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Daniel Hwang

Daniel Hwang

  • Adjunct Professor, Department of Nutrition
  • USDA ARS Western Human Nutrition Research Center Scientist

211 WHNRC

(530) 754-4838

daniel.hwang@ars.usda.gov

Email

Education

  • B.S., Pharmacy, Seoul National University
  • MPH, Public Health, Seoul National University
  • Ph.D., Nutrition, Colorado State University
  • Postdoctoral fellow, Cornell University

Research Interests

Toll-like receptors (TLRs) and oligomerization domain containing proteins (Nods) are two major pattern recognition receptors (PRR) involved in host defense against microbial pathogens. Recent evidence suggests that certain TLRs and Nods can be activated by endogenous molecules including saturated fatty acids leading to the induction of sterile inflammation. Chronic inflammation is considered as one of key pathological conditions leading to the development of many chronic diseases including atherosclerosis, cancer and insulin resistance. Results from epidemiological and genetic studies linked TLRs to risk modification of many chronic diseases. Then, dietary and pharmacological agents that can suppress PRR-mediated inflammation may have preventive efficacy for such chronic diseases.

Dr. Hwang’s group, for the first time, demonstrated that saturated fatty acids stimulate but polyunsaturated fatty acids (PUFAs) particularly n-3 PUFAs, inhibit TLR signaling pathways and the expression of target genes (J. Biol. Chem. 2001: J Lipid Res. 2003; J Biol. Chem 2004). Dr. Hwang’s subsequent work (J Immunology 2005) demonstrated that saturated and n-3 PUFAs reciprocally modulate dendritic cell functions and T-lymphocyte activation as a functional consequence of the reciprocal modulation of TLR-signaling pathways and target gene expression. These findings provided a conceptual foundation that dietary fatty acids can modulate TLR4-mediated chronic inflammation and consequent risk of chronic disease. In addition, the results from Dr. Hwang’s recent studies showed that certain plant polyphenols inhibit TLR4 and its target gene expression (Biochem Pharmacol 2006). It was also revealed that another pattern recognition receptor, Nods are also reciprocally modulated by saturated and n-3 PUFAs (J. Biol. Chem 2007). Dr. Hwang’s recent studies further delineated the mechanism as to how fatty acids modulate the activation of TLR4. There is no evidence that fatty acids can directly bind TLRs. Fatty acids modulate the activation of TLR4 by regulating dimerization and recruitment of the receptor into lipid rafts in a reactive oxygen species-dependent manner (J Biol Cem 2009). These findings define a new paradigm for the molecular mechanism by which dietary fatty acids regulate TLR4-mediated signaling pathways, target gene expression and cellular (immune) responses. TLR-mediated chronic inflammation can lead to increased risk of development and progression of many chronic diseases including atherosclerosis and insulin resistance. It is now recognized that TLRs and Nods are key pattern recognition receptors that can be activated by endogenous molecules leading to sterile inflammation. Therefore, Dr. Hwang’s research interest is focused in understanding how pattern recognition receptor-mediated sterile inflammation and risk of chronic disease can be modulated by what we eat with emphasis on dietary fatty acids and phytochemicals.

Selected Publications

  • Lee, S.H., Soyoola, E., Chanmugam, P., Hart, S., Zhong, H., Simmons, D., and Hwang, D. Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide.  J. Biol. Chem.  267:25934-25938, 1992.
  • Feng, L., Sun, W., Xia, Y., Tang, W.W., Chanmugam, P., Lion, S., Soyoola, E., Wilson, C.B., and Hwang, D.H.  Cloning two isoforms of rat cyclooxygenase: differential regulation of their expression.  Arch. Biochem. Biophys. 307:361-368, 1993.
  • Jacobs, A., Hwang, D., Julian, J., and Carlson, D.D. Regulated expression of prostaglandin endoperoxide synthase-2 (PGS-2) by uterine stroma. Endocrinology, 135:1807-1815, 1994.
  • Chanmugam, P., Feng, L., Xia, Y., Liou, S., Lee, J., Jang, B.C., Yu, G., Kwon, H.J., Beppu, T., Yoshida, M., Wilson, C.B., and Hwang, D. Radicicol, a protein tyrosine kinase inhibitor, suppresses the expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide and in experimental glomerulonephritis. J. Biol. Chem., 270:5418-5426, 1995.
  • Feng, L., Xia, Y., Garcia, G.E., Hwang, D., and Wilson, C.B. IL-1, TNF and LPS induce cyclooxygenase-2 (COX-2) expression through an oxidant-dependent mechanism.  J. Clin. Invest. 95:1669-1675, 1995.
  • Hwang, D.,  Fischer, Nicholas, H. Jang, Byeong C. , Tak , Heekyung, and Kim, Jin K. Inhibition of the expression of inducible cyclooxygenase and proinflammatory cytokines by sesquiterpene lactones in macrophages correlates with the inhibition of MAP kinases.  Biochem. Biophys. Res. Comm., 266:810-818, 1996.
  • Feng, Lili,, Jang, Byeong C., and Hwang, D. Inhibitor of protein tyrosine kinase, radicicol, suppresses the expression of cyclooxygenase and pro-inflammatory cytokines in LPS-stimulated rat alveolar macrophage in part by accelerating degradation of mRNA.  Adv. Exp. Med. Biol. 407:281-288, 1997.
  • Hwang, D., Jang, Byeong C., Yu, Gang, and Boudreau, Mary. Expression of mitogen-inducible cyclooxygenase induced by lipopolysaccharide: mediation through both MAP kinase and NF-kB signaling pathways in macrophages.  Biochem. Pharmacol. 54:87-96, 1997.
  • Hwang, D., Chanmugam, Prithiva S., Ryan, Donna H. Ryan, Boudreau, Mary, Windhauser, Marlene, Tulley, Richard, Brooks, Ellen R., and Bray, George A. Does vegetable oil attenuate the beneficial effects of fish oil in reducing risk factors for cardiovascular disease?  Am. J. Clin. Nutri. 66:89-96, 1997. (Selected for editorial comments and press release)
  • Adams, Linda B., Gillis, Thomas P., Hwang, Daniel H., and Krahenbuhl, James L. Effects of essential fatty acid deficiency on PGE2 production and cell mediated immunity in a mouse model of leprosy.  Infection and Immunity 65:1152-1157, 1997.
  • Hayek, Michael G., Mura, Casilda, Wu, Dayong, Han, Sung Nim, Beharka, Alison A., Paulson, Eric, Hwang, Daniel, and Meydani, Simin Nikbin. Enhanced expression of inducible cyclooxygenase with age in murine macrophages.  J. Immunology 159:2445-2451, 1997.
  • Wu, D., Mura, C., Beharka, A.A., Han, S.N., Paulson, K.E., Hwang, D., and Meydani, S.N. Age associated increase in prostaglandin E2 synthesis and cyclooxygenase activity in murine macrophage is reversed by vitamin E. Am. J. Physiology 275 (Cell Physiology 44):C661-C668, 1998.
  • Hwang, D., Scollard, D., Byrne, Jane, and Levine, E.  Expression of cyclooxygenase -1 and -2 in breast cancer  J. Natl. Cancer Inst. 90:455-460, 1998.
  • Hwang, D.H. and Rhee, S.H.  Receptor-mediated signaling pathways:  potential modulation by dietary fatty acids.  Am. J. Clin. Nutr. 70:545-556, 1999.
  • Hwang, D.H., Chanmugam, P., Boudreau, M., Sohn, K.H., Stone, K. and Pryor, W.A.  Activation and inactivation of cyclooxygenase in rat alveolar macrophages by aqueous cigarette tar extracts.  Free Radical Biology & Medicine 27: 673-682, 1999.
  • Paik, J.H., Ju, J.H., Lee, J.Y., Boudreau, M,. and Hwang, D.H. Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of mitogen-inducible cyclooxygenase – mediation through different signaling pathways.  J. Biol. Chem. 275:28173-28179, 2000.
  • Lefevre, M., Lovejoy, J.C., DeFelice, S.M., Keener, J.W., Bray, G.A., Ryan, D.H., Hwang, D.H., and Greenway, F.L.  Common apolipoprotein A-IV variants are associated with differences in BMI levels and percent body fat.  Int . J. Obes. & Related Metabolic Disorders 24(8):945-953, 2000.
  • Rhee, S.H. and Hwang, D.H.  Murine toll-like receptor-4 confers lipopolysaccharide responsiveness as determined by activation of NFkB and expression of the inducible cyclooxygenase.  J. Biol. Chem. 275:34035-34040, 2000.
  • Hwang, D.H. Fatty acids and immune responses – a new perspective in searching for clues to mechanism. Annual Review of Nutrition 20:431-56, 2000.
  • Boudreau, M.D., Sohn, K.H., Rhee, S.H., Lee, S.W., Hunt, J.D., and Hwang, D.H.  Suppression of tumor cell growth both in nude mice and in culture by n-3 polyunsaturated fatty acids—mediation through cyclooxygenase-independent pathways.  Cancer Res.  61:1386-1391, 2001.
  • Lee, J.Y., Sohn, K.H., Rhee, S.H., and Hwang, D.H.  Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4.  J. Biol. Chem. 276:16683-16689, 2001.
  • Hwang, D.H.  Modulation of the expression of cyclooxygenase-2 by fatty acids mediated through Toll-like receptor 4-derived signaling pathways. FASEB J. 15:2556-2564, 2001.
  • Paik, J.H., Lee, J.Y., and Hwang, D.  Signaling pathways for TNFa-induced COX-2 expression:  mediation through MAP kinases and NFkB, and inhibition by certain nonsteroidal anti-inflammatory drugs.  Eicosanoids  and Other Bioactive Lipids in Cancer, Inflammation and Radiation Injuries. Advances in Experimental Medicine and Biology 57:503-508, 2002
  • Hwang, D.H., Fung, V. And Dannenberg, A.J.  National Cancer Institute Workshop on Chemopreventive Properties of Non-steroidal Anti-inflammatory Drugs:  Role of COX-Dependent and –Independent Mechanisms.  Neoplasia 4:1-7, 2002.
  • Bray, G.A., Lovejoy, J.C., Smith, S.R., Delany, J.P., Lefevre, M., Hwang, D.H., Ryan, D. H., York, D.A.  The influence of different fats and fatty acids on obesity, insulin resistance and inflammation.  J. Nutr.   132:2488-2491,2002.
  • Han, J.A., Kim, J.I., Hwang, D.H., Ballou, L.R., Mahale, A., Aaronson, S.A., and Lee, Sam W.  P53 induction of COX-2 attenuates p53-or genotoxic stress-mediated apoptosis EMBO J  21;5635-5644, 2002
  • Lee, J.Y. and Hwang, D.H. Docosahexaenoic acid suppresses the activity of peroxisome proliferator-activated receptors in a colon tumor cell line. Biochim Biophys Res Comm. 298:667-674, 200
  • Gao, Z., Hwang, D.H., Bataille, F.,  Michael, L., York, D., Quon, M. J., and Ye, J.  Serine phosphorylation of insulin receptor substrate 1(IRS-1) by inhibitor Kappa B kinase(IKK) complex. J. Biol. Chem.  277:48115-48121, 2002
  • Lee, J. Y., Plakidas, A., Lee, W. H., Heikkinen, A., Chanmugam, P., Bray, B., and Hwang, D. H.. Differential modulation of toll-like receptors by fatty acids--Preferential inhibition by n-3 polyunsaturated fatty acids. J. Lipid. Res. 44(3), 479-486, 2003.
  • Lee, J.Y., Ye, J., Gao, Z., Youn, H.S., Lee, W.H., Zhao, L., Sizemore, N., and Hwang, D.H. Reciprocal Modulation of Toll-like Receptor-4 Signaling Pathways Involving MyD88 and Phosphatidylinositol 3-Kinase/AKT by Saturated and Polyunsaturated Fatty Acids. J Biol Chem 278, 37041-37051, 2003.
  • Lee, J.Y., Zhao, L., Youn, H.S., Weatherill, A.R., Tapping, R., Feng, L., Lee, W.H., Fitzgerald, K.A., and Hwang, D.H. (2004) Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem 279:16971-16979, 2004.
  • Gao, Z., Xiaoying Zhang, Amir Zuberi, Daniel Hwang, Michaerl J. Quon, Michael Lefevre, and Jianping Ye. Inhibition  of Insulin Sensitivity by Free Fatty Acids Requires Activation of Multiple Serine Kinases in 3T3-L1 Adipocytes. , Mol Endocrinol 18:2024-2034,2004.
  • Weatherill, A. R., Lee, Joo-Young, Zhao, Ling, Lemay, D.G., Hwang, D. H. Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through Toll-like receptors. J  Immunology 174:5390-7, 2005.
  • Hyung S. Youn, Joo Y. Lee, Katherine A. Fitzgerald, Howard A. Young ,   Shizuo Akira, and Daniel H. Hwang. Specific inhibition of MyD88-independent signaling pathways of Toll‑like receptor 3 and 4 by resveratrol:molecular targets are TBK1 and RIP1 in TRIF complex. J Immunology 175:3339-3346, 2005.
  • Lee, J.Y. Lowell,C.A., Young, H.A., Lemay,D., Youn,H.S., Rhee, S.H., Sohn, K.H., Jang, B., Ye,J., Chung, J.H.,and Daniel H. Hwang. The suppression of inducible nitric oxide synthase expression by Src kinase inhibitors mediated through MyD88-independent signaling pathways of Toll‑like receptor 4. Biochem Pharmacol 70:1231-1240, 2005.
  • Lee, J.Y., and Daniel H. Hwang. The Modulation of Inflammatory Gene Expression by Lipids: Mediation through Toll-like Receptors. Molecules and Cells 21:174-185, 2006.
  • Sung Y.M., He, G, Hwang, D.H., and Fischer, S.M. Overexpression of the prostaglandin E2 receptor EP2 results in enhanced  skin tumor development. Oncogene 25:5507- 5516, 2006.
  • Lemay, D. and Hwang. D.H. Genome-wide identification of peroxisome proliferator  response elements using  integrated computational genomics.   J Lipid Res 47:1583- 1587, 2006 (highlighted in the cover page). 
  • Youn, H.S., Saitoh,S.I., Miyake,K., and Hwang,D.H. Inhibition of homodimerization of Toll-like receptor 4 by  curcumin. Biochem Pharmacol 72:62-69, 2006.
  • Youn, H.S. Lee,J.Y., Saitoh, S.I., Miyake,K., and Daniel H. Hwang.  Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4.  Biochem Biophys Res Commun  350:866-877, 2006.
  • Youn, H.S., Lee, J.Y., Saitoh,S.I., Miyake, K., Kang, K.W., Choi,Y.J., and Hwang, D.H. Suppression of MyD88- and TRIF-dependent signaling pathways of Toll-like receptor by (-)-epigallocatechin-3-gallate, a polyphenol component of green tea. Biochem Pharmacol 72:850-859, 2006.
  • Lee, J.K, Hwang, D.H and Lee, J.Y. Toll-like receptors in the pathogenesis of  inflammatory diseases. J. Organ Dysfunction  3: 1-10, 2007.
  • Zhao L, Kwon MJ, Huang S, Lee JY, Fukase K, Inohara N, and Hwang DH.  Differential Modulation of Nods Signaling Pathways by Fatty Acids in Human Colonic Epithelial HCT116 Cells.  J. Biol Chem. 282:11618-28,2007.
  • Youn, H., Lim, H., Lee, H., Hwang, D.H., Yang, M., Jeon, R., Ryu, J. 2008. Garlic (Allium sativum) Eextracts inhibits Lipopolysaccharide-Induced Toll-Like Receptor 4 Dimerization.  Bioscience Biotechnology and   Biochemistry 72:368-375, 2008.
  • Youn,H.S., Lee,J.K., Choi,Y.J., Saitoh,S.I., Miyake,K., Hwang,D.H., and  Lee, J.Y. Cinnamaldehyde suppresses toll-like receptor 4 activation mediated through the inhibition of receptor oligomerization. Biochem Pharmacol 75:494-502, 2008.  
  • Zhao, L, Lee, JY, and Hwang, DH. The Phosphatidylinositol 3- Kinase/Akt Pathway Negatively Regulates Nod2-Mediated NF-kappaB Pathway. Biochemical Pharmacol 75:1515-1525, 2008.
  • Jeon-Soo Lee, Joo Young Lee, Mi Young Lee, Daniel H. Hwang and  Hyung Sun Youn. Acrolein with an alpha, beta-unsaturated Carbonyl  Group Inhibits LPS-induced Homodimerization of Toll-like Receptor 4. Molecules and Cells 2:253-257, 2008.
  • Huang, S., Zhao,L.,Kim, K., Lee, D.S. and Hwang. D. H. Inhibition of Nod2 signaling and target gene expression by curcumin.  Molecular Pharmacol 74:274-281, 2008.
  • Dasu, M.R., Devaraj, S., Zhao,L., Hwang,D.H.,and Jialal, I.  High glucose induces Toll- like receptor expression in human monocytes: mechanism of action. Diabetes 57:3090-3098, 2008.
  • Lee, J.K., Kim, S.Y., Kim, Y.S., Lee,W.H., Hwang, D.H., and Lee,J.Y. . Suppression of the TRIF-dependent signaling pathway of Toll-like receptors by luteolin. Biochem Pharmacol  77:1391-1400,  2009.
  • Adams,S.H., Hoppel,C.L., Lok, K.H., Zhao, L., Wong, S., Minkler, P.E., Hwang,D.H., Newman,J.W., and Garvey,W.T. Plasma Acylcarnitine Profiles Suggest Incomplete Long Chain Fatty Acid β-Oxidation and Altered TCA Cycle Activity in Type 2 Diabetes. J. Nutrition 139:1073-1081, 2009.
  • Wong,S.W., Kwon,M.J., Choi,A.M.K., Kim, H.P., Nakahira,K., and Hwang, D.H. Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts. J Biol Chem 284:27384-27392, 2009.
  • Hwang, D.H., Ogawa, Y., Schaeffler, A. Saturated fatty acid-induced activation of  Toll- like receptors (TLRs) is  fatty acid-specific effect. Letter to the Editor, Arteriosclerosis Thrombosis, and Vascular Biology (online publication, October 23, 2009).
  • Youn, H.S., Kim,Y.S., Park,Z.Y., Kim,S.Y., Choi,N.Y., Joung,S.M., Seo,J.A., Lim, K.M., Kwak,M.K., Hwang,  D.H., and Lee, J.Y.. Sulforaphane  suppresses oligomerization of TLR4 in a thiol-dependent manner. J. Immunology 184:411-419, 2010.
  • Lee,J.Y., Zhao, L., and Hwang, D.H. Modulation of pattern recognition receptor- mediated inflammation and risk of chronic diseases by dietary fatty acids. Nutr Rev 68:38-61, 2010 (invited review).