The Role of Coregulator Liver Arginine and Glutamate Rich 1 in the Transcriptional and Physiologic Regulation of Fasting and High-Fat Diet Feeding

Speaker: Sarah Cash

Supervisor: Dr. Carolyn Cummins
Abstract
Dysregulation of the transcriptome mediating lipid and carbohydrate metabolism can result in the exacerbation of metabolic diseases. Many lipid and carbohydrate metabolic pathways are regulated by nuclear receptors, which are ligand-activated transcription factors. Nuclear receptors associate with coregulator proteins that either activate or repress transcription. Our laboratory identified a novel protein, termed ARGLU1 (Arginine and Glutamate Rich 1), that acts as a coregulator for numerous nuclear receptors involved in metabolic processes, including GR, ER, FXR and PPARs. This thesis characterized ARGLU1 as a coactivator for PPAR (peroxisome proliferator-activated receptors) in vitro and found sex- and gene-dependent effects in vivo. While ARGLU1 appeared to behave as a corepressor in the livers of male mice upon PPARα ligand treatment; with fasting, ARGLU1 displayed sex- and gene-dependent regulation of gene expression. Further analysis of hepatic ARGLU1 demonstrated a role in lipid metabolism in both female and male mice. When liver Arglu1 is knocked out (LKO), the mice are resistant to diet-induced obesity. The LKO mice have significantly reduced body weight and adipose tissue weight, however, this is not attributed to decreased food intake, increased
locomotion, or increased energy expenditure. Notably, the LKO mice demonstrate reduced lipid absorption, supported by increased fecal triglyceride content and improved lipid tolerance. Using liver RNA-sequencing, we identified that the cholesterol-bile acid axis is affected in LKO mice. Further studies established that the synthesis of 12α-hydroxylated bile acids is lowered in LKO mice, impacting the ability of bile to efficiently absorb dietary lipids. To explore whether this could be exploited therapeutically, we induced obesity in mice first, and then performed viral knockdown of hepatic Arglu1. We found that this treatment paradigm did reduce body weight. Finally, to determine the molecular mechanism of ARGLU1’s role on transcription, we identified transcription factors and proteins that interact with RNA polymerase II, that could explain the transcriptional regulation of metabolic pathways. Overall, we characterized ARGLU1 as a diverse coregulator protein that has potential to act as a therapeutic target to address the ongoing metabolic disease epidemic that is affecting billions of individuals globally.