Pediatric Research

Paul W. Hruz, M.D., Ph.D. Hruz_P@wustl.edu

Associate Professor of Pediatrics, Endocrinology and Diabetes

Associate Professor of Pediatrics, Cell Biology & Physiology

View my lab

Cell Biology & Physiology Endocrinology and Diabetes

phone: (314) 454-6051

Research Interests

Dr. Hruz's research interests include intermediary carbohydrate metabolism, glucose transporter structure and function and mechanism of insulin action. Currently, the mechanism(s) by which HIV protease inhibitors cause serious adverse metabolic effects including peripheral lipoatrophy, visceral adiposity, hypertriglyceridemia, and insulin resistance are being investigated. The laboratory has discovered that HIV protease inhibitors selectively and reversibly inhibit the GLUT4 facilitative glucose transporter. Ongoing studies are being directed toward elucidating the selectivity of these drugs in blocking the activity of each of the known facilitative glucose transport proteins. The tertiary structure of the facilitative glucose transporters is also being investigated using state-of-the-art biophysical approaches.

Education

BS, Marquette University, 1987
PhD, Medical College of Wisconsin, 1993
MD, Medical College of Wisconsin, 1994

Training

Pediatric Residency, University of Washington, 1994 - 1997
Pediatric Endocrinology Fellowship, Washington University, 1997 - 2000
Certification in Healthcare Ethics, National Catholic Bioethics Center, 2017

Licensure and Board Certification

Board Certified in General Pediatrics, 1997 - Pres
MO, Stae License, 2000 - Pres
Board Certified in Pediatric Endocrinology & Metabolism, 2001 - Pres

Honors

National Institute of Chemists Research and Recognition Award, 1987
Phi Beta Kappa, 1987
Phi Lambda Upsilon (Honorary Chemical Society), 1987
American Heart Association Predoctoral Fellowship Award, 1988
Alpha Omega Alpha, 1994
Armond J. Quick Award for Excellence in Biochemistry, 1994
NIDDK/Diabetes Branch Most Outstanding Resident, 1994
Pfizer Postdoctoral Fellowship Award, 1998
Scholar, Child Health Research Center of Excellence in Developmental Biology at Washington University, 2002
Julio V Santiago, M.D. Scholar in Pediatrics, 2013
Redemptor Hominis Award for Outstanding Contributions to the Study of Bioethics, 2017
Eli Lilly Outstanding Contribution to Drug Discovery: Emerging Biology Award, 2018

Selected Publications view all (53)

Publication Co-Authors

Audrey R. Odom John, M.D., Ph.D.

David A. Rudnick, M.D., Ph.D.

Brian DeBosch, M.D., Ph.D.

Yumirle Turmelle, M.D., M.S.P.H.

1.	Hresko RC, Kraft TE, Quigley A, Carpenter EP, Hruz PW. Mammalian Glucose Transporter Activity is Dependent upon Anionic and Conical Phospholipids. J Biol Chem. 2016. doi:10.1074/jbc.M116.730168 PMID:27302065
2.	DeBosch BJ, Heitmeier MR, Mayer AL, Higgins CB, Crowley JR, Kraft TE, Chi M, Newberry EP, Chen Z, Finck BN, Davidson NO, Yarasheski KE, Hruz PW, Moley KH. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci Signal. 2016;9(416):ra21. doi:10.1126/scisignal.aac5472 PMID:26905426
3.	Kraft TE, Armstrong C, Heitmeier MR, Odom AR, Hruz PW. The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir. Antimicrob Agents Chemother. 2015;59(10):6203-9. doi:10.1128/AAC.00899-15 PMCID:PMC4576095 PMID:26248369
4.	Kraft TE, Hresko RC, Hruz PW. Expression, purification, and functional characterization of the insulin-responsive facilitative glucose transporter GLUT4. Protein Sci. 2015. doi:10.1002/pro.2812 PMID:26402434
5.	Mishra RK, Wei C, Hresko RC, Bajpai R, Heitmeier M, Matulis SM, Nooka AK, Rosen ST, Hruz PW, Schiltz GE, Shanmugam M. In Silico Modeling-based Identification of Glucose Transporter 4 (GLUT4)-selective Inhibitors for Cancer Therapy. J Biol Chem. 2015;290(23):14441-53. doi:10.1074/jbc.M114.628826 PMID:25847249
6.	Hresko RC, Kraft TE, Tzekov A, Wildman SA, Hruz PW. Isoform-selective inhibition of facilitative glucose transporters: elucidation of the molecular mechanism of HIV protease inhibitor binding. J Biol Chem. 2014;289(23):16100-16113. doi:10.1074/jbc.M113.528430 PMCID:PMC4047383 PMID:24706759
7.	Vyas AK, Aerni-Flessner LB, Payne MA, Kovacs A, Jay PY, Hruz PW. Saxagliptin Improves Glucose Tolerance but not Survival in a Murine Model of Dilated Cardiomyopathy. Cardiovasc Endocrinol. 2012;1(4):74-82. doi:10.1097/XCE.0b013e32835bfb24 PMCID:PMC3686315 PMID:23795310
8.	Aerni-Flessner L, Abi-Jaoude M, Koenig A, Payne M, Hruz PW. GLUT4, GLUT1, and GLUT8 are the dominant GLUT transcripts expressed in the murine left ventricle. Cardiovasc Diabetol. 2012;11:63. doi:10.1186/1475-2840-11-63 PMCID:PMC3416696 PMID:22681646
9.	Remedi MS, Agapova SE, Vyas AK, Hruz PW, Nichols CG. Acute sulfonylurea therapy at disease onset can cause permanent remission of KATP-induced diabetes. Diabetes. 2011;60(10):2515-22. doi:10.2337/db11-0538 PMCID:PMC3178299 PMID:21813803
10.	Hruz PW. Molecular mechanisms for insulin resistance in treated HIV-infection. Best Pract Res Clin Endocrinol Metab. 2011;25(3):459-68. doi:10.1016/j.beem.2010.10.017 PMCID:PMC3115529 PMID:21663839

1.	Heitmeier MR, Hresko RC, Edwards RL, Prinsen MJ, Ilagan MXG, Odom John AR, Hruz PW. Identification of druggable small molecule antagonists of the Plasmodium falciparum hexose transporter PfHT and assessment of ligand access to the glucose permeation pathway via FLAG-mediated protein engineering. PLoS One. 2019;14(5):e0216457. PMCID:PMC6508677 PMID:31071153
2.	Laidlaw MK, Van Meter QL, Hruz PW, Van Mol A, Malone WJ. Letter to the Editor: "Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 2019;104(3):686-687. PMID:30476120
3.	Emfinger CH, Yan Z, Welscher A, Hung P, McAllister W, Hruz PW, Nichols CG, Remedi MS. Contribution of systemic inflammation to permanence of K_ATP-induced neonatal diabetes in mice. Am J Physiol Endocrinol Metab. 2018;315(6):E1121-E1132. PMCID:PMC6336961 PMID:30226997
4.	Zhang Y, Higgins CB, Mayer AL, Mysorekar IU, Razani BB, Graham MJ, Hruz PW, DeBosch BJ. TFEB-dependent Induction of Thermogenesis by the Hepatocyte SLC2A Inhibitor Trehalose. Autophagy. 2018. PMID:29996716
5.	Heitmeier MR, Payne MA, Weinheimer C, Kovacs A, Hresko RC, Jay PY, Hruz PW. Metabolic and Cardiac Adaptation to Chronic Pharmacologic Blockade of Facilitative Glucose Transport in Murine Dilated Cardiomyopathy and Myocardial Ischemia. Sci Rep. 2018;8(1):6475. PMID:29691457
6.	Wei C, Heitmeier M, Hruz PW, Shanmugam M. Evaluating the Efficacy of GLUT Inhibitors Using a Seahorse Extracellular Flux Analyzer. Methods Mol Biol. 2018;1713:69-75. PMID:29218518
7.	Wei C, Bajpai R, Sharma H, Heitmeier M, Jain AD, Matulis SM, Nooka AK, Mishra RK, Hruz PW, Schiltz GE, Shanmugam M. Development of GLUT4-selective antagonists for multiple myeloma therapy. Eur J Med Chem. 2017;139:573-586. PMCID:PMC5603412 PMID:28837922
8.	Edwards RL, Brothers RC, Wang X, Maron MI, Ziniel PD, Tsang PS, Kraft TE, Hruz PW, Williamson KC, Dowd CS, John ARO. MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis. Sci Rep. 2017;7(1):8400. PMCID:PMC5567135 PMID:28827774
9.	Mayer AL, Higgins CB, Heitmeier MR, Kraft TE, Qian X, Crowley JR, Hyrc KL, Beatty WL, Yarasheski KE, Hruz PW, DeBosch BJ. SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy. Sci Rep. 2016;6:38586. PMCID:PMC5138640 PMID:27922102
10.	Kraft TE, Heitmeier MR, Putanko M, Edwards RL, Ilagan MX, Payne MA, Autry JM, Thomas DD, Odom AR, Hruz PW. A Novel Fluorescence Resonance Energy Transfer-Based Screen in High-Throughput Format To Identify Inhibitors of Malarial and Human Glucose Transporters. Antimicrob Agents Chemother. 2016;60(12):7407-7414. PMCID:PMC5119023 PMID:27736766
11.	Hresko RC, Kraft TE, Quigley A, Carpenter EP, Hruz PW. Mammalian Glucose Transporter Activity is Dependent upon Anionic and Conical Phospholipids. J Biol Chem. 2016. doi:10.1074/jbc.M116.730168 PMID:27302065
12.	DeBosch BJ, Heitmeier MR, Mayer AL, Higgins CB, Crowley JR, Kraft TE, Chi M, Newberry EP, Chen Z, Finck BN, Davidson NO, Yarasheski KE, Hruz PW, Moley KH. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci Signal. 2016;9(416):ra21. doi:10.1126/scisignal.aac5472 PMID:26905426
13.	Hruz PW. Commentary. Clin Chem. 2015;61(12):1444. PMID:26614228
14.	Kraft TE, Armstrong C, Heitmeier MR, Odom AR, Hruz PW. The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir. Antimicrob Agents Chemother. 2015;59(10):6203-9. doi:10.1128/AAC.00899-15 PMCID:PMC4576095 PMID:26248369
15.	Kraft TE, Hresko RC, Hruz PW. Expression, purification, and functional characterization of the insulin-responsive facilitative glucose transporter GLUT4. Protein Sci. 2015. doi:10.1002/pro.2812 PMID:26402434
16.	Mishra RK, Wei C, Hresko RC, Bajpai R, Heitmeier M, Matulis SM, Nooka AK, Rosen ST, Hruz PW, Schiltz GE, Shanmugam M. In Silico Modeling-based Identification of Glucose Transporter 4 (GLUT4)-selective Inhibitors for Cancer Therapy. J Biol Chem. 2015;290(23):14441-53. doi:10.1074/jbc.M114.628826 PMID:25847249
17.	Hruz PW. HIV and endocrine disorders. Endocrinol Metab Clin North Am. 2014;43(3):xvii-xviii. PMID:25169571
18.	Hresko RC, Kraft TE, Tzekov A, Wildman SA, Hruz PW. Isoform-selective inhibition of facilitative glucose transporters: elucidation of the molecular mechanism of HIV protease inhibitor binding. J Biol Chem. 2014;289(23):16100-16113. doi:10.1074/jbc.M113.528430 PMCID:PMC4047383 PMID:24706759
19.	Vyas AK, Aerni-Flessner LB, Payne MA, Kovacs A, Jay PY, Hruz PW. Saxagliptin Improves Glucose Tolerance but not Survival in a Murine Model of Dilated Cardiomyopathy. Cardiovasc Endocrinol. 2012;1(4):74-82. doi:10.1097/XCE.0b013e32835bfb24 PMCID:PMC3686315 PMID:23795310
20.	Aerni-Flessner L, Abi-Jaoude M, Koenig A, Payne M, Hruz PW. GLUT4, GLUT1, and GLUT8 are the dominant GLUT transcripts expressed in the murine left ventricle. Cardiovasc Diabetol. 2012;11:63. doi:10.1186/1475-2840-11-63 PMCID:PMC3416696 PMID:22681646
21.	Remedi MS, Agapova SE, Vyas AK, Hruz PW, Nichols CG. Acute sulfonylurea therapy at disease onset can cause permanent remission of KATP-induced diabetes. Diabetes. 2011;60(10):2515-22. doi:10.2337/db11-0538 PMCID:PMC3178299 PMID:21813803
22.	Hruz PW. Molecular mechanisms for insulin resistance in treated HIV-infection. Best Pract Res Clin Endocrinol Metab. 2011;25(3):459-68. doi:10.1016/j.beem.2010.10.017 PMCID:PMC3115529 PMID:21663839
23.	Hruz PW, Yan Q, Tsai L, Koster J, Xu L, Cihlar T, Callebaut C. GS-8374, a novel HIV protease inhibitor, does not alter glucose homeostasis in cultured adipocytes or in a healthy-rodent model system. Antimicrob Agents Chemother. 2011;55(4):1377-82. doi:10.1128/AAC.01184-10 PMCID:PMC3067185 PMID:21245443
24.	Vyas AK, Yang KC, Woo D, Tzekov A, Kovacs A, Jay PY, Hruz PW. Exenatide improves glucose homeostasis and prolongs survival in a murine model of dilated cardiomyopathy. PLoS One. 2011;6(2):e17178. doi:10.1371/journal.pone.0017178 PMCID:PMC3040766 PMID:21359201
25.	Hresko RC, Hruz PW. HIV protease inhibitors act as competitive inhibitors of the cytoplasmic glucose binding site of GLUTs with differing affinities for GLUT1 and GLUT4. PLoS One. 2011;6(9):e25237. doi:10.1371/journal.pone.0025237 PMCID:PMC3179492 PMID:21966466
26.	Gazit V, Weymann A, Hartman E, Finck BN, Hruz PW, Tzekov A, Rudnick DA. Liver regeneration is impaired in lipodystrophic fatty liver dystrophy mice. Hepatology. 2010;52(6):2109-17. doi:10.1002/hep.23920 PMCID:PMC2991544 PMID:20967828
27.	Vyas AK, Koster JC, Tzekov A, Hruz PW. Effects of the HIV protease inhibitor ritonavir on GLUT4 knock-out mice. J Biol Chem. 2010;285(47):36395-400. doi:10.1074/jbc.M110.176321 PMCID:PMC2978568 PMID:20864532
28.	Guo W, Wong S, Pudney J, Jasuja R, Hua N, Jiang L, Miller A, Hruz PW, Hamilton JA, Bhasin S. Acipimox, an inhibitor of lipolysis, attenuates atherogenesis in LDLR-null mice treated with HIV protease inhibitor ritonavir. Arterioscler Thromb Vasc Biol. 2009;29(12):2028-32. doi:10.1161/ATVBAHA.109.191304 PMCID:PMC2783673 PMID:19762785
29.	Tu P, Bhasin S, Hruz PW, Herbst KL, Castellani LW, Hua N, Hamilton JA, Guo W. Genetic disruption of myostatin reduces the development of proatherogenic dyslipidemia and atherogenic lesions in Ldlr null mice. Diabetes. 2009;58(8):1739-48. doi:10.2337/db09-0349 PMCID:PMC2712781 PMID:19509018
30.	Flint OP, Noor MA, Hruz PW, Hylemon PB, Yarasheski K, Kotler DP, Parker RA, Bellamine A. The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: cellular mechanisms and clinical implications. Toxicol Pathol. 2009;37(1):65-77. doi:10.1177/0192623308327119 PMCID:PMC3170409 PMID:19171928
31.	Hruz PW. HIV protease inhibitors and insulin resistance: lessons from in-vitro, rodent and healthy human volunteer models. Curr Opin HIV AIDS. 2008;3(6):660-5. doi:10.1097/COH.0b013e3283139134 PMCID:PMC2680222 PMID:19373039
32.	Hruz PW, Yan Q, Struthers H, Jay PY. HIV protease inhibitors that block GLUT4 precipitate acute, decompensated heart failure in a mouse model of dilated cardiomyopathy. FASEB J. 2008;22(7):2161-7. doi:10.1096/fj.07-102269 PMID:18256305
33.	Hruz PW, Yan Q. Tipranavir without ritonavir does not acutely induce peripheral insulin resistance in a rodent model. J Acquir Immune Defic Syndr. 2006;43(5):624-5. doi:10.1097/01.qai.0000245883.66509.b4 PMID:17133213
34.	Turmelle YP, Shikapwashya O, Tu S, Hruz PW, Yan Q, Rudnick DA. Rosiglitazone inhibits mouse liver regeneration. FASEB J. 2006;20(14):2609-11. doi:10.1096/fj.06-6511fje PMID:17077279
35.	Hruz PW. Molecular Mechanisms for Altered Glucose Homeostasis in HIV Infection. Am J Infect Dis. 2006;2(3):187-192. PMCID:PMC1716153 PMID:17186064
36.	Yan Q, Hruz PW. Direct comparison of the acute in vivo effects of HIV protease inhibitors on peripheral glucose disposal. J Acquir Immune Defic Syndr. 2005;40(4):398-403. PMCID:PMC1360159 PMID:16280693
37.	Hertel J, Struthers H, Horj CB, Hruz PW. A structural basis for the acute effects of HIV protease inhibitors on GLUT4 intrinsic activity. J Biol Chem. 2004;279(53):55147-52. doi:10.1074/jbc.M410826200 PMCID:PMC1403823 PMID:15496402
38.	Shteyer E, Liao Y, Muglia LJ, Hruz PW, Rudnick DA. Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice. Hepatology. 2004;40(6):1322-32. doi:10.1002/hep.20462 PMID:15565660
39.	Liao Y, Shikapwashya ON, Shteyer E, Dieckgraefe BK, Hruz PW, Rudnick DA. Delayed hepatocellular mitotic progression and impaired liver regeneration in early growth response-1-deficient mice. J Biol Chem. 2004;279(41):43107-16. doi:10.1074/jbc.M407969200 PMID:15265859
40.	Koster JC, Remedi MS, Qiu H, Nichols CG, Hruz PW. HIV protease inhibitors acutely impair glucose-stimulated insulin release. Diabetes. 2003;52(7):1695-700. PMCID:PMC1403824 PMID:12829635
41.	Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS. 2002;16(6):859-63. PMID:11919487
42.	Hruz PW, Murata H, Qiu H, Mueckler M. Indinavir induces acute and reversible peripheral insulin resistance in rats. Diabetes. 2002;51(4):937-42. PMID:11916910
43.	Murata H, Hruz PW, Mueckler M. Investigating the cellular targets of HIV protease inhibitors: implications for metabolic disorders and improvements in drug therapy. Curr Drug Targets Infect Disord. 2002;2(1):1-8. PMID:12462148
44.	Hruz PW, Murata H, Mueckler M. Adverse metabolic consequences of HIV protease inhibitor therapy: the search for a central mechanism. Am J Physiol Endocrinol Metab. 2001;280(4):E549-53. PMID:11254460
45.	Hruz PW, Mueckler MM. Structural analysis of the GLUT1 facilitative glucose transporter (review). Mol Membr Biol. 2001;18(3):183-93. PMID:11681785
46.	Hruz PW, Mueckler MM. Cysteine-scanning mutagenesis of transmembrane segment 11 of the GLUT1 facilitative glucose transporter. Biochemistry. 2000;39(31):9367-72. PMID:10924131
47.	Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem. 2000;275(27):20251-4. doi:10.1074/jbc.C000228200 PMID:10806189
48.	Hruz PW, Mueckler MM. Cysteine-scanning mutagenesis of transmembrane segment 7 of the GLUT1 glucose transporter. J Biol Chem. 1999;274(51):36176-80. PMID:10593902
49.	Roberts JR, Narasimhan C, Hruz PW, Mitchell GA, Miziorko HM. 3-Hydroxy-3-methylglutaryl-CoA lyase: expression and isolation of the recombinant human enzyme and investigation of a mechanism for regulation of enzyme activity. J Biol Chem. 1994;269(27):17841-6. PMID:8027038
50.	Hruz PW, Anderson VE, Miziorko HM. 3-Hydroxy-3-methylglutaryldithio-CoA: utility of an alternative substrate in elucidation of a role for HMG-CoA lyase's cation activator. Biochim Biophys Acta. 1993;1162(1-2):149-54. PMID:8095409
51.	Mitchell GA, Robert MF, Hruz PW, Wang S, Fontaine G, Behnke CE, Mende-Mueller LM, Schappert K, Lee C, Gibson KM, Miziorko HM. 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency. J Biol Chem. 1993;268(6):4376-81. PMID:8440722
52.	Hruz PW, Miziorko HM. Avian 3-hydroxy-3-methylglutaryl-CoA lyase: sensitivity of enzyme activity to thiol/disulfide exchange and identification of proximal reactive cysteines. Protein Sci. 1992;1(9):1144-53. doi:10.1002/pro.5560010908 PMCID:PMC2142181 PMID:1304393
53.	Hruz PW, Narasimhan C, Miziorko HM. 3-Hydroxy-3-methylglutaryl coenzyme A lyase: affinity labeling of the Pseudomonas mevalonii enzyme and assignment of cysteine-237 to the active site. Biochemistry. 1992;31(29):6842-7. PMID:1637819