# Molecular Biology of Bile Acid Synthesis

> **NIH NIH R01** · NORTHEAST OHIO MEDICAL UNIVERSITY · 2022 · $351,000

## Abstract

Project Summary
Bile acid signaling through FXR and TGR5 plays a critical role in the control of metabolism and inflammation in
the liver. Accumulation of high levels of toxic bile acids causes liver inflammation and injury, contributing to the
pathogenesis of chronic non-alcoholic fatty liver disease (NAFLD), diabetes and obesity. These inflammatory
liver metabolic diseases have reached epidemic status in the U.S. population, and NAFLD occurs with a higher
prevalence in males than females. A plethora of bile acid research in the last two decades has unveiled a
complex network of pathways that integrate bile acid-activated farnesoid X receptor (FXR) and the bile acid-
activated G protein-coupled receptor TGR5 signaling to regulate lipid, glucose, and energy metabolism and
homeostasis. Bile acid synthesis is tightly regulated by a negative feedback mechanism to inhibit transcription
of the gene encoding cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting synthesis enzyme, and sterol
12α-hydroxylase (CYP8B1), required for cholic acid synthesis, in the classic bile acid synthesis pathway. The
alternative pathway is regulated by oxysterol 7α-hydroxylase (CYP7B1). The gut microbiota regulates bile acid
pool size, bile acid composition and enterohepatic circulation of bile acids. The anti-inflammatory action of bile
acid-activated receptors has been recognized recently. However, the underlying molecular mechanisms of bile
acid signaling in the regulation of hepatic metabolic homeostasis and inflammation are not fully understood.
During the current funding period, we have used Cyp7a1-/-, Fxr-/- and Tgr5-/- mice to study the role of bile acid
signaling in metabolic regulation. Activation of intestinal FXR reshaped the gut microbiota to activate TGR5,
stimulating glucagon-like-peptide 1 (GLP-1) secretion, promoting white adipose tissue browning, and improving
insulin sensitivity and glucose tolerance in obese and diabetic mice. We have successfully bred Fxr and Tgr5
double knockout (DKO) mice. DKO mice have increased bile acid synthesis and pool size and induction of the
taurocholic acid-activated sphingosine-1-phosphate receptor 2 (S1PR2), the role of which in hepatic
metabolism is not understood. Two specific aims are designed to 1) study the mechanisms of bile acid
signaling in the regulation of hepatic bile acid synthesis and metabolic homeostasis, and 2) to study the role
and mechanism of bile acid signaling in the pathogenesis of NAFLD. Metabolomics, 16S RNA-sequencing of
the gut microbiome, and RNA-sequencing of the transcriptome will be used to study bile acid synthesis and
hepatic metabolism in both male and female Fxr-/-, Tgr5-/- and DKO mice. This study is highly significant in
elucidating the molecular mechanism of the regulation of bile acid synthesis and lipid homeostasis, and the
mechanistic pathogenesis of liver-related metabolic diseases affecting a large population in the United States
and worldwide.

## Key facts

- **NIH application ID:** 10456309
- **Project number:** 5R01DK044442-26
- **Recipient organization:** NORTHEAST OHIO MEDICAL UNIVERSITY
- **Principal Investigator:** Jessica Marie Ferrell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $351,000
- **Award type:** 5
- **Project period:** 1997-09-30 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456309

## Citation

> US National Institutes of Health, RePORTER application 10456309, Molecular Biology of Bile Acid Synthesis (5R01DK044442-26). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10456309. Licensed CC0.

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