METHODS AND COMPOSITIONS FOR TREATING LIVER DISESASES
The present invention relates to a method for treating a subject suffering from a liver disease comprising a step of administering said subject with a therapeutically effective amount of an inhibitor of the endoribonuclease activity of IRE1α. Inventors have shown that in livers of tunicamycin-treated BI-1-/- mice aIRE1α-dependent NLRP3 inflammasome activation, an hepatocyte death, a fibrosis and a dysregulated lipid homeostasis that led to liver failure within a week. To test whether the pharmacological inhibition of IRE1α endoribonuclease activity would block the transition to NASH, mice were injected with the small molecule STF-083010 twice a week for 2 weeks towards the end of a 3-month HFD. In BI-1-/- mice, STF-083010 treatment effectively counteracted IRE1α endoribonuclease activity, improving glucose tolerance and rescuing from NASH. The hepatocyte-specific role of IRE1α's RNase activity in mediating NLRP3 inflammasome activation and programmed cell death was confirmed in primary mouse hepatocytes through knockdown experiments and with STF-083010.
- Hepatology. 2018 Aug;68(2):515-532. doi: 10.1002/hep.29847. Epub 2018 May 18.