Post-transcriptional regulation of hepatokines and systemic metabolism

University Of California Los Angeles, Los Angeles CA

Investigators

Abstract

ABSTRACT Nutrient availability affects many cellular processes that are important for health and disease, including metabolic diseases such as diabetes, obesity, fatty liver and cardiovascular disease. The liver is the central hub of metabolism and is intricately involved in coordinating and maintaining metabolic health. The liver coordinates systemic metabolism is via secreted peptides, or hepatokines, which enter the circulation and can trigger responses in a number of distal tissues. There are well established transcriptional mechanisms that control hepatokine production, such as the PPAR-dependent transcriptional regulation of FGF21, a hepatokine that controls energy balance. Here we describe a novel mechanism by which the liver controls maintains homeostasis in the fasted state, via post-transcriptional control of mRNA stability by a family of RNA binding proteins (RBPs). Using global unbiased RNA-Seq analysis, we have identified a key hepatokine as a specific target of the RBP family. We then show that hepatic loss of these RBPs results in pronounced increases in the levels of mRNA as well as increased circulating levels of the hepatokine. We have generated extensive metabolic analysis showing that loss of all three members of the RBP family in the liver dramatically impacts body weight and energy balance. We also generated an inducible knockout mouse model where the RBPs and the hepatokine are deleted in hepatocytes, demonstrating that the hepatokine plays a significant role in the metabolic regulation of the RBPs. In Specific Aim 1, we will test the hypothesis that the RBPs regulate the hepatokine in the context of fasting, where they limit the surge in expression for the hepatokine in the fasted state. Then, using a complementary gain-of-function model for one of the redundant RBPs, we will use an inducible RBP overexpression model to identify direct RBP targets in the liver. In Specific Aim 2, we have identified a second hepatokine that is also regulated by our family of RBPs. We will determine the relative contribution of this hepatokine to the systemic changes in metabolism we observe following liver-specific loss of RBPs. Lastly, we have identified human variants in the 3’UTRs of both hepatokines, and will test whether these variants affect mRNA stability and contribute to human GWA loci for metabolic traits. Our studies will provide a novel layer of control for hepatokines and aid our understanding for how the liver regulates systemic metabolism, which may open up novel therapeutic avenues to modulate and treat metabolic disease.