# Regulation of Bile Acid Metabolism and Signaling in Metabolic Diseases

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $316,723

## Abstract

Project Summary
Diabetes and non-alcoholic fatty liver disease (NAFLD) are closely associated with hepatic fat and cholesterol
accumulation, hepatocyte organelle dysfunction, low grade inflammation, and dyslipidemia. Patients with
diabetes and NAFLD have significantly higher risk of cardiovascular disease, which remains the leading cause
of death worldwide. Hepatic bile acid synthesis is the only major cholesterol catabolism mechanism in the
body. Furthermore, bile acids act as signaling molecules to critically control metabolic homeostasis and
inflammatory response. Different therapeutic approaches targeting the bile acid dynamics and signaling
pathways have shown great promise for treating metabolic and chronic liver diseases. However, how
modulating the enterohepatic bile acid signaling impacts the complex metabolic network via distinct
mechanism of actions is still incompletely understood. New mechanistic insights are clearly needed to
establish the molecular basis for developing effective bile acid-based therapies. The goal of this study is to
define a new role of Transcriptional Factor EB (TFEB) in the regulation of hepatic bile acid metabolism. TFEB
belongs to the basic helix-loop-helix leucine zipper family of transcriptional factors and was recently identified
as a nutrient and stress-sensing master regulator of lysosomal biogenesis in various cell types, which has led
to a paradigm shift in our understanding of how lysosomal pathways can be dynamically regulated in response
to various nutrient and stress signals to maintain cellular homeostasis. Current studies suggest that TFEB may
be an attractive target for treating neurodegenerative diseases, lysosomal storage disease, and metabolic
diseases. However, the role of TFEB in regulating the complex hepatic metabolism is incompletely understood,
and the TFEB regulation of hepatic bile acid metabolism has not been explored. Here we found that TFEB is a
strong inducer of bile acid synthesis, and hepatic TFEB itself is inhibited by the intestine bile acid sensing
hormone FGF15/19. Identification of this gut-liver signaling crosstalk has led to an interesting new concept of
pharmacologically targeting this regulatory loop to enhance hepatic TFEB function and improve metabolic
homeostasis. Three specific aims are designed to first establish that liver TFEB is a novel bile acid sensing
transcriptional factor and a key effector in the gut-liver bile acid signaling crosstalk regulation of liver
metabolism, and further determine the pathophysiological significance and therapeutic implications of this
signaling regulatory loop. This study will employ several experimental mouse models through AAV8-mediated
hepatocyte-specific gene delivery, tissue-specific genetic knockout, and pharmacological treatment
approaches. These models will be investigated with a combination of physiological, molecular biology, and cell
biology techniques and unbiased proteomics approaches. By employing these state-of-the-a...

## Key facts

- **NIH application ID:** 10065771
- **Project number:** 7R01DK117965-02
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Tiangang Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $316,723
- **Award type:** 7
- **Project period:** 2019-02-05 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065771

## Citation

> US National Institutes of Health, RePORTER application 10065771, Regulation of Bile Acid Metabolism and Signaling in Metabolic Diseases (7R01DK117965-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065771. Licensed CC0.

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