Fluorofenidone ameliorates cholestasis and fibrosis by inhibiting hepatic Erk/-Egr-1 signaling and Tgfβ1/Smad pathway in mice
| Autor: | Huiwen Wang, Jian Zhang, Xiaoxun Zhang, Nan Zhao, Zongtao Zhou, Lijian Tao, Lei Fu, Shifang Peng, Jin Chai |
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| Rok vydání: | 2022 |
| Předmět: |
Inflammation
Liver Cirrhosis Male Cholestasis Interleukin-6 Pyridones Tumor Necrosis Factor-alpha Ursodeoxycholic Acid Anti-Inflammatory Agents Alanine Transaminase Alkaline Phosphatase Fibrosis Bile Acids and Salts Mice Inbred C57BL Mice Animals Molecular Medicine Aspartate Aminotransferases Molecular Biology |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1868:166556 |
| ISSN: | 0925-4439 |
| Popis: | Cholestasis is characterized by intrahepatic accumulation of bile acids (BAs), resulting in liver injury, fibrosis, and liver failure. To date, only ursodeoxycholic acid and obeticholic acid have been approved for the treatment of cholestasis. As fluorofenidone (AKF-PD) was previously reported to play significant anti-fibrotic and anti-inflammatory roles in various diseases, we investigated whether AKF-PD ameliorates cholestasis. A mouse model of cholestasis was constructed by administering a 0.1 % 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) diet for 14 days. Male C57BL/6 J mice were treated with either AKF-PD or pirfenidone (PD) orally in addition to the DDC diet. Serum and liver tissues were subsequently collected and analyzed. We found that AKF-PD significantly reduced the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bile salts (TBA), as well as hepatic bile acids (BAs) levels. Hepatic histological analyses demonstrated that AKF-PD markedly attenuated hepatic inflammation and fibrosis. Further mechanistic analyses revealed that AKF-PD markedly inhibited expression of Cyp7a1, an enzyme key to BAs synthesis, by increasing Fxr nuclear translocation, and decreased hepatic inflammation by attenuating Erk/-Egr-1-mediated expression of inflammatory cytokines and chemokines Tnfα, Il-1β, Il-6, Ccl2, Ccl5 and Cxcl10. Moreover, AKF-PD was found to substantially reduce liver fibrosis via inhibition of Tgfβ1/Smad pathway in our mouse model. Here, we found that AKF-PD effectively attenuates cholestasis and hepatic fibrosis in the mouse model of DDC-induced cholestasis. As such, AKF-PD warrants further investigation as a candidate drug for treatment of cholestasis. |
| Databáze: | OpenAIRE |
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