Modulating Metabolic Gene Expression with Small Molecule Agonists for LRH-1

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Project Summary/Abstract Liver homolog receptor (LRH-1) is a nuclear receptor that plays a key role in hepatic metabolic signaling. Targeting LRH-1 in the context of obesity results in marked improvements in insulin sensitivity and hepatic lipid homeostasis. This suggests that LRH-1 could be an important therapeutic target in metabolic diseases such as Type 2 diabetes and fatty liver disease. Using structure-based design, novel LRH-1 modulators have been developed that potently activate LRH-1 both in vitro and in vivo. However, it remains unknown how activating LRH-1 with synthetic agonists will modulate gene expression and metabolic signaling pathways. In Aim 1, RNA-seq and ChIP-seq methods will be used to examine how synthetic agonists with different binding mechanisms can alternately regulate LRH-1 target genes in primary human hepatocytes. In Aim 2, diet-induced obese mice will be dosed with a synthetic LRH-1 agonist to treat their metabolic dysfunction. Parameters of lipid and glucose homeostasis will be measured to elucidate the effectiveness of an LRH-1 agonist in reversing metabolic symptoms. To ensure agonist specificity for LRH-1, LRH-1 KO mice will be used as experimental controls. As one of the first studies to target LRH-1 in vivo with synthetic agonists, this research will provide vital information about the therapeutic potential of targeting LRH-1 to treat metabolic diseases. Fellowship training will be conducted in the departments of Biochemistry and Surgery at Emory University School of Medicine and will include hands-on training in transcriptomic sequencing, lipidomics, and mouse transgenics and physiology. Training will take place in the stimulating intellectual environment at Emory University and draw upon the expertise of several collaborators and research cores. The IRACDA Fellowships in Research and Science Teaching (FIRST) program and the Office of Postdoctoral Education will also provide additional teaching and professional development opportunities. In summary, the pioneering research described here in combination with the exceptional training environment will ensure the successful development of this applicant into an independent research investigator.