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Research in Lipid Sciences
Dr. Paul Dawson

Paul A. Dawson, PhD

Professor of Pathology (Lipid Sciences) and Internal Medicine (Gastroenterology)
Tel: (336) 716-4633
Fax: (336) 716-6376
pdawson@wfubmc.edu

Education:
  • Undergraduate: University of Florida, BA, 1981
  • Postgraduate: State University of New York at Stony Brook, PhD, 1986
  • Fellowship: University of Texas Southwestern Medical Center, 1986-90 
Interests:
  • Teaching: Molecular Medicine, Molecular Genetics
  • Research: Molecular Biology of Cholesterol and Bile Acid Metabolism; Intestinal Transporters; Inflammatory Bowel Disease 
Current Research: Bile acids, cholesterol metabolism, molecular cloning, gene expression and regulation, molecular genetics 
  1. Molecular Genetics of Ileal Bile Acid Transporter. My lab identified and cloned the human ileal bile acid transporter cDNA and gene. These probes are being used to identify dysfunctional mutations in patients with bile acid malabsorption. Various classes of dysfunctional mutations in the ileal bile acid transporter gene have been identified. In addition to null mutations (i.e., splicing defects), we have also identified missense mutations that interfere with bile acid transporter processing and mechanism of action. The Class 2 mutations cause misfolding and ER retention of the transporter. More interesting are the Class 3 and 4 mutations that block bile acid transport at the substrate binding and solute translocation steps. The actions of these mutations are being studied to gain insight into the molecular mechanism of sodium-coupled solute transport. The association of these mutations with other gastrointestinal and lipid metabolism disorders including gallstone disease, irritable bowel syndrome, hypocholesterolemia, and hypertriglyceridemia is currently being investigated.

  2. Ileal Bile Acid Transporter Biology. In addition to the ileum, the ileal bile acid transporter is expressed in the proximal tubules of the kidney and in the cholangiocytes lining the bile ducts. The role of the transporter in the ileum and kidney is the quantitative reclamation of bile acids. However, its role in bile duct epithelium is unknown. We are generating an ileal bile acid transporter knockout mouse as a model to further understand the physiological role of the transporter in different tissues.

  3. Intracellular Lipid Transport. 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. Currently, we have identified and cloned cDNAs for the apical membrane transporter responsible for the initial uptake of bile acids, and the cytoplasmic binding protein thought to be responsible for the transcellular transport. We are devising expression-cloning strategies to identify additional bile acid transporters as well as the basolateral membrane transporter. Using the cloned transporters in polarized cells, the entire pathway can be reconstituted and analyzed. This model system should yield insight into more complex pathways for intracellular lipid trafficking. 

This figure shows the structure of the mouse ileal bile acid transporter gene (slc10a2), the targeting vector, as well as the predicted disrupted gene.

FIGURE LEGEND: Disruption of the Ileal Bile Acid Transporter Gene in Mice. A) This figure shows the structure of the mouse ileal bile acid transporter gene (slc10a2), the targeting vector, as well as the predicted disrupted gene. Exons are numbered and indicated by the boxes. TK, viral thymidine kinase gene; NEO, neomycin resistance gene. B) The lower panel shows the results of PCR analysis of the ileal bile acid transporter gene in wild type mice (+/+) or mice that are heterozygous (+/-) or homozygous (-/-) for disruption of slc10a2. The results are shown for a Neo-specific probe (Neo gene), the wild type Slc10a2 gene, or lecithin cholesterol acyl-transferase (LCAT) as control.
Recent Publications:

Jung D, Inagaki T, Dawson PA, Kliewer SA, Mangelsdorf DJ, Moschetta A. FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption. J Lipid Res. 2007 Sep 6; [Epub ahead of print]

Montagnani M, Abrahamsson A, Galman C, Eggertsen G, Marschall HU, Ravaioli E, Einarsson C, Dawson PA. Analysis of ileal sodium/bile acid cotransporter and related nuclear receptor genes in a family with multiple cases of idiopathic bile acid malabsorption. World J Gastroenterol. 2006 Dec 21;12(47):7710-4.

Splinter PL, Lazaridis KN, Dawson PA, LaRusso NF. Cloning and expression of SLC10A4, a putative organic anion transport protein. World J Gastroenterol. 2006 Nov 14;12(42):6797-805.

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.

Hofmann AF, Kim RB, Shneider BL, Pang KS. Transactivation of rat apical sodium-dependent bile acid transporter and increased bile acid transport by 1alpha,25-dihydroxyvitamin D3 via the vitamin D receptor. Mol Pharmacol. 2006 Jun;69(6):1913-23.

Frankenberg T, Rao A, Chen F, Haywood J, Shneider BL, Dawson PA. Regulation of the mouse organic solute transporter alpha-beta, Ostalpha-Ostbeta, by bile acids. Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G912-22.

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.

Shelness GS, Dawson PA. In memoriam: David L. Williams 1946-2004. J Lipid Res. 2004 Dec;45(12):2388-9.

Harris MJ, Kagawa T, Dawson PA, Arias IM. Taurocholate transport by hepatic and intestinal bile acid transporters is independent of FIC1 overexpression in Madin-Darby canine kidney cells. J Gastroenterol Hepatol. 2004 Jul;19(7):819-825.

Dawson PA, Craddock AL. Expression cloning of receptor ligand transporters. Methods Enzymol. 2003;364:322-39.

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 May 30;278(22):19909-16.

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.