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

Area of Science:

• Metabolic regulation
• Post-transcriptional control
• Liver function

Background:

• The liver is crucial for glucose homeostasis, employing complex regulatory mechanisms.
• The role of RNA-binding protein HuR (ELAVL1) in adult liver energy metabolism is largely unknown.
• HuR influences mRNA stability during stress and development.

Purpose of the Study:

• To investigate the role of hepatic HuR in glucose homeostasis and metabolic challenges.
• To elucidate the molecular mechanisms by which HuR regulates liver metabolism.
• To assess HuR as a potential therapeutic target for metabolic diseases.

Main Methods:

• In vivo studies using models of fasting, caloric restriction, high-fat diet, and type 2 diabetes.
• Assessment of HuR expression and its targets in mouse liver.
• In vivo immunoprecipitation and sequencing of ribonucleoprotein complexes.
• siRNA-mediated silencing of hepatic Elavl1.

Main Results:

• Hepatic HuR expression is induced by various metabolic challenges.
• HuR directly modulates Cebpb mRNA, enhancing PCK1 expression and gluconeogenesis.
• Silencing hepatic HuR (Elavl1) improves insulin sensitivity, glycemic control, and increases glycogen synthesis.
• Increased hepatic glycogen reduces food intake, adiposity, and body weight.

Conclusions:

• HuR is a key post-transcriptional regulator of hepatic glucose metabolism.
• The HuR/Cebpb/PCK1 axis is critical for adaptive metabolic responses.
• Targeting hepatic HuR offers a promising therapeutic avenue for metabolic disorders like type 2 diabetes.