HuR enhances the stability of FGF19 mRNA to suppress Kupffer cell activation and mitigate inflammation and fibrosis in non-alcoholic fatty liver disease.

Abstract

This study explores how human antigen R (HuR) stabilizes fibroblast growth factor 19 (FGF19) mRNA, inhibiting Kupffer cell (KC) activation to reduce inflammation and fibrosis in non-alcoholic fatty liver disease (NAFLD). An animal model of NAFLD was established in mice by administering a high-fat diet (HFD). In vitro study utilized a lipopolysaccharide-induced immortalized mouse KC model. HuR expression markedly decreased in HFD-induced NAFLD liver tissue. Overexpression of HuR via adeno-associated virus (AAV) vectors mitigated key pathological features of NAFLD, including hepatic inflammation and fibrosis. Moreover, HuR overexpression suppressed KC activation in both in vitro and in vivo models. Mechanistically, HuR bound AU-rich elements in FGF19 mRNA, enhancing its stability. FGF19 overexpression similarly mitigated HFD-induced liver pathology. Conversely, FGF19 silencing reversed HuR's inhibition of KC activation and abrogated HuR's protection against liver inflammation and fibrosis. This research elucidates a novel mechanism underlying the interaction between HuR and FGF19 in mitigating the pathological progression of NAFLD, providing potential therapeutic targets for this prevalent liver disease.