Characterization of intestinal small heterodimer partner and farnesoid X receptor in bile acid and lipid metabolism
Nguyễn, James Thiêntoàn
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https://hdl.handle.net/2142/121315
Description
Title
Characterization of intestinal small heterodimer partner and farnesoid X receptor in bile acid and lipid metabolism
Author(s)
Nguyễn, James Thiêntoàn
Issue Date
2023-07-05
Director of Research (if dissertation) or Advisor (if thesis)
Anakk, Sayeepriyadarshini
Doctoral Committee Chair(s)
Anakk, Sayeepriyadarshini
Committee Member(s)
Gaskins, Rex
Nelson, Erik R
Wang, Bo
Department of Study
Molecular & Integrative Physl
Discipline
Molecular & Integrative Physi
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Small intestine, Nuclear receptors, Farnesoid X receptor, fxr, Nr1h4, Small heterodimer partner, Nr0b2, Shp, bile acid, lipid, metabolism, circadian
Abstract
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.
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