# Role of Intestinal Bile Acid Signaling in Liver Diseases

> **NIH VA I01** · VA NEW JERSEY HEALTH CARE SYSTEM · 2024 · —

## Abstract

PROJECT SUMMARY
 The prevalence of cirrhosis and decompensated liver disease has doubled, whereas the prevalence of
hepatocellular carcinoma (HCC) has increased 10-fold in the veteran population. Worldwide, HCC has
emerged as a major cause of cancer-related death. There is an urgent need to further understand HCC
pathogenesis and discover new biomarkers that could accurately predict HCC development in patients with
chronic liver diseases, so that we can provide better and more effective strategies for HCC prevention and/or
treatment in veteran population. Bile acids (BAs) are well known to be cytotoxic due to their detergent-like
properties and overt BAs promote HCC development. In humans, increased levels of secondary BAs,
especially deoxycholic acid, is associated with the development of HCC in veteran patients with cirrhosis. BA
homeostasis is tightly regulated by farnexoid X receptor (FXR). FXR expression and function are reduced in
patients with HCC, and FXR knockout (KO) mice develop spontaneous HCC. FXR suppresses BA levels
mainly by fibroblast growth factor 15 (FGF15; FGF19 in humans) mediated gut liver crosstalk and by promoting
BA enterohepatic circulation. FGF15/19 emerges to be critical endocrine hormones to suppress BA synthesis,
promote liver regeneration and regulate energy homeostasis. Long-term overexpression of FGF15 in vivo
(Fgf15 transgenic-Tg mice) results in reduced growth hormone (GH) signaling in the liver and GH signaling is
involved in cell proliferation and HCC formation. In this proposal, we will determine the mechanisms by which
long-term FGF15 overexpression protects the liver from HCC development in FXR KO mice. Using a novel
mouse model we generated, Fgf15 Tg mice, and the newly generated FXR KO/Fgf15 Tg mice, we provided
preliminary data showing that FGF15 overexpression completely protected FXR KO mice from developing
spontaneous HCC. In addition, overexpression of FGF15 led to a marked reduction in BA levels and GH
signaling. Based on these compelling preliminary data, we generate a novel hypothesis: overexpression of
FGF15 prevents HCC development through two interactive mechanisms: suppression of BA levels and
reduction of GH signaling to reduce cell injury and cell proliferation. This novel hypothesis will be tested in two
independent but related specific aims. Aim 1. Determine to what extent reduction of BAs is the mechanism for
suppressing HCC development in cholestasis mouse models. Aim 2. Determine the extent of GH signal
blockage, and to what extent the reduced GH signal in the Fgf15 Tg mice prevents HCC development. This
proposal is highly innovative because we will provide a profound understanding of the molecular mechanisms
by which endocrine FGF15 collectively suppresses BA levels and GH signaling, which can markedly prevent
HCC development during cholestasis. It is also very technically innovative due to the unique and novel animal
models we have generated for in vivo studies. Furthermore, we will p...

## Key facts

- **NIH application ID:** 10726620
- **Project number:** 5I01BX002741-06
- **Recipient organization:** VA NEW JERSEY HEALTH CARE SYSTEM
- **Principal Investigator:** GRACE L GUO
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10726620

## Citation

> US National Institutes of Health, RePORTER application 10726620, Role of Intestinal Bile Acid Signaling in Liver Diseases (5I01BX002741-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10726620. Licensed CC0.

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