# Regulation of Bile Acid Synthesis by Nuclear Receptors

> **NIH NIH R37** · NORTHEAST OHIO MEDICAL UNIVERSITY · 2020 · $362,703

## Abstract

Type 2 diabetes and obesity is associated with dyslipidemia, hyperglycemia and insulin resistance. Hepatic
steatosis contributes to insulin resistance and non-alcoholic fatty liver disease. Bile acids play a key role in
regulation of lipid, glucose and energy metabolism by activating a nuclear hormone receptor FXR, and G
protein-coupled receptor TGR5. Our central hypothesis is that nutrients, growth hormone, circadian rhythm
and gut microbiota regulate bile acid synthesis to maintain metabolic homeostasis, and impairment of this
regulatory response contributes to dyslipidemia, glucose intolerance, insulin resistance, fatty liver disease
and obesity. Specific aim 1 will study the role of bile acid receptor signaling in regulation of hepatic
metabolism. The mechanism of growth hormone-STAT5 regulation of bile acid synthesis and a male
predominant Cyp7b1 will be studied using reporter assay and chromatin immuno- precipitation assay to
identify STAT5 binding sites and epigenetic regulation of Cyp7b1 promoter by STAT5. Tgr5-/-, Cyp7a1-/-
and adenovirus-Cyp8b1 over-expressed mice with different bile acid composition and Cyp7a1, Cyp8b1 and
cyp7b1 expression will be used to study growth hormone regulation. Specific aim 2 will study the role of bile
acid receptor signaling in fatty liver, insulin resistance and diabetes. The mechanism of FXR and TGR5 in
GLP-1 secretion and glucose metabolism will be studied. Tgr5-/- mice will be used to study effect of vertical
sleeve gastrectomy on improving insulin resistance, dyslipidemia and microbiome before and after surgery.
Specific aim 3 will study circadian rhythm of bile acid synthesis in metabolic homeostasis. The liver-gut
microbiota axis plays a critical role in bile acid metabolism and disturbance of circadian rhythm is linked to
metabolic diseases. Dysbiosis is associated with obesity, and inflammatory bowel diseases. Tgr5-/-, FXR-/-
and Cyp7a1-/- with different bile acid pool size and/or composition will be used for time-restricted feeding of
Western high fat/high cholesterol diet to study bile acid metabolism and gut microbiome by RNA
sequencing. Cyp7a1-/-, Fxr-/-, and Tgr5-/- will be used to determine how time-restricted feeding in day time
or night time affect affect hepatic gene rhythms and overall bile acid homeostasis.

## Key facts

- **NIH application ID:** 9923618
- **Project number:** 5R37DK058379-33
- **Recipient organization:** NORTHEAST OHIO MEDICAL UNIVERSITY
- **Principal Investigator:** JOHN Y. L. CHIANG
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,703
- **Award type:** 5
- **Project period:** 2016-05-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923618

## Citation

> US National Institutes of Health, RePORTER application 9923618, Regulation of Bile Acid Synthesis by Nuclear Receptors (5R37DK058379-33). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9923618. Licensed CC0.

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