Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function.

ABSTRACT: Inflammatory liver diseases are a major cause of morbidity and mortality worldwide; however, underlying mechanisms are incompletely understood. Here we show that deleting the focal adhesion protein Kindlin-2 expression in hepatocytes using the Alb-Cre transgenic mice causes a severe inflammation, resulting in premature death. Kindlin-2 loss accelerates hepatocyte apoptosis with subsequent compensatory cell proliferation and accumulation of the collagenous extracellular matrix, leading to massive liver fibrosis and dysfunction. Mechanistically, Kindlin-2 loss abnormally activates the tumor necrosis factor (TNF) pathway. Blocking activation of the TNF signaling pathway by deleting TNF receptor or deletion of Caspase 8 expression in hepatocytes essentially restores liver function and p

SUBMITTER: Gao H 

PROVIDER: S-EPMC9848388 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature