Characterization of intestinal small heterodimer partner and farnesoid X receptor in bile acid and lipid metabolism

Bile acids (BAs) facilitate the digestion and absorption of dietary fats and fat-soluble vitamins through emulsification. This process helps break down fats into fatty acids for easier absorption. In addition, BAs can act as ligands for receptors that can coordinate a wide range of biological processes, such as cell proliferation and differentiation, immune response, and lipid metabolism. Farnesoid X receptor (FXR) and small heterodimer partner (SHP) are nuclear receptors, a superfamily of transcription factors important for maintaining BA homeostasis. Although there have been decades of extensive research on the regulation of bile acids through the FXR-SHP axis, intestine-specific studies are still lacking. Therefore, this dissertation is focused on (i) understanding the intestine-specific role of FXR and SHP in bile acid and lipid metabolism and (ii) how nutritional excess or stress may influence the crosstalk between the intestine and liver. Intestine-specific Shp knockout (IShpKO) mice were newly generated to study bile acid metabolism, therefore in Chapter 2, I found how short-term high cholic acid diet can lead to acute changes in the IShpKO mice before the onset of adaptation. In Chapter 3, I investigated the BA and lipid metabolic response after 4-weeks of high-fat diet in mice lacking intestinal FXR and/or SHP. I showed that the liver and small intestine gene expression relating to BA, lipid, inflammation, and barrier function were altered and, moreover, the changes within the small intestine occurred in a region-specific manner. Also, the diet and genotype affected the serum and liver bile acid composition. Lastly, in Chapter 4, my preliminary data showed circadian changes in the Shp gene expression throughout the small intestine. We hope to assess if the absence of intestinal SHP can affect other rhythmic and metabolic genes throughout the day and night. Together, these results show that intestinal FXR and SHP can potentially coordinate or individually regulate different aspects of BA and lipid metabolism and, in turn, can also affect overall health.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Molecular & Integrative Physi

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2023

Author dc:creator

• Nguyễn, James Thiêntoàn

Contributors dc:contributor

• Anakk, Sayeepriyadarshini
• Gaskins, Rex
• Nelson, Erik R
• Wang, Bo

• Small Intestine
• Nuclear Receptors
• Farnesoid X Receptor
• Fxr
• Nr1h4
• Small Heterodimer Partner
• Nr0b2
• Shp
• Bile Acid
• Lipid
• Metabolism
• Circadian

Statement dc:rights

• Copyright 2023 James Nguyễn

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/121315

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F121315