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University of Cincinnati UNIVERSITY OF CINCINNATI Date:___________________ I, _________________________________________________________, hereby submit this work as part of the requirements for the degree of: in: It is entitled: This work and its defense approved by: Chair: _______________________________ _______________________________ _______________________________ _______________________________ _______________________________ ii Intestinal lipid uptake and secretion of VLDL and chylomicron By: Andromeda Nauli August 2005 Previous degree: Bachelor of Science in Biomedical Sciences Degree to be conferred: Ph.D. Department of Pathology and Laboratory Medicine College of Medicine University of Cincinnati Committee chair: Patrick Tso, Ph.D. iii ABSTRACT Despite decades of research, our understanding of intestinal lipid absorption is limited. In this Ph.D. thesis, I have dealt with two main aspects of intestinal lipid absorption, namely the uptake of lipids and the formation and secretion of triacylglycerol-rich lipoproteins (very low density lipoproteins [VLDL] and chylomicrons). In terms of uptake, CD36 is one of the plasma membrane proteins implicated in mediating lipid uptake by the intestine. In order to test this hypothesis, we utilized the CD36 knockout mouse model equipped with intraduodenal and lymph cannulas. Our studies showed that the disruption of the CD36 gene led to a significant decrease in the uptake of cholesterol but not of fatty acids. Interestingly, the role of CD36 was not limited to uptake but also appeared to affect the formation and secretion of chylomicrons, the major lipoproteins carrying the absorbed dietary fat from the gut (Chapter 2). It was first proposed by Tso et al. (202) that the small intestine secretes both VLDL and chylomicrons. Previous work by Vahouny et al. (212) suggested that female rats produced more VLDL than male rats. In addition, personal communication with Dr. Renee LeBoeuf leads us to believe that the female C57BL/6 mice may absorb lipids less efficiently than the male mice. We therefore studied the formation and secretion of lipoproteins in male and female C57BL/6 mice. Our data agree with those of Vahouny in that the female mice had a slightly higher ratio of VLDL to chylomicron secretion relative to that of the male mice. In addition, we also found that the intestinal lymphatic lipid transport of the C57BL/6 iv female mice segregated into two groups, a phenomenon that was absent in the male mice. In summary, our work suggests that CD36 is involved not only in intestinal cholesterol uptake, but also in regulating the formation and secretion of chylomicrons. In addition to the regulation by CD36, our studies also show that the regulation of the formation and secretion of chylomicrons are potentially different between male and female animals. v vi Acknowledgements I would like to express my gratitude to all of the individuals who helped me throughout this study. I am particularly thankful to Dr. Patrick Tso for all of his guidance as my mentor. I also wish to thank my committee members, Drs. Stephen Woods, Simon Newman, Ronald Jandacek, and Sean Davidson for their continuous support. I would also like to express my appreciation to University of Cincinnati Department of Pathology and Laboratory Medicine. Finally, I would like to thank my family, Susan, Surya, and mom. 1 Table of Contents Committee Approval Form……………………………………………………… i Title page………………………………………………………………………… ii Abstract…………………………………………………………………………... iii Acknowledgements……………………………………………………………... vi Table of Contents………………………………………………………………... 1 List of Tables and Figures………………………………………………………. 4 List of Abbreviations…………………………………………………………….. 6 Chapter 1: Review of the Literature and Study Rationale………………….. 8 1.1. Introduction…………………………………………………………. 9 1.1.1. Defining intestinal lipid absorption……………………………... 9 1.1.2. The importance of intestinal lipid absorption…………………. 10 1.1.3. Limitation of the in vitro models……………………………….. 12 1.2. Anatomy of the small intestine…………………………………… 14 1.2.1. Structure supports function…………………………………….. 14 1.2.2. Understanding the histological layers…………………………. 15 1.3. Dietary lipids………………………………………………………... 17 1.3.1. The detrimental effect of saturated fat………………………… 17 1.3.2. The significance of non-dietary cholesterol…………………... 18 1.4. Digestion of dietary lipids…………………………………………. 21 1.4.1. The early digestion processes…………………………………. 21 1.4.2. The significance of pancreatic lipase…………………………. 22 2 1.4.3 .Hydrolysis of cholesteryl esters……………………………….. 23 1.5. Uptake of lipid digestion products by enterocytes……………... 23 1.5.1. The significance of micelles……………………………………. 23 1.5.2. The significance of bile acids…………………………………… 24 1.5.3. Fatty acid uptake……………………………………………….... 25 1.5.3.1. Fatty acid transporters…………………………………………. 25 1.5.3.2. Mode of transport across plasma membrane……………….. 27 1.5.4. Cholesterol uptake……………………………………………….. 28 1.5.4.1. The significance of bile-acid micelles………………………… 28 1.5.4.2. Cholesterol transporters………………………………………… 29 1.6. Re-esterification of lipid digestion products inside enterocytes.... 30 1.6.1. Lipid transport to the ER………………………………………….. 31 1.6.2. TG re-synthesis……………………………………………………. 32 1.6.3. Cholesterol esterification…………………………………………. 34 1.7. Formation and secretion of lipoproteins…………………………… 35 1.7.1. Intestinal lipoproteins………………………………………………. 35 1.7.2. Assembly of lipoproteins…………………………………………… 36 1.7.3. Separate pathway for VLDL and chylomicron assembly………. 37 1.7.4. ER to Golgi transport………………………………………………. 37 1.8. Regulation of lymphatic vs. portal transport………………………. 38 1.9. Study Rationale………………………………………………………. 39 Chapter 2: CD36 is important for intestinal cholesterol uptake and for the formation and secretion of chylomicrons………..……………………….. .. …... 41 3 Abstract……………………………………………………………………... 42 Introduction…………………………………………………………………. 43 Materials and methods…………………………………………………… 45 Results……………………………………………………………………… 50 Discussion………………………………………………………………..... 55 Chapter 3: Sex differences in intestinal lipid absorption in mice…………..... 76 Abstract…………………………………………………………………….. 77 Introduction………………………………………………………………… 78 Materials and methods…………………………………………………… 81 Results………………………………………………………………………. 85 Discussion…………………………………………………………………. 92 Chapter 4: General Conclusions and Future Directions…………………….. 115 1. Insights gained on the lipid uptake…………………………………... 116 2. Insights gained on the lipoprotein secretion………………………… 119 Literature Cited………………………………………………………………….... 124 Appendix 1………………………………………………………………………… 169 CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood Appendix 2………………………………………………………………………… 170 Enterocyte fatty acid uptake and intestinal fatty acid- binding protein 4 List of Tables and Figures Table 1.1. The amount of biliary components secreted into the intestinal lumen… 20 Figures 1.1. Diagram of the small intestine……………………………………………. 16 2.1. Analysis of fatty acid uptake by the small intestines of CD36 null and wild type mice…………………………………………. 64 2.2. Lymph [ 3H]-TG transport (A), TG mass (B), and [ 14 C]-cholesterol transport (C) during continuous intraduodenal lipid infusion………….. 65 2.3. Total recovery of the infused TG (A) and cholesterol (B) in the stomach, colon, intestinal lumen, intestinal mucosa, and lymph at the end of the 6-h infusion period……………………………………… 67 2.4. Distribution of the infused TG (A) and cholesterol (B) along 4 equal-length segments of the small intestine…………………………. 68 2.5. Mucosal distribution of [ 3H]-fatty acids from infused triolein into the major lipid classes………………………………………………… 69 2.6. Mucosal distribution of [ 14 C]-cholesterol from infusate into the major lipid classes………………………………………………… 70 2.7. Lipoprotein particle size in the lymph of fasted mice…………………… 71 2.8. Lipoprotein particle size of lymph from lipid infused mice……………... 72 2.9. Lipid composition of chylomicrons from lipid infused mice…………….. 73 5 2.10. Apolipoprotein secretion into the lymph by fasted or lipid infused mice.. 74 3.1. The histograms of the total lymphatic triacylglycerol recovery in the male (A) and the female mice (B)……………………………………101 3.2. The lymph flow rate during the continuous intraduodenal lipid infusion.. 104 3.3. The hourly lymphatic triacylglycerol output during continuous intraduodenal lipid infusion…………………………………………………..105 3.4. The hourly lymphatic cholesterol output during the continuous intraduodenal lipid infusion…………………………………………………..106 3.5. The total radioactive triacylglycerol recovery in the lymph and the segments of gastrointestinal tract………………………………. 107 3.6. The total radioactive cholesterol recovery in the lymph and the segments of gastrointestinal tract………………………………… 108 3.7. Distribution of different classes of [ 3H]-labeled lipids in intestinal mucosa………………………………………………………….. 109 3.8. Distribution of different classes of [ 14 C]-labeled lipids in intestinal mucosa………………………………………………………….. 110 3.9. Lipoprotein particle size of fasting lymph………………………………….. 111 3.10. Lipoprotein particle size of lipid-infused lymph…………………………... 113 6 List of Abbreviations ACAT = acyl coenzyme A:cholesterol acyltransferase Apo = apolipoprotein ASBT = apical sodium-dependent bile acid transporter CE = cholesterol ester CMC = critical micellar concentration COP = coat protein DG = diacylglycerol DGAT = diacylglycerol acyltransferase FA = fatty acid FATP = fatty acid transport protein G-3-P = glycerol-3-phosphate HDL = high density lipoprotein IBAT = ileal bile acid transporter I-FABP = intestinal fatty
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