# Nuclear receptor mediated bile acid alterations and coagulopathy in protein-energy undernutrition

> **NIH NIH K08** · BAYLOR COLLEGE OF MEDICINE · 2020 · $162,615

## Abstract

PROJECT SUMMARY/ABSTRACT
Protein-energy undernutrition (PEU) is implicated in half of all global deaths under five years of age and
remains one of the most pressing challenges in pediatrics today. PEU sets into motion a vicious cycle of liver
function abnormalities that further erode health. For example, intestinal bile acids are markedly reduced in
children with PEU, resulting in poor dietary fat absorption and impaired weight gain. In severe cases, vitamin K-
independent coagulopathy can lead to catastrophic bleeding. Mechanisms by which PEU alters these two
processes are unknown, although evidence implicates the nutrient-sensing nuclear receptors, farnesoid X
receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)α. FXR is activated in the fed state by bile
acids, while PPARα is activated in the fasted state by products of lipolysis. These receptors regulate bile acid
homeostasis and other liver functions, competing for binding to many of the same promoter regions with opposite
transcriptional effects. Children with mutations in the gene encoding FXR also have vitamin K-independent
coagulopathy with transcriptional repression of multiple coagulation factors including fibrinogen, implicating FXR
signaling in the coagulopathy of PEU. To investigate the role of nuclear receptors in these two liver functions,
we examined mouse models of early-life PEU, each of which exhibits globally decreased bile acids and
coagulopathy. Gene expression patterns in our young adult mice demonstrate Pparα activation, Fxr signal loss,
and transcriptional repression of genes that promote bile acid synthesis and coagulation. Based on these
findings, our hypothesis is that Pparα activation by products of lipolysis generated in PEU
transcriptionally represses key genes in bile acid synthesis leading to decreased intestinal bile acids
and impaired weight gain. Furthermore, we hypothesize that activated Pparα displaces Fxr from shared
DNA promoter regions, mediating coagulopathy by decreasing transcription of Fxr-dependent genes.
This hypothesis will be tested with two specific aims. In Aim 1, PEU and healthy wild type mice treated with
Pparα agonist or antagonist, along with PEU and healthy Pparα-/- mice, will be used to determine how Pparα
drives changes in the expression of genes that regulate bile acid pool size by qPCR, bile acid concentrations by
LC-MS/MS, and growth impairment over time. In Aim 2, wild type mice treated with Pparα and Fxr agonists and
antagonists will be used to determine whether competitive DNA binding between the two nuclear receptors
results in coagulopathy through transcriptional repression of Fxr-dependent coagulation factors; these studies
will employ ChIP-seq, RNA-seq, and plasma coagulation measurements. Our expected outcomes are
characterization of a novel molecular link, mediated by nuclear hormone receptors, between the regulation of
bile acid homeostasis and coagulation, both of which are pathologically altered in PEU. Thes...

## Key facts

- **NIH application ID:** 10007815
- **Project number:** 5K08DK113114-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Geoffrey A Preidis
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,615
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007815

## Citation

> US National Institutes of Health, RePORTER application 10007815, Nuclear receptor mediated bile acid alterations and coagulopathy in protein-energy undernutrition (5K08DK113114-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10007815. Licensed CC0.

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