CD133‐Src‐TAZ signaling stimulates ductal fibrosis following DDC diet‐induced liver injury. Issue 12 (17th October 2022)

• Record Type: Journal Article
• Authors: Oh, Ho Taek; Heo, Woong; Yoo, Gi Don; Kim, Kyung Min; Hwang, Jun‐Ha; Hwang, Eun Sook; Ko, Jesang; Ko, Young‐Gyu; Hong, Jeong‐Ho
• Is Part Of: Journal of cellular physiology. Volume 237:Issue 12(2022)
• Page Start: 4504
• Page End: 4516
• Publication Date: 2022-10-17
• Subjects: bile ducts -- CD133 -- liver fibrosis -- organoids -- Src -- TAZ; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30899
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: 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. Abstract : Diethyl 1, 4‐dihydro‐2, 4, 6‐trimethyl‐3, 5‐pyridinedicarboxylate diet‐induced liver damage increased transcriptional co‐activator with PDZ‐binding motif (TAZ) and CD133 expression levels in cholangiocytes. CD133 stabilized and activated TAZ via Src. The activated TAZ further stimulated the fibrosis marker genes, 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 ). Thus, the CD133‐Src‐TAZ axis was identified as a novel fibrogenic signaling pathway.