Metabolic improvement and liver regeneration by inhibiting CXXC5 function for non-alcoholic steatohepatitis treatment

Seol Hwa Seo; Eunhwan Kim; Minguen Yoon; Soung Hoon Lee; Byung Hyun Park; Kang Yell Choi

doi:10.1038/s12276-022-00851-8

Metabolic improvement and liver regeneration by inhibiting CXXC5 function for non-alcoholic steatohepatitis treatment

Seol Hwa Seo, Eunhwan Kim, Minguen Yoon, Soung Hoon Lee, Byung Hyun Park, Kang Yell Choi

Research output: Contribution to journal › Article › peer-review

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Abstract

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that results from multiple metabolic disorders. Considering the complexity of the pathogenesis, the identification of a factor mediating the multiple pathogenic phenotypes of NASH will be important for treatment. In this study, we found that CXXC5, a negative feedback regulator of the Wnt/β-catenin pathway, was overexpressed with suppression of Wnt/β-catenin signaling and its target genes involved in hepatic metabolism in obese-NASH patients. Cxxc5^−/− mice were found to be resistant to NASH pathogenesis with metabolic improvements. KY19334, a small molecule that activates the Wnt/β-catenin pathway via interference of the CXXC5-Dvl interaction, reversed the overall pathogenic features of NASH as Cxxc5^−/− mice. The improvement in NASH by KY19334 is attributed to its regenerative effects through restorative activation of the suppressed Wnt/β-catenin signaling. Overall, the pronounced metabolic improvements with the stimulation of liver regeneration by interfering with the CXXC5-Dvl interaction provide a therapeutic approach for NASH.

Original language	English
Pages (from-to)	1511-1523
Number of pages	13
Journal	Experimental and Molecular Medicine
Volume	54
Issue number	9
DOIs	https://doi.org/10.1038/s12276-022-00851-8
Publication status	Published - 2022 Sept

Bibliographical note

Funding Information:
This work was supported by a grant from the National Research Foundation (NRF), the Ministry of Information and Science and ICT of Korea: 2019R1A2C3002751; 2020M3E5E2040018. S.H.S., E.K., and M.Y. were supported by the BK21 PLUS program.

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Clinical Biochemistry

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Cite this

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title = "Metabolic improvement and liver regeneration by inhibiting CXXC5 function for non-alcoholic steatohepatitis treatment",

abstract = "Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that results from multiple metabolic disorders. Considering the complexity of the pathogenesis, the identification of a factor mediating the multiple pathogenic phenotypes of NASH will be important for treatment. In this study, we found that CXXC5, a negative feedback regulator of the Wnt/β-catenin pathway, was overexpressed with suppression of Wnt/β-catenin signaling and its target genes involved in hepatic metabolism in obese-NASH patients. Cxxc5−/− mice were found to be resistant to NASH pathogenesis with metabolic improvements. KY19334, a small molecule that activates the Wnt/β-catenin pathway via interference of the CXXC5-Dvl interaction, reversed the overall pathogenic features of NASH as Cxxc5−/− mice. The improvement in NASH by KY19334 is attributed to its regenerative effects through restorative activation of the suppressed Wnt/β-catenin signaling. Overall, the pronounced metabolic improvements with the stimulation of liver regeneration by interfering with the CXXC5-Dvl interaction provide a therapeutic approach for NASH.",

author = "Seo, {Seol Hwa} and Eunhwan Kim and Minguen Yoon and Lee, {Soung Hoon} and Park, {Byung Hyun} and Choi, {Kang Yell}",

note = "Funding Information: This work was supported by a grant from the National Research Foundation (NRF), the Ministry of Information and Science and ICT of Korea: 2019R1A2C3002751; 2020M3E5E2040018. S.H.S., E.K., and M.Y. were supported by the BK21 PLUS program. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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AU - Seo, Seol Hwa

AU - Kim, Eunhwan

AU - Yoon, Minguen

AU - Lee, Soung Hoon

AU - Park, Byung Hyun

AU - Choi, Kang Yell

N1 - Funding Information: This work was supported by a grant from the National Research Foundation (NRF), the Ministry of Information and Science and ICT of Korea: 2019R1A2C3002751; 2020M3E5E2040018. S.H.S., E.K., and M.Y. were supported by the BK21 PLUS program. Publisher Copyright: © 2022, The Author(s).

PY - 2022/9

Y1 - 2022/9

N2 - Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that results from multiple metabolic disorders. Considering the complexity of the pathogenesis, the identification of a factor mediating the multiple pathogenic phenotypes of NASH will be important for treatment. In this study, we found that CXXC5, a negative feedback regulator of the Wnt/β-catenin pathway, was overexpressed with suppression of Wnt/β-catenin signaling and its target genes involved in hepatic metabolism in obese-NASH patients. Cxxc5−/− mice were found to be resistant to NASH pathogenesis with metabolic improvements. KY19334, a small molecule that activates the Wnt/β-catenin pathway via interference of the CXXC5-Dvl interaction, reversed the overall pathogenic features of NASH as Cxxc5−/− mice. The improvement in NASH by KY19334 is attributed to its regenerative effects through restorative activation of the suppressed Wnt/β-catenin signaling. Overall, the pronounced metabolic improvements with the stimulation of liver regeneration by interfering with the CXXC5-Dvl interaction provide a therapeutic approach for NASH.

AB - Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that results from multiple metabolic disorders. Considering the complexity of the pathogenesis, the identification of a factor mediating the multiple pathogenic phenotypes of NASH will be important for treatment. In this study, we found that CXXC5, a negative feedback regulator of the Wnt/β-catenin pathway, was overexpressed with suppression of Wnt/β-catenin signaling and its target genes involved in hepatic metabolism in obese-NASH patients. Cxxc5−/− mice were found to be resistant to NASH pathogenesis with metabolic improvements. KY19334, a small molecule that activates the Wnt/β-catenin pathway via interference of the CXXC5-Dvl interaction, reversed the overall pathogenic features of NASH as Cxxc5−/− mice. The improvement in NASH by KY19334 is attributed to its regenerative effects through restorative activation of the suppressed Wnt/β-catenin signaling. Overall, the pronounced metabolic improvements with the stimulation of liver regeneration by interfering with the CXXC5-Dvl interaction provide a therapeutic approach for NASH.

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Metabolic improvement and liver regeneration by inhibiting CXXC5 function for non-alcoholic steatohepatitis treatment

Abstract

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