Lipid metabolism and small intestine homeostasis

Enterocytes play a major role in lipid absorption. In the enterocytes, dietary lipids are packed into chylomicrons and ultimately secreted into the circulation. The dysregulation of chylomicron biogenesis has been linked to various metabolic disorders including obesity. However, the regulation and production of chylomicron is not yet fully understood. Our first study demonstrated that SEC16B, an endoplasmic reticulum (ER) scaffold protein, regulates chylomicron and obesity in vivo. The single-nucleotide polymorphisms (SNPs) in the SEC16B gene have been identified by numerous genome-wide association studies (GWAS) to be associated with obesity and higher body mass index (BMI). Our study showed that Sec16b deletion in mouse intestines, especially in females, alleviates high-fat diet-induced obesity and improves glucose metabolism. We also demonstrated that mice with dysfunctional Sec16b have significantly reduced post-prandial serum triglyceride (TG) contents when orally administered with lipid bolus. Mechanistically, loss of Sec16b impairs apoB-48 lipidation and hinders pre-chylomicron export from the ER. In summary, our first study identified Sec16b as an essential regulator for chylomicron biogenesis and obesity. Enterocytes work in hazardous environments and need constant replenishment. Our second study focuses on the regulation of intestinal epithelium renewal. Intestinal stem cells (ISCs) in crypts drive enterocyte renewal and are regulated by several factors including lipids. A previous study showed increased cholesterol biosynthesis and cellular cholesterol levels stimulate crypt proliferation. However, whether circulating cholesterol will affect ISC proliferation is still unknown. Our results showed that deletion of low-density lipoprotein receptor (LDLR) moderately enhances ISC proliferation. Treating crypts with LDL ex vivo impairs initial organoid formation but enhances the stemness of the surviving organoids. Unexpectedly, Ldlr-/- and wild-type (WT) organoids reacted similarly to LDL treatment, suggesting that the effect of LDL is not dependent on LDLR. Moreover, loss of Ldlr-/- hinders small intestine regeneration. Taken together, these findings underline the complex role of circulating LDL-cholesterol in ISC homeostasis and self-renewal.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

VMS - Comparative Biosciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Shi, Ruicheng

Contributors dc:contributor

• Wang, Bo
• Nelson, Erik R
• Spinella, Michael J
• Mei, Wenyan

• Small Intestine
• Lipid Metabolism
• Obesity
• Sec16b
• Chylomicron
• Stem Cell
• Regeneration

Statement dc:rights

• Copyright 2024 Ruicheng Shi

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/124651

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F124651