in hepatocytes during pathogenesis of NASH. Furthermore, we carried out the proof-of-concept study to demonstrate that the allosteric IRE1α RNase Inhibitor serves as a promising therapeutic agent for the treatment of NASH.

Keywords

IRE1α; KIRA8; NASH; Reporter mouse model; XBP1 splicing.

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