Paul A. Dawson, PhD
Professor, Internal Medicine (Gastroenterology)
Professor, Pathology (Comparative Medicine)
To contact Dr. Dawson:
Tel: (336) 716-4633
Fax: (336) 716-6279
Education:
- Undergraduate: University of Florida, B.S. 1981
- Postgraduate: State University of New York at Stony Brook, PhD 1986
- Fellowship: University of Texas Southwestern Medical Center, 1986-1990
Interests:
- Teaching: Molecular Medicine, Molecular Genetics
- Research: Molecular Biology of Cholesterol and Bile Acid Metabolism; Intestinal Transporters; Inflammatory Bowel Disease
Current Projects: Bile acids, cholesterol metabolism, molecular cloning, gene expression and regulation, molecular genetics
1. Molecular Genetics of Ileal Apical Bile Acid Transporter
My lab originally identified and cloned the human ileal bile acid transporter cDNA and gene. These probes are being used to identify dysfunctional mutations in the gene that are associated with primary bile acid malabsorption. The association of these mutations with other GI and lipid metabolism disorders including gallstone disease, irritable bowel syndrome, and hypertriglyceridemia is also being investigated.
2. The Role of the Ileal Apical Bile Acid Transporter in Lipid Metabolism
The ileal bile acid transporter is thought to be the major mechanism responsible for the intestinal absorption of bile acids. In order to understand the role of the ileal bile acid transporter in normal physiology and the pathophysiology of GI and lipid disorders, we have generated an ileal bile acid transporter knockout mouse. This unique model of primary bile acid malabsorption is providing new insights to the relationships between cholesterol, bile acid, and triglyceride metabolism.
3. Identification of the Ileal Basolateral Bile Acid Transporter
The transcellular transport of bile acids is a defined process that involves uptake across the apical membrane, trafficking to the basolateral membrane and secretion across the basolateral membrane. The identity of the basolateral bile acid transporter has been a critical “missing link” in our understanding of the enterohepatic circulation of bile acids. We have employed a transcriptional profiling approach to identify the heteromeric Organic Solute Transporter, OSTalpha-OSTbeta as a potential ileal basolateral bile acid transporter. We have recently generated an OSTalpha knockout mouse as an experimental model to test the hypothesis that OSTalpha-OSTbeta is the major mechanism responsible for export of bile acids across the ileal basolateral domain. Additional studies are in progress to elucidate the function of the individual transporter subunits and to understand how their expression is regulated.
4. Bile Acids and Colon Cancer
A new project in the lab involves the relationship between bile acids, vitamin D, and colon cancer. Bile acids have been proposed to act as tumor promoters in the colon. In fact, dietary fiber is thought to be protective against colon cancer by physically binding bile acids in the colon and preventing their interaction with colonocytes. It has also been proposed that Vitamin D protects against colon cancer by inducing the colonic catabolism of bile acids. The data for this hypothesis is derived largely from epidemiological studies and the hypothesis has not been rigorously tested. However, this has not kept the model from being widely quoted (for example, see Science 296, 1313-1316, 2002). In collaboration with Dr. Sandy Pang, we have demonstrated that ASBT gene expression is induced by vitamin D, providing another potential mechanism to protect the colon from excess bile acids.
Studies are in progress to use the ileal bile acid transporter knockout mouse, the only animal model with a pure bile acid malabsorption, to evaluate the relationship between bile acid malabsorption and colon cancer. Those studies include evaluating colonic crypt hyperplasia in this model as well as crossing the ileal bile acid transporter knockout into colon cancer susceptible backgrounds such as the Apc+/- mouse to test this hypothesis.
Recent Publications:
Neimark E, Chen F, Li X, Magid MS, Alasio TM, Frankenberg T, Sinha J, Dawson PA, Shneider BL. c-Fos Is a Critical Mediator of Inflammatory-Mediated Repression of the Apical Sodium-Dependent Bile Acid Transporter. Gastroenterology. 2006 Aug;131(2):554-67. PMID: 16890608
Frankenberg T, Rao A, Chen F, Haywood J, Shneider BL, Dawson PA. Regulation of the Mouse Organic Solute Transporter {alpha}-{beta}, Ost{alpha}-Ost{beta}, by Bile Acids. Am J Physiol Gastrointest Liver Physiol. 2005 Dec 15;
Ballatori N, Christian WV, Lee JY, Dawson PA, Soroka CJ, Boyer JL, Madejczyk MS, Li N. OSTalpha-OSTbeta: a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology. 2005 Dec;42(6):1270-9.
Belinsky MG, Dawson PA, Shchaveleva I, Bain LJ, Wang R, Ling V, Chen ZS, Grinberg A, Westphal H, Klein-Szanto A, Lerro A, Kruh GD. Analysis of the in vivo functions of Mrp3. Mol Pharmacol. 2005 Jul;68(1):160-8.
Dawson PA, Hubbert M, Haywood J, Craddock AL, Zerangue N, Christian WV, Ballatori N. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter.
J Biol Chem. 2005 Feb 25;280(8):6960-8.
Dawson PA, Haywood J, Craddock AL, Wilson M, Tietjen M, Kluckman K, Maeda N, Parks JS. Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. J Biol Chem. 2003 Sep 5;278(36):33920-7.
Yao L, Dawson PA, Woollett LA. Increases in biliary cholesterol-to-bile acid ratio in pregnant hamsters fed low and high levels of cholesterol. Am J Physiol Gastrointest Liver Physiol. 2003 Feb;284(2):G263-8.
Chen F, Ma L, Dawson PA, Sinal CJ, Sehayek E, Gonzalez FJ, Breslow J, Ananthanarayanan M, Shneider BL. Liver receptor homologue-1 mediates species- and cell line-specific bile acid dependent negative feedback regulation of the apical sodium-dependent bile acid transporter. J Biol Chem. 2003 278;19909-19916.
Veggi LM, Crocenzi FA, Roma MG, Dawson PA, Pellegrino JM, Sanchez Pozzi EJ, Mottino AD. Dapsone-induced cholestasis and impairment of bile salt output in the rat. Biochem Pharmacol. 2002 Apr 15;63(8):1553-63.
Dresser GK, Bailey DG, Leake BF, Schwarz UI, Dawson PA, Freeman DJ, Kim RB. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther. 2002 Jan;71(1):11-20.
Mottino AD, Hoffman T, Dawson PA, Luquita MG, Monti JA, Sanchez Pozzi EJ, Catania VA, Cao J, Vore M. Increased expression of ileal apical sodium-dependent bile acid transporter in postpartum rats. Am J Physiol Gastrointest Liver Physiol. 2002 Jan;282(1):G41-50.
Bensen JT, Dawson PA, Mychaleckyj JC, Bowden DW. Identification of a novel human cytokine gene in the interleukin gene cluster on chromosome 2q12-14. J Interferon Cytokine Res. 2001 Nov;21(11):899-904.
Love MW, Craddock AL, Angelin B, Brunzell JD, Duane WC, Dawson PA. Analysis of the ileal bile acid transporter gene, SLC10A2, in subjects with familial hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2001 Dec;21(12):2039-45.
Dawson PA, Mychaleckyj JC, Fossey SC, Mihic SJ, Craddock AL, Bowden DW. Sequence and functional analysis of GLUT10: a glucose transporter in the Type 2 diabetes-linked region of chromosome 20q12-13.1. Mol Genet Metab. 2001 Sep-Oct;74(1-2):186-99.
Montagnani M, Love MW, Rossel P, Dawson PA, Qvist P. Absence of dysfunctional ileal sodium-bile acid cotransporter gene mutations in patients with adult-onset idiopathic bile acid malabsorption. Scand J Gastroenterol. 2001 Oct;36(10):1077-80.
Walters HC, Craddock AL, Fusegawa H, Willingham MC, Dawson PA. Expression, transport properties, and chromosomal location of organic anion transporter subtype 3. Am J Physiol Gastrointest Liver Physiol. 2000 Dec;279(6):G1188-200.
Lazaridis KN, Tietz P, Wu T, Kip S, Dawson PA, LaRusso NF. Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties. Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11092-7.
Book Chapter:
Dawson PA. Chaper 54: Bile secretion and the enterohepatic circulation of bile acids. In: Feldman M, Friedman LS, and Sleisenger MH. (eds), Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 7th ed. Philadelphia, W.B. Saunders, 2002, 1051-1064.