Abstract
EXPLORING THE ROLE OF X-BINDING PROTEIN-1 (XBP1) IN THE GUT- LIVER AXIS DURING ALCOHOL-RELATED LIVER DISEASE (ARLD)
Background:
In the context of alcohol-related liver disease (ArLD), changes in the homeostasis of the gut-liver axis have become a focus of major
attention in the past few years. The transcription factor X-Binding protein-1 (XBP1) is a major regulator of UPR, mediating adaptation to ER stress. In the present study, we aimed to analyze the function of XBP1 in the gut (intestinal epithelial cells, IECs), and in the liver (hepatocytes) in promoting ArLD.
Methods:
Eight- to 13-week-old female and male mice with specific deletion of XBP1 in IECs (XBP1ΔIEC), XBP1 in Hepatocytes (XBP1ΔHEPA), and XBP1-floxed wildtype (XBP1f/f) mice were subjected different experimental models of ArLD: (i) Lieber-DeCarli control and ethanol diet for 8 weeks plus a multiple PBS or EtOH gavage, respectively, and (ii) DUAL diet, a preclinical model of non-alcoholic fatty fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) characterized by the development of metabolic syndrome. Upon sacrifice, organs were extracted, and markers of liver damage, histopathological examination and techniques of Biochemistry and Molecular Biology were performed. Finally, antibiotic treatment (Abx) was performed as a therapeutic approach.
Results:
Serum markers of liver damage (e.g.: AST, ALT) were statistically increased in XBP1ΔIEC compared with XBP1f/f after both preclinical models, and associated with significantly higher cell death. Concomitantly, H&E staining of XBP1ΔIEC livers displayed macrovesicular ballooning accompanied by significantly elevated markers of inflammation including TNFa, IL-6, MCP-1, TLR2/4, liver fibrosis (Sirius red and collagen I deposition), and signs of bacterial translocation into the liver (LPS, LTA and bacterial DNA). Furthermore, the content of intrahepatic triglycerides revealed significantly increased lipid deposition in XBP1ΔIEC compared with XBP1f/f after both types of preclinical models. Presence of autophagic vacuoles, decreased lysozyme granules and dilation of the Golgi cisterns associated with loss of Paneth cells and increased gut permeability (Mucin-2, ZO-1) was characteristic of XBP1ΔIEC compared with XBP1f/f ilea, after both models of ArLD. Microbiota analysis revealed significantly increased abundance of Lachnospiraceae, Muribaculaceae and Romboutsia in in XBP1ΔIEC
mice. Abx therapeutics reversed the inflammatory phenotype of DUAL-ArLD with reduced liver injury, steatosis and fibrosis.
Conclusion:
Our results clearly suggest that loss of XBP1 in IECs trigger significant inflammation in the gut-liver axis, opening a novel therapeutic avenue for research in the context of ER stress and ArLD.
Related Speaker and Session
Carlos Sanz-García, Complutense School of MedicineDate: Sunday, November 12th
Time: 2:00 - 3:30 PM EST