# Intestinally restricted LXR agonism in ameliorating liver failure in short gut syndrome

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $604,462

## Abstract

ABSTRACT
Short gut syndrome (SGS) results from surgery that removes a significant length of small intestine in response
to different conditions, like necrotizing enterocolitis. In children, the mortality associated with SGS is ~25%,
making it one of the most lethal conditions in infancy and childhood. After surgery, remodeling of the remaining
bowel segment can facilitate absorptive function and survival. Nonetheless, some patients require long-term
parenteral nutrition. Beyond loss of absorptive capacity, a significant complication in SGS patients that survive
bowel resection is intestinal failure-associated liver disease (IFALD), regardless of whether patients receive
nutrition enterally or parenterally. Clinically, therapies designed to target IFALD after SGS remain elusive. In
the first round of funding of this continuation application, The Warner and Randolph lab have shown in mouse
models of small bowel resection that gut-derived LPS transiting to the liver from the portal vein initiatesTLR4
signaling in liver macrophages that ultimately drives onset of fibrosis. A significant break on LPS-TLR4
interaction occurred by the binding and neutralization of gut-derived LPS to portal vein high density lipoprotein
(HDL). HDL is synthesized in the liver and is also generated by enterocytes in the mice or human ileum, where
it depends on expression of the polypeptide apoA1 and the lipid transporter ABCA1 that donates the first lipids
to the nascent HDL particle. Loss of enterocyte ABCA1 greatly reduced portal vein HDL, allowing for enhanced
LPS activity to reach the liver and exacerbate liver injury after small bowel resection. Conversely, when we
increased intestinal HDL by giving the liver X receptor (LXR) agonist GW9365 orally at a low dose to trigger
HDL production in the intestine but avoid direct LXR agonism of the liver, the drug was effective in reducing the
onset of liver fibrosis in a manner that was dependent upon enterocyte-derived ABCA1. These findings raise
the concept that intestinal epithelial activation of the transcription factor LXR may provide therapeutic benefit
toward treating IFALD. This grant is designed to consider this concept with the intent to further define the role
of LXR and HDL in protecting the liver in SGS models and to move in a translational direction that may support
later clinical development of a therapeutic to treat IFALD. We will study how LXR agonism protects the liver in
a mouse model of SGS using a novel orally restricted LXR agonist compound WUSTL0717 synthesized by
Principal Investigator Elgendy. Pharmacokinetic analysis in mice reveals that WUSTL0717 is indeed restricted
to the intestine. To further consider the translational potential of WUSTL0717, Principal Investigator Ajay Jain
will provide expertise in SGS studied in piglets. One major advantage of incorporating a piglet model into
studies of SGS is that piglets can be provided parenteral nutrition like humans and thus model aspects of the
disease n...

## Key facts

- **NIH application ID:** 10880154
- **Project number:** 2R01DK119147-06
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Bahaa Elgendy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $604,462
- **Award type:** 2
- **Project period:** 2019-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880154

## Citation

> US National Institutes of Health, RePORTER application 10880154, Intestinally restricted LXR agonism in ameliorating liver failure in short gut syndrome (2R01DK119147-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10880154. Licensed CC0.

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