The Foxo1-YAP-Notch1 axis reprograms STING-mediated innate immunity in NASH progression.

ABSTRACT: Innate immune activation is critical for initiating hepatic inflammation during nonalcoholic steatohepatitis (NASH) progression. However, the mechanisms by which immunoregulatory molecules recognize lipogenic, fibrotic, and inflammatory signals remain unclear. Here, we show that high-fat diet (HFD)-induced oxidative stress activates Foxo1, YAP, and Notch1 signaling in hepatic macrophages. Macrophage Foxo1 deficiency (Foxo1^M-KO) ameliorated hepatic inflammation, steatosis, and fibrosis, with reduced STING, TBK1, and NF-κB activation in HFD-challenged livers. However, Foxo1 and YAP double knockout (Foxo1/YAP^M-DKO) or Foxo1 and Notch1 double knockout (Foxo1/Notch1^M-DKO) promoted STING function and exacerbated HFD-induced liver injury. Interestingly, Foxo1

SUBMITTER: Xu D 

PROVIDER: S-EPMC11372114 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature