Abstract
AbstractCholestasis causes ductular reaction in the liver where the reactive cholangiocytes not only proliferate but also gain a neuroendocrine-like phenotype, leading to inflammatory cell infiltration and extracellular matrix deposition and contributing to the development and progression of cholestatic liver fibrosis. This study aims to elucidate the role of miR-200c in cholestasis-induced biliary liver fibrosis and cholangiocyte activation. We found that miR-200c was extremely abundant in cholangiocytes but was reduced by cholestasis in a bile duct ligation (BDL) mouse model; miR-200c was also decreased by bile acids in vitro. Phenotypically, loss of miR-200c exacerbated cholestatic liver injury, including periductular fibrosis, intrahepatic inflammation, and biliary hyperplasia in both the BDL model and the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) model. We identified sestrin 1 (SESN1) as a target of miR-200c. Sesn1−/−-BDL mice showed mitigation of cholestatic liver injury. On a molecular level, the pro-proliferative IL-6/AKT feedback loop was activated in Mir200c−/− livers but was inhibited in Sesn1−/− livers upon cholestasis in mice. Furthermore, rescuing expression of miR-200c by the adeno-associated virus serotype 8 ameliorated BDL-induced liver injury in Mir200c−/− mice. Taken together, this study demonstrates that miR-200c restrains the proliferative and neuroendocrine-like activation of cholangiocytes by targeting SESN1 and inhibiting the IL-6/AKT feedback loop to protect against cholestatic liver fibrosis. Our findings provide mechanistic insights regarding biliary liver fibrosis, which may help to reveal novel therapeutic targets for the treatment of cholestatic liver injury and liver fibrosis.Cholangiocytes are the primary targets of cholangiopathies. This study elucidates the role of miR-200c in maintaining cholangiocyte homeostasis making use of cell culture and mouse models of cholestasis. MiR-200c restrains the proliferative and neuroendocrine-like activation of cholangiocytes by targeting sestrin 1(SESN1) and inhibiting the IL-6/AKT feedback loop to prevent cholestatic liver injury. The findings provide critical mechanistic insights into biliary liver fibrosis and suggest miR-200c may be a novel therapeutic target of cholangiopathies.
Highlights
Cholestatic liver diseases arise from intrahepatic retention of cytotoxic bile acids (BAs) because of impaired bile formation and/ or flow, accounting for a significant part of end-stage liver disease
We examined the expression level of miR-200c in cholangiocytes exposed to several BAs, which represent distinct hydrophilicity and are the major BA species in both mouse and human BA pools, the level of lithocholic acid (LCA) is very low in mice[30]
Expression of miR-200c was reduced in both MLC and HuCCT-1 cells treated with several BAs, including CA, taurocholic acid (TCA), chenodeoxycholic acid (CDCA) and/or ursodeoxycholic acid (UDCA), for 24 h and further decreased in MLC cells exposed to CA for 48 h (Fig. 1B and Supporting Fig. 1D)
Summary
Cholestatic liver diseases arise from intrahepatic retention of cytotoxic bile acids (BAs) because of impaired bile formation and/ or flow, accounting for a significant part of end-stage liver disease. BA-contributed injury to bile ducts and hepatocytes can lead to abnormal liver biochemistry, ductular reaction, biliary fibrosis, and disease progression to cirrhosis[1]. The activation and transdifferentiation of quiescent hepatic stellate cells (HSCs) into fibrogenic myofibroblasts are the key cellular events in liver fibrosis. HSCs increasingly express ACTA2 (actin alpha 2, smooth muscle; alias α-SMA) and other proteins (e.g., collagens) forming the connective tissue and synthesize and release tissue inhibitors of metalloproteinase (TIMP)-1 and -2. A recognized common notion is that liver fibrosis is impacted by other liver cell types and regulated by a broad spectrum of cytokines, chemokines, growth factors, and hormones[2]
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