ChREBP in Liver Metabolism: Defining Mechanisms and Resolving Controversies

This project investigates the role of Carbohydrate Responsive Element Binding Protein (ChREBP), a key transcription factor in metabolic regulation and disease, particularly focusing on its isoforms and their effects in the liver. ChREBP has been implicated in metabolic-associated steatohepatitis (MASLD), dyslipidemia, and cardiometabolic diseases, yet the specific functions of its isoforms remain controversial and poorly understood, in part due to conflicting reports published in a variety of gain- and loss-of-function ChREBP mouse models. In this project we aim to resolve the contradictory roles of ChREBP isoforms in liver metabolism, thereby enhancing our understanding of metabolic disease mechanisms. This will serve our long- term objectives of providing foundational principles of liver metabolism that may ultimately lead to improved diagnostic and therapeutic strategies for metabolic disorders including dyslipidemia, diabetes, and MASLD. The study employs genetic interventions (knockouts and overexpression) in mouse models and molecular phenotyping to dissect the metabolic pathways and molecular physiology influenced by ChREBP isoforms. Techniques include GalNAc-siRNA-mediated knockdown, ADV-mediated overexpression, and AAV-TBG- Crispr modifications in mouse models. This approach will enable a detailed analysis of the physiological impacts of ChREBP under various metabolic contexts, offering insights into its dual roles in metabolic diseases. In Aim 1, we aim to define the role of hepatic ChREBP-beta in a model where ChREBP-alpha has been ablated, testing if modest increases in its expression are sufficient to adversely affect liver and systemic metabolism. In Aim 2, we will explore dose-dependent effects of ChREBP overexpression on liver function and systemic metabolism, focusing on glucose homeostasis and mitochondrial dysfunction. Aim 3 investigates the activation of ChREBP by specific carbohydrate metabolites under different dietary conditions, employing Crispr strategies to modify key enzymes in metabolite pathways that may provide metabolites that activate ChREBP.