CD133-Src-TAZ signaling stimulates ductal fibrosis following DDC diet-induced liver injury

Ho Taek Oh, Woong Heo, Gi Don Yoo, Kyung Min Kim, Jun Ha Hwang, Eun Sook Hwang, Jesang Ko, Young Gyu Ko, Jeong Ho Hong

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2 Scopus citations


Chronic liver injury follows inflammation and liver fibrosis; however, the molecular mechanism underlying fibrosis has not been fully elucidated. In this study, the role of ductal WW domain-containing transcription regulator 1 (WWTR1)/transcriptional coactivator with PDZ-binding motif (TAZ) was investigated after liver injury. Ductal TAZ-knockout (DKO) mice showed decreased liver fibrosis following a Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) diet compared to wild-type (WT) mice, as evidenced by decreased expression levels of fibrosis inducers, including connective tissue growth factor (Ctgf)/cellular communication network factor 2 (CCN2), cysteine-rich angiogenic inducer 61 (Cyr61/CCN1), and transforming growth factor beta 1 (Tgfb1), in DKO mice. Similarly, TAZ-knockout (KO) cholangiocyte organoids showed decreased expression of fibrosis inducers. Additionally, the culture supernatant of TAZ-KO cholangiocyte organoids decreased the fibrogenic gene expression in liver stellate cells. Further studies revealed that prominin 1 (PROM1/CD133) stimulated TAZ for fibrosis. After the administration of DDC diet, fibrosis was decreased in CD133-KO (CD133-KO) mice compared to that in WT mice. Similarly, CD133-KO cholangiocyte organoids showed decreased Ctgf, Cyr61, and Tgfb1 expression levels compared to WT cholangiocyte organoids. Mechanistically, CD133 stabilized TAZ via Src activation. Inhibition of Src decreased TAZ levels. Similarly, CD133-knockdown HCT116 cells showed decreased TAZ levels, but reintroduction of active Src recovered the TAZ levels. Taken together, our results suggest that TAZ facilitates liver fibrosis after a DDC diet via the CD133-Src-TAZ axis.

Original languageEnglish
Pages (from-to)4504-4516
Number of pages13
JournalJournal of Cellular Physiology
Issue number12
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This study was supported by the Basic Science Research Program of NRF funded by the Ministry of Education (2021R1A2C1007461, 2015R1A5A1009024, 2020R1A2C2004679, and 2018R1A5A2025286) and Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (HN22C0723), Republic of Korea. This study was also supported by a grant offered by Korea University.

Publisher Copyright:
© 2022 Wiley Periodicals LLC.


  • CD133
  • Src
  • TAZ
  • bile ducts
  • liver fibrosis
  • organoids


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