# Vitamin D Receptor Regulation of Liver Organogenesis and Disease

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2021 · $33,743

## Abstract

PROJECT SUMMARY/ABSTRACT
Chronic liver disease and liver cancer are significant sources of morbidity and mortality, accounting for an
estimated 2 million deaths annually. Non-alcoholic fatty liver disease (NAFLD) is a pertinent public health
threat because it can lead to impaired metabolic function, cirrhosis, and primary liver cancer, and it affects up
to 25% of U.S. adults. Our laboratory utilizes chemical and genetic modulation of liver development and adult
liver function in zebrafish to identify signaling pathways that regulate liver growth, homeostasis, and disease.
We have found that Vitamin D Receptor (Vdr) activity during embryonic liver development is essential for
normal liver growth, and that Vdr stimulation modulates transcription of lipid metabolic effectors during early
liver formation. Impaired VDR function is associated with a NAFLD, liver fibrosis, cirrhosis, and liver cancer in
humans and animal models, but the functions of VDR signaling in liver development and disease are unknown.
Our objective is to characterize the cellular and molecular functions of Vdr activity in zebrafish liver
development and to evaluate the functions of Vdr in adult liver homeostasis and metabolic stress. In Aim 1, we
will utilize chemical and genetic modulation of Vdr activity to define the impact of Vdr signaling on liver
progenitor expansion and liver outgrowth. We will investigate mutant lines to characterize the consequence of
vdr deficiency and impaired vitamin D metabolism on liver growth. Based on preliminary RNA-seq data, we will
investigate the functions of PI3K/mTOR signaling and other candidate signaling pathways in vitamin D
induction of liver growth. These experiments will uncover the impacts of Vdr signaling during liver formation. In
Aim 2, we will characterize the functions of Vdr activity during adult liver homeostasis using histological and
transcriptomic analysis, with a focus on hepatic fat accumulation and lipid metabolism. In addition, we will
determine the impact of hepatocyte-specific Vdr impairment in zebrafish subjected to a high-fat high-
cholesterol diet challenge. Since Vdr impairment is associated with NAFLD, we anticipate that Vdr impairment
will sensitize adult fish to NAFLD pathogenesis following a high-fat high-cholesterol diet challenge. This work
will provide detailed mechanistic insight into the functions of VDR signaling in liver development and disease
and will illuminate the potential of vitamin D/VDR modulation as a strategy to prevent and/or treat chronic liver
disease.

## Key facts

- **NIH application ID:** 10165459
- **Project number:** 5F31DK122619-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Scott Hull Freeburg
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,743
- **Award type:** 5
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165459

## Citation

> US National Institutes of Health, RePORTER application 10165459, Vitamin D Receptor Regulation of Liver Organogenesis and Disease (5F31DK122619-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10165459. Licensed CC0.

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