The RNA-binding protein HuR promotes nonalcoholic steatohepatitis (NASH) progression by enhancing death signaling pathway

Abstract

Hepatocyte death triggers liver inflammation, liver injury, and fibrosis, which contributes to non-alcoholic steatohepatitis (NASH) pathogenesis. However, whether RNA processing regulates death signaling pathway during NASH progression is not investigated. In this study, we show that HuR, a widely expressed RNA-binding protein, promotes NASH progression by increasing DR5/caspase8/caspase3-mediated hepatocyte death. Cytosolic HuR levels are abnormally elevated in human patients with NASH. Hepatocyte-specific deletion of HuR protects against MCD-induced NASH by decreasing liver steatosis, inflammation and cell death, whereas hepatic overexpression of HuR induces liver injury by increasing DR5-induced hepatocyte death. Furthermore, in primary hepatocytes, HuR deficiency ameliorates PA & TNFα-induced hepatocyte death due to decreased DR5/caspase8/caspase 3 signaling pathway while overexpression of HuR induces hepatocyte death by increasing DR5/caspase8/caspase 3 signaling pathway. Mechanistically, HuR directly binds to 3?-UTR of DR5 transcript and promotes its mRNA stability, contributing to the hepatocyte death during NASH progression. Our data reveal a novel mechanism by which HuR promotes mRNA stability of DR5, which contributes to NASH progression.

The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma

“…Sirtuin 1, encoded by the SIRT1 gene, can deacetylate an RNA-binding protein quaking 5 (QKI 5), which inhibits TG synthesis in vivo and in vitro via the PPARα/FoxO1 signaling pathway and suppresses NAFLD progression in mice [96]. Another study showed that a broadly expressed RNA-binding protein human antigen R (HuR) can accelerate NASH progression by increasing death receptor 5 (DR5)/caspase 8/caspase 3-mediated hepatocyte death and liver injury [97].…”