FXR stops hepatocellular apoptosis and liver fibrosis

Release date:2018-10-30  Release:主页英文版

Researchers from the State Key Laboratory of Natural Medicines, China Pharmaceutical University, have found that Farnesoid X Receptor (FXR), an important nuclear receptor in charge of expression of numerous downstream genes, acts as an intrinsic apoptosis inhibitor in hepatocytes to prevent liver fibrosis via transactivation-independent manner. This study can be retrieved in EBioMedicine (IF 6.183), published by The Lancet.

 

Liver fibrosis can lead to various complications and has become an important health issue all over the world. Elucidating the pathogenic mechanism of liver fibrosis and developing the novel therapeutics are highly in need. Farnesoid X receptor (FXR), a member of nuclear receptor superfamily, is highly expressed in hepatocytes and shuttles between nucleus and cytoplasm upon various stimuli. Previous efforts mainly focused on how FXR functions as a ligand-dependent transcriptional factor in controlling the metabolic homeostasis of bile acids and lipids and its potential benefit in the therapy of various liver diseases. However, little is known about its transactivation independent function and its contribution in liver diseases. The study co-led by Prof. Haiping Hao and Prof. Guangji Wang found that cytosolic FXR is an intrinsic apoptosis inhibitor via physically interacting with CASP8, thus inhibiting death receptors-engaged apoptosis, the hallmark of the pathogenesis of various liver diseases.


  

“Our previous work published in Cell Metabolism last year discovered that FXR can regulate NLRP3 inflammasome through direct protein-protein interaction. For further investigation into the transcriptional independent function of FXR, we employed various methods to identify and validate the FXR-Caspase 8 interaction in the cytosol. Finally, we found that FXR overexpression does protect against acute hepatocellular apoptosis as well as chronic liver fibrosis” said Yangtze River Scholar Distinguished Prof. Hao, the Dean of CPU School of Pharmacy and Deputy Director of State Key Laboratory of Natural Medicines.

  

“To further confirm our results and findings in the animal models, we collected human specimens from 112 patients who were clinically diagnosed with liver fibrosis. Histological and biochemical results are both consistent with our studies on animals.” said Dr. Hong Wang, the first author of this work.

  

Previous study mainly focused on the transactivation roles of FXR, promoting the development of various FXR agonists for various liver diseases. Satisfactorily, obeticholic acid was approved by FDA and EMEA for the therapy of primary biliary cholangitis. Additionally, several other FXR agonists are on clinical trials for other liver diseases, such as nonalcoholic steatohepatitis. However, several serious side effects and deficiency in several syndromes were observed in patients when taken FXR agonists, raising the question of how FXR should be better targeted. In this study, Prof. Hao et al. demonstrated the transactivation-independent function of FXR in preventing hepatocellular apoptosis and liver fibrosis, proposing a novel strategy targeting FXR by preventing its degradation or enhancing its association with Caspase 8.

  

This work was financed by National Natural Science Foundation of China, the Project for Major New Drug Innovation and Development and Overseas Expertise Introduction Project for Discipline Innovation. Dr. Wang was also supported by China Postdoctoral Science Foundation. 


Article provided by Professor WANG, Hong (first author of this article)