# Tissue-specific roles of FXR in CVD and NASH

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $433,973

## Abstract

PROJECT SUMMARY
Project 2. Tissue-specific roles of FXR in CVD and NASH
Hyperlipidemia and insulin resistance are commonly associated with both cardiovascular and liver diseases,
however causal relationships between atherosclerosis and NASH are not well established. The farnesoid X
receptor (FXR) is a regulator of systemic sterol and glucose homeostasis, and is known to contribute to the
initiation and progression of both cardiovascular and liver diseases. Loss of hepatic FXR, but not intestinal
FXR, results in elevated circulating and hepatic cholesterol and triglyceride levels. In contrast, both hepatic and
intestinal FXR enhance hepatic repair and cholesterol excretory activities. Consistent with this, FXR agonists
reliably reduce atherosclerosis and have been reported to show promising effects in liver disease models.
Thus, the goal of Project 2 is to dissect the tissue-specific activities of FXR in the context of integrative
hepatovascular pathophysiology. Specifically, we will explore the notion that FXR drives distinct protective
programs in cardiovascular and liver diseases.
The macrophage is central in the development of atherosclerosis and steatotic hepatitis through the deposition
of vascular fatty lesions, as well as driving or resolving liver damage. As a key regulator of inflammation and
multiple steps in the reverse cholesterol transport and excretion pathways, FXR is an established target for
mitigating the development of foam cells that underlie vascular plaque deposition. Our preliminary findings
indicate that plaque deposition and facets of liver disease are divisible with tissue-specific modulation of FXR
activities.
This project will explore the hypothesis that tissue-specific modulation of FXR will affect the progression of
CVD and NASH. To achieve this goal, proprietary FXR agonists that target either the liver (hepFexD) or gut
(intFexD) will be used in combination with ldlr-/- mice lacking FXR expression in either the liver (hepFXRko) or
the intestine (intFXRko) to dissect the association of fatty liver disease and CVD risk. In Aim 1, the impact of
hepatic FXR on atherosclerosis and liver disease will be explored, including the contribution from FXR-
regulated crosstalk between parenchymal and non-parenchymal cells in collaboration with Project 1, and the
role for hepatic FXR in OSE levels or clearance in collaboration with Project 3. In Aim 2, the ability of systemic
signaling from intestinal FXR to affect macrophage cholesterol homeostasis will be determined in collaboration
with Project 1. Finally, the relevance of our pre-clinical findings studies to human disease will be determine by
interrogating curated clinical samples for biomarkers of FXR activity in collaboration with Project 4. The
proposed comprehensive genetic, pharmacologic and comparative biological approach will provide a better
understanding of the physiology and mechanisms by which tissue-specific FXR crosstalk impacts
atherosclerosis and steatohepatitis...

## Key facts

- **NIH application ID:** 9936775
- **Project number:** 1P01HL147835-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** RONALD M EVANS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $433,973
- **Award type:** 1
- **Project period:** 2020-09-21 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936775

## Citation

> US National Institutes of Health, RePORTER application 9936775, Tissue-specific roles of FXR in CVD and NASH (1P01HL147835-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9936775. Licensed CC0.

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