University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 12-2014 Role of vitamin A status and its catabolism in the regulation of glucose and lipid homeostasis in rats under physiological and disease conditions Yang Li University of Tennessee - Knoxville, [email protected] Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Molecular, Genetic, and Biochemical Nutrition Commons Recommended Citation Li, Yang, "Role of vitamin A status and its catabolism in the regulation of glucose and lipid homeostasis in rats under physiological and disease conditions. " PhD diss., University of Tennessee, 2014. https://trace.tennessee.edu/utk_graddiss/3150 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Yang Li entitled "Role of vitamin A status and its catabolism in the regulation of glucose and lipid homeostasis in rats under physiological and disease conditions." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Nutritional Sciences. Guoxun Chen, Major Professor We have read this dissertation and recommend its acceptance: Jay Whelan, Ling Zhao, Michael Karlstad Accepted for the Council: Carolyn R. Hodges Vice Provost and Dean of the Graduate School (Original signatures are on file with official studentecor r ds.) Role of vitamin A status and its catabolism in the regulation of glucose and lipid homeostasis in rats under physiological and disease conditions A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Yang Li December 2014 ii Copyright © 2014 by Yang Li All rights reserved. iii Dedication I dedicate this dissertation work to my mother Aidong Lu. Without her emphasis of my education as an important thing in my life and her endless support through these years, it will not be possible for me to complete this work. I also want to dedicate this work to my fiancé Ming Qi who supports me during the past four and half years. iv Acknowledgements I would like to use this opportunity to thank my mentor Dr. Guoxun Chen. His guidance and mentorship have been essential for the accomplishment of this dissertation. His passion and dedication to scientific research will influence me for years to come. I would like to thank my committee members, Drs. Michael Karlstad, Jay Whelan and Ling Zhao, for their guidance and help during the course of this dissertation. I also would like to thank my past lab members, Drs. Rui Li, Yan Zhang, and Yuebin Ge, and Ms. Meredith Howell; and current lab members, Wei Chen, Matt Goff and Jennifer Eastep for any help that they have provided. v Abstract The increased number of individuals with metabolic diseases has become a public health concern. Vitamin A (VA, retinol) is required to maintain the general health of an individual. How VA contributes to the regulation of glucose and lipid homeostasis in normal and metabolic disease states is unclear. VA’s physiological activities are mainly mediated by its metabolite, retinoic acid (RA), which activates several transcriptional factors in the nuclear receptor super family and in turn, regulates the expression of numerous genes for macronutrient metabolism. For the RA production, retinol is first oxidized into retinal and then from retinal to RA. We hypothesize that VA status and dynamic production of RA play a role in the control of glucose and fatty acid metabolism. This dissertation summarized my investigation of VA’s role in metabolism: (1) We compared the expression levels of RA-producing enzymes in the liver of Zucker lean (ZL) and fatty (ZF) rats. We found that the hepatic expression levels of retinaldehyde dehydrogenase family 1 gene ( Raldh1 ) mRNA and RALDH1 protein were higher in ZF rats than that in ZL rats. This elevated RALDH1 expression may cause the excessive RA production, which may enhance the hepatic lipogenesis and lead to the hepatic insulin resistance; (2) We compared the expression levels of insulin-regulated genes in the liver of VA deficient (VAD) and VA sufficient (VAS) ZL rats in response to the cycle of fasting and refeeding, a normal physiological condition. We observed that VA status and its dietary availability play a role in the expression levels of insulin- regulated gene in the rat liver; (3) We further used streptozotocin (STZ) to induce insulin- dependent diabetes mellitus in both VAD and VAS rats, a disease condition. The hepatic vi expression levels of insulin-regulated genes in these animals treated with control, RA, insulin and insulin + RA were investigated. The effects of VA status and RA production on the regulation of the hepatic gene expression were also observed. We conclude that VA status and dynamic RA production contribute to the expression of hepatic genes, which in turn regulate glucose and fatty acid homeostasis. vii Table of Contents Chapter One Introduction ................................................................................................... 1 1. Vitamin A................................................................................................................. 1 1.1. The Discovery of vitamin A ............................................................................. 1 1.2. Sources, Digestion, and Absorption of VA ...................................................... 2 1.2.1. Sources of VA................................................................................................... 2 1.2.2. Recommended dietary allowance of VA .......................................................... 4 1.2.3. Digestion and Absorption of VA ...................................................................... 4 1.3. Storage of VA ................................................................................................... 6 1.4. Cellular Metabolism of Retinol ........................................................................ 6 1.4.1. Cellular Retinol Binding Proteins..................................................................... 6 1.4.2. The conversion of retinol to retinal................................................................... 7 1.4.3. The conversion of retinal to retinoic acids........................................................ 9 1.4.4. The further catabolism of RA, studies of CYP26A1 ...................................... 14 1.5. Isomers of retinoic acids ................................................................................. 15 1.6. Retinol transport and distribution ................................................................... 16 1.6.1. Transport of retinol from the liver to other tissues ......................................... 16 1.6.2. RBP4 and its role in insulin resistance ........................................................... 17 1.7. Functions of VA.............................................................................................. 19 1.7.1. Roles of VA in vision ..................................................................................... 19 1.7.2. Roles of VA in immunity................................................................................ 20 1.7.3. Roles of VA in differentiation ........................................................................ 21 1.7.4. The toxicity of excess VA intake.................................................................... 21 1.8. Regulation of gene expression........................................................................ 22 1.8.1. The nuclear receptor super family and their activation mechanism ............... 22 1.8.2. Retinoic acid receptors.................................................................................... 23 1.8.3. Retinoid X receptors ....................................................................................... 24 1.8.4. Other nuclear receptors................................................................................... 24 2. Metabolic diseases ................................................................................................. 24 2.1. Obesity ............................................................................................................ 24 2.1.1. Causes of obesity ............................................................................................ 26 2.1.2. Treatment of obesity ....................................................................................... 27 2.2. Diabetes........................................................................................................... 28 2.2.1. Definition of diabetes mellitus........................................................................ 28 2.2.2. The link of obesity and T2DM........................................................................ 30 2.2.3. Treatment of T2DM........................................................................................ 31 2.3. Insulin resistance............................................................................................. 31 2.3.1. Insulin secretion.............................................................................................