Hepatic HuR modulates glucose metabolism through the C/EBPβ/PCK1 pathway

The liver plays a pivotal role in glucose homeostasis, adapting to metabolic challenges through transcriptional and post-transcriptional mechanisms. While the RNA-binding protein HuR/ELAVL1 is known to regulate mRNA stability during development and stress, its role in adult liver energy metabolism remains largely unexplored. Here, we demonstrate that hepatic HuR expression is dynamically induced in response to diverse metabolic challenges, including in vivo models of fasting (glucagon stimulation), caloric restriction, high-fat diet (HFD), and type 2 diabetes (T2D). Mechanistically, HuR modulates Cebpb mRNA, thereby enhancing the expression of phosphoenolpyruvate carboxykinase (PCK1), a key gluconeogenic enzyme. This interaction was assessed by in vivo immunoprecipitation and sequencing of ribonucleoprotein (RNP) complexes from mouse liver, which confirmed Cebpb modulation HuR-dependent. Silencing hepatic Elavl1 via siRNA delivery downregulated the C/EBPβ/PCK1 axis, increased glycogen synthesis, and improved hepatic insulin sensitivity and glycemic control. Furthermore, this increase in hepatic glycogen content led to reduced food intake, adiposity, and body weight in both healthy and diabetic mice. Collectively, our in vivo findings uncover HuR as a central post-transcriptional regulator of glucose metabolism in the liver and position it as a promising therapeutic target in metabolic disease.