RT Journal Article
SR Electronic
T1 The Lack of Nrf2 Causes Hepatocyte Dedifferentiation and Reduced Albumin Production in an Experimental Extrahepatic Cholestasis Model
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.26.441515
DO 10.1101/2021.04.26.441515
A1 Guo-Ying Wang
A1 Veronica Garcia
A1 Joonyong Lee
A1 Jennifer Yanum
A1 Huaizhou Jiang
A1 Guoli Dai
YR 2021
UL http://biorxiv.org/content/early/2021/04/27/2021.04.26.441515.abstract
AB The transcription factor Nrf2 modulates the initiation and progression of a number of diseases including liver disorders. The aim of this study was to evaluate whether Nrf2 mediates hepatic adaptive responses to cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation (BDL) or a sham operation. Various assessments were performed at different days after surgery. Significant genotype-dependent changes in liver size, biliary ductular reaction, hepatocyte proliferation, and fibrotic response were not observed. However, as cholestasis progressed to Day 15 post-BDL, hepatocytes in the wild-type mice exhibited a tendency to dedifferentiate, indicated by the very weak expression of hepatic progenitor markers: CD133 and fibroblast growth factor-inducible 14 (Fn14). During the same period, Nrf2 deficiency augmented this tendency, manifested by higher CD133 expression, earlier, stronger, and continuous induction of Fn14 expression, and markedly reduced albumin production. Remarkably, as cholestasis advanced to the late stage (40 days after BDL), hepatocytes in the wild-type mice exhibited a Fn14+ phenotype and strikingly upregulated the expression of deleted in malignant brain tumor 1 (DMBT1), a protein essential for epithelial differentiation during development. In contrast, at this stage, hepatocytes in the Nrf2-null mice entirely inhibited the upregulation of DMBT1 expression, displayed a strong CD133+/Fn14+ phenotype indicative of severe dedifferentiation, and persistently reduced albumin production. Collectively, our studies revealed that Nrf2 maintains hepatocytes in the differentiated state potentially via the increased activity of the Nrf2/DMBT1 pathway during cholestasis. These findings enable us to gain novel insight into how hepatocytes respond to cholestasis.New and Noteworthy We found that, when hepatocytes are exposed to cholestasis, they exhibit a tendency of dedifferentiation. In this case, Nrf2 is highly activated to markedly up-regulate the expression of epithelial differentiation gene DMBT1, which potentially prevent hepatocytes from dedifferentiation. Our findings revealed a plastic property of hepatocytes in response to cholestasis and demonstrated a novel Nrf2/DMBT1 pathway likely controlling this property of hepatocytes.Competing Interest StatementThe authors have declared no competing interest.BDLbile duct ligationDMBT1deleted in malignant brain tumor 1EGFRepidermal growth factor receptorFn14fibroblast growth factor-inducible 14Nrf2nuclear factor erythroid 2-related factor 2NQO1NAD(P)H quinone dehydrogenase 1YAPyes-associated protein