Key result
Immunoblocking of cAngptl4 reduces T-cell overactivation via modulation of eIF2α signaling, thereby delaying hepatic inflammation and fibrosis aggravation in diet-induced NAFLD.
Why the study?
Pathological intrahepatic T-cell landscape plays a role in NAFLD propagation, but the mechanisms driving its activation remain unknown.
Angptl4 is a crucial determinant in shaping intrahepatic adaptive immunity during fibrosis in NAFLD, and its inhibition delays disease progression in a murine model.
No immediate clinical implications; hypothesis-generating for intrahepatic T-cell targeting in human NAFLD.
Adaptive T-cell immune response is essential in conferring protective immunity, a process requiring tight cellular homeostasis regulation. Pathological intrahepatic T-cell landscape has a role in NAFLD propagation; however, its activation remains unknown. To address this gap, we extensively characterized a novel diet-induced NAFLD murine model (LIDPAD) featuring key phenotypic and genetic attributes reflective of human NAFLD. Comparative transcriptomic-guided staging of human and murine NASH reinforced the robustness of LIDPAD in recapitulating critical transitory stages of human NAFLD. We found that angiopoietin-like 4 (Angptl4) shapes activation of the intrahepatic T-cell landscape through the modulation of eIF2α signaling during fibrosis. Single-immune cell analysis and hepatic transcriptomics during fibrosis, and kinase inhibitor screening confirmed that Angptl4 orchestrates the hyperactivation of intrahepatic adaptive immunity via eIF2α signaling. Consistently, immunoblocking of cAngplt4 reduces T-cell overactivation, delaying disease aggravation. Taken together, Angptl4 is a crucial determinant in shaping intrahepatic adaptive immunity during fibrosis in NAFLD.
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Low et al. (2023) studied Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH). cAngptl4 neutralizing antibody or Angptl4 genetic deficiency vs. Control diet or wild-type mice was evaluated on Hepatic inflammation and fibrosis progression. Immunoblocking of cAngptl4 reduces T-cell overactivation via modulation of eIF2α signaling, thereby delaying hepatic inflammation and fibrosis aggravation in diet-induced NAFLD.
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