# Developing chemoproteomic approaches to decipher the regulatory network of LRH-1, a nuclear receptor implicated in hepatic metabolism

> **NIH NIH F31** · SCRIPPS FLORIDA · 2020 · $32,520

## Abstract

Project Summary/Abstract: Liver receptor homolog-1 (LRH-1; NR5A2) is a phospholipid-sensing nuclear
receptor (NR) expressed predominantly in the liver, pancreas, and ovaries that plays an important role in
metabolic physiologies and pathophysiologies. Specifically, it has been characterized to regulate bile acid
metabolism, cholesterol homeostasis, and steroidogenesis, and in turn is involved in various disease states such
as type 2 diabetes, atherosclerosis, nonalcoholic fatty liver disease as well as a multitude of cancers. These
diseases are all risk factors for metabolic syndrome that affects nearly a third of the US population. This
represents a significant health concern as individuals diagnosed with metabolic syndrome have increased risk
for developing cardiovascular diseases as well as hepatocellular, gastric, and colon cancers; cancers that have
been associated with overexpression of LRH-1. This suggests LRH-1 to be a promising therapeutic target for
such metabolic diseases and cancers. However, a lack of a wholistic understanding of the receptors regulatory
mechanism presents a significant limitation to the success of LRH-1 as a therapeutic target. Similar to other
nuclear receptors, LRH-1's activity is tightly regulated via a multitude of pathways including cellular localization,
ligand binding, DNA binding, post-translational modifications, and coregulator interactions. Cellular localization
is central to these pathways as it determines the receptors milieu and thus available interacting partners. While,
multiple nuclear localization signals and nuclear export signals have been identified to facilitate receptor shuttling
in and out of the nucleus, there is no information regarding LRH-1 intranuclear trafficking, a key process that
directly modulates DNA binding and transcriptional output. This propels the need to develop effective and specific
tools to modulate LRH-1 localization and activity. While the use of chemical approaches to probe NRs in
metabolism has increased over the years, the use of chemoproteomics in this area remains limited. Proteomic
analysis of nuclear receptors remains problematic as they are relatively low abundant and tightly bound to
chromatin. As such, there is a need for tools to probe and capture endogenous LRH-1 and LRH-1 transcriptional
complexes. I propose the following specific aims to develop and employ LRH-1 specific chemoproteomic tools
to elucidate the role of acetylation and a novel coregulator lamina associated polypeptide 2 (LAP2) in regulating
LRH-1 intranuclear trafficking and signaling. In Aim 1, I will establish two LRH-1 specific probes to more
efficiently modulate and/or capture LRH-1 and LRH-1 transcriptional complexes. These include a biotinylated
LRH-1 response element oligo probe and SR1848, small molecule inhibitor of LRH-1 signaling. In Aim 2, I will
identify LRH-1 acetylated residues and validate LAP2 isoforms as novel LRH-1 coregulators that coordinate to
fine tune LRH-1 intranuclear ...

## Key facts

- **NIH application ID:** 10150496
- **Project number:** 1F31DK126394-01A1
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Valentine Virginie Courouble
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,520
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150496

## Citation

> US National Institutes of Health, RePORTER application 10150496, Developing chemoproteomic approaches to decipher the regulatory network of LRH-1, a nuclear receptor implicated in hepatic metabolism (1F31DK126394-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10150496. Licensed CC0.

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