Eileen Wynne
Research Mentor(s): Xin Tong
Mentor Department: Molecular & Integrative Physiology
Authors: Yuee Zhao
Session: Session 6 (3:00pm – 3:50pm)
Presentation Type: Poster 99
Abstract
Background: Sustained activation of hepatic stellate cells (HSCs) drives liver fibrosis in response to chronic liver injury. Profibrogenic signals from stressed hepatocytes evoke fibrogenic responses in HSCs. Hepatocytes, the dominant liver cell type, respond to TGFß by releasing pro-fibrogenic factors. TGFß signaling, through SMAD-dependent and -independent pathways, drives fibrosis during chronic inflammation. While transient TGFß activation promotes tissue repair, persistent signaling in chronic liver disease (CLD) leads to fibrosis. Blocking hepatocyte TGFß signaling protects against fibrosis, but direct inhibition may disrupt liver regeneration. Thus, targeting downstream effectors of TGFß signaling may offer a safer therapeutic approach. Approach and Results: In the previous experiments, hepatic ChREBPa was reduced in mouse models of chemical-induced liver fibrosis models. Chrebp?-LKO mice are highly sensitive to either CCl4-or TAA-induced liver injury and develop more advanced liver fibrosis without affecting liver lipid contents. The RNA-Seq analysis revealed that E2F1, a novel effector of a TGFß-mediated fibrogenic pathways, was highly induced in the lover of the Chrebp?-LKO mice. In my research, adenovirus-mediated overexpression of E2F1 promotes the protein expression of CTGF and THBS1 in hepatocyte cells, whereas Knockdown E2F1 by adenovirus-mediated shRNA does the opposite. CHRBPaplha can inhibit E2F1 induced CTGF and THBS1 expression which also inhibits fibrosis. Conclusion: These findings demonstrate that hepatocyte ChREBP? monitors hepatic microenvironment and suppresses the activation of HSCs by inhibiting the E2F1-mediated induction of profibrogenic factors THBS1 and CTGF. Higashi, T., S.L. Friedman, and Y. Hoshida, Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev, 2017. 121: p. 27-42.2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. Tsuchida, T. and S.L. Friedman, Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol, 2017. 14(7): p. 397-411. Dhar, D., et al., Mechanisms of liver fibrosis and its role in liver cancer. Exp Biol Med (Maywood), 2020. 245(2): p. 96-108. Zhang, D., et al., Suppression of hepatic ChREBP?-CYP2C50 axis-driven fatty acid oxidation sensitizes mice to diet-induced MASLD/MASH. Mol Metab, 2024: p. 101957. Tong, X., et al., DDB1 E3 ligase controls dietary fructose-induced ChREBPalpha stabilization and liver steatosis via CRY1. Metabolism, 2020. 107: p. 154222.
