# Elucidating the role of the FXR-PTEN-PI3K-AKT-mTOR axis in liver progenitor cell-driven liver regeneration

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $502,844

## Abstract

Chronic liver diseases are among the leading causes of mortality and morbidity in the U.S., with 5.5 million
people suffering from these diseases. Currently, liver transplantation is the only definitive treatment for end-stage
liver diseases; however, the shortage of donor livers makes this therapy extremely limited. Augmenting innate
liver regeneration in advanced liver diseases is an attractive therapeutic alternative. To develop such a therapy,
it is crucial to understand the molecular mechanisms of liver regeneration, particularly in the diseased liver. Upon
liver injury, hepatocytes proliferate to yield more hepatocytes to restore lost liver mass and maintain liver function.
However, when hepatocyte proliferation is compromised, a phenomenon observed in advanced liver diseases,
or when massive hepatocyte necrosis occurs, liver progenitor cells (LPCs) are activated and these LPCs expand
and are able to differentiate into hepatocytes. A correlation between disease severity and LPC numbers in
patients with chronic liver diseases suggests the occurrence of LPC activation in the diseased livers but its poor
differentiation into hepatocytes. In addition, LPCs secrete pro-inflammatory, pro-fibrogenic cytokines that can
perpetuate inflammation and contribute to subsequent fibrosis. Thus, augmenting innate LPC-driven liver
regeneration is expected to have beneficial effects in liver patients by generating more functional hepatocytes
and by concomitantly reducing inflammation and fibrosis. Despite this significance, the molecular basis of LPC-
driven liver regeneration remains poorly understood. Our long-term goal is to completely delineate the molecular
mechanisms underlying LPC-driven liver regeneration. In pursuit of this goal, during the previous grant cycle, we
elucidated the crucial role of bone morphogenetic protein (BMP) signaling in LPC-driven liver regeneration; in
this renewal grant application, we propose to determine how the nuclear receptor farnesoid X receptor (FXR)
regulates LPC-driven liver regeneration. We have established both zebrafish and mouse liver injury models for
LPC-driven liver regeneration. Using the zebrafish model, we performed chemical screening and discovered that
treatment with a synthetic FXR agonist, GW4064, impaired LPC-driven regeneration. Given the beneficial effects
of FXR agonists on hepatic steatosis, fibrosis, and hepatocyte-driven liver regeneration and the multiple clinical
trials of the agonists, their negative effect on LPC-driven liver regeneration is unexpected and surprising,
justifying an extensive mechanistic investigation. Based on our preliminary findings, we hypothesize that FXR
activation impairs LPC-driven liver regeneration by repressing the PI3K-AKT-mTOR pathway. We will test this
hypothesis by elucidating the effects of FXR activation and suppression on LPC-driven liver regeneration (Aim
1) and by determining the role of the PTEN-PI3K-AKT-mTOR axis in the regeneration process (Aim 2).
Success...

## Key facts

- **NIH application ID:** 10133629
- **Project number:** 5R01DK101426-07
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Donghun Shin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $502,844
- **Award type:** 5
- **Project period:** 2014-09-25 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133629

## Citation

> US National Institutes of Health, RePORTER application 10133629, Elucidating the role of the FXR-PTEN-PI3K-AKT-mTOR axis in liver progenitor cell-driven liver regeneration (5R01DK101426-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133629. Licensed CC0.

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