Date Available

10-21-2016

Year of Publication

2015

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Pharmacology and Nutritional Sciences

First Advisor

Dr. Gregory Graf

Second Advisor

Dr. Nancy Webb

Abstract

The small intestine is the main organ for food digestion and nutrient absorption. It is constantly exposed to antigen and immunomodulatory agents from diet and commensal microbiota. Thus, the intestine is the largest compartment of the immune system in the body. Peanuts and many other allergen resources contain triglycerides, which may affect the antigen absorption through the intestine, but their effects on sensitization and anaphylaxis are unknown. We found that medium chain triglycerides (MCT) promoted antigen absorption into Peyer’s Patches, rather than into the blood directly. Both gavage and feeding of MCT plus peanut protein induced spontaneous allergic sensitization. MCT-sensitized mice experienced the IgG-dependent anaphylaxis from systemic challenges and the IgE-dependent anaphylaxis from oral challenges. Furthermore, MCT alone had direct pharmaceutical effect on enterocytes, like stimulating Jejunal-epithelial Th2 cytokine responses compared with what was seen in the long chain triglycerides (LCT) treated group. Moreover, the oral challenges conducted with peanut protein in MCT significantly exacerbated anaphylaxis compared with the LCT challenges.

The intestine also plays an important role in whole body cholesterol homeostasis due to its exclusive function in cholesterol absorption. The researchers found that the intestine function in cholesterol secretion and elimination, but it has not been proven directly until recently. This pathway that facilitate the cholesterol secretions through intestine was named the Transintestinal Cholesterol Efflux (TICE) and has not been well studied yet.

To find the possible transporter candidates involved in TICE, we compared both biliary and intestinal cholesterol excretion rates in wild-type (WT) and G5G8 deficient (KO) mice of both sexes. All mice were maintained on a plant-sterol free diet beginning at weaning to prevent the development of secondary phenotypes associated with Sitosterolemia. We found that WT mice had higher biliary cholesterol excretion rates compared to their G5G8 KO littermates as previously reported. However, this difference is significantly greater in females compared to males. Interestingly, intestinal cholesterol excretions increased in female KO mice compared to their WT littermates, a difference not observed in males. This data suggests a sexually dimorphic adaptive mechanism to maintain cholesterol elimination in the absence of G5G8. Whereas male mice maintain a greater level of biliary output in the absence of G5G8, female mice upregulate an alternate intestinal elimination route.

To determine the origin of intestinally secreted cholesterol, we compared both hepatobiliary and intestinal cholesterol secretion rates in male wild-type (WT) and CETP transgenic (CETP TG) mice at the age of 12 weeks. Cholesteryl ester transfer protein (CETP) facilitates the transport of cholesteryl esters and triglycerides between lipoproteins in plasma and alters the lipoprotein distribution of plasma cholesterol. We found that WT and CETP TG mice did not differ in either biliary or intestinal cholesterol secretion rates when maintained on a standard chow diet. However, CETP TG mice showed increased biliary cholesterol secretion rates and decreased intestinal cholesterol secretion rates compared to the WT group in response to a Western diet. We next determined the effect of CETP on the delivery of radiolabeled HDL-cholesterol ester to bile and intestinal lumen. Unlike bulk cholesterol secretions, HDL-derived cholesterol esters were preferentially delivered to the intestine in CETP TG mice. This data suggests that CETP alter the routes of total and HDL cholesterol elimination from the body in mice.

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