UCDavis University of California

Education

• B.S., Pharmacy, Seoul National University
• MPH, Public Health, Seoul National University
• Ph.D. degree in nutrition from Colorado State University

Research Interests

The overall goal of Dr. Hwang´s research is to elucidate molecular mechanisms by which different types of dietary fatty acids modify risks of chronic diseases. Dr. Hwang has been investigating how different dietary fatty acids modulate receptor-mediated signaling pathways, target gene expression, and subsequent cellular responses. Further aim is to determine how this modulation is related to risks of developing chronic diseases.

Growing evidence now suggests that fatty acids, in addition to their roles as structural components of membrane lipids and as precursors of eicosanoids, can act as second messengers or regulators of signal transducing molecules. The modulatory roles of dietary fatty acids on immune responses are understood largely based on experimental observations demonstrating the cause and effect relationship. However, molecular mechanisms by which fatty acids regulate immune and inflammatory responses are not well understood.

Results from Dr. Hwang's recent studies demonstrated that saturated fatty acids activate NFkB and the expression of mitogen inducible cyclooxygenase (COX-2) in macrophages. However, all unsaturated fatty acids tested inhibit NFkB activation and COX-2 expression induced by saturated fatty acids or bacterial lipopolysaccharide (LPS). Furthermore, this modulation by fatty acids is mediated through toll-like receptors (TLR)-derived signaling pathways. Toll-like receptors play a critical role in the induction of inflammatory and immune responses against pathogen associated molecular patterns.

These results document a novel mechanism by which fatty acids modulate the expression of COX-2 and further suggest that TLR-mediated signaling pathways, target gene expressions, and subsequent inflammatory and immune responses can be differentially modulated by the types of dietary fatty acids consumed. Since inflammation is considered as an important risk for many chronic diseases, these results suggest the possibility that beneficial or detrimental effects of different types of dietary fatty acids on the risk of the development of many chronic inflammatory diseases are in part mediated through the modulation of TLRs.

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 NF?B 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. Signaling pathways for the expression of cyclooxygenase-potential targets of modulation by nutrient. FASEB J. 15:2556-2564, 2001.
• Paik, J.H., Lee, J.Y., and Hwang, D. Signaling pathways for TNF?-induced COX-2 expression: mediation through MAP kinases and NF?B, 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, 2002
• 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
• Zhanguo Gao, 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
• Joo Y. Lee, Clifford A. Lowell, Howard A. Young, Danielle Lemay, Hyung S. Youn, Sang H. Rhee, Kyung H. Sohn, Byeong Jang, Jianping Ye, jin h. Chung 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
• Joo Y. Lee 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 YM, He, G, Hwang DH and Fischer SM. Overexpression of the prostaglandin E2 receptor EP2 results in enhanced skin tumor development. Oncogene 25:5507-5516, 2006
• Danielle Lemay and Daniel Hwang. Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics. J Lipid Res 47:1583-1587, 2006 (highlighted in the cover page)
• Hyung S. Youn, Shin I. Saitoh, Kensuke Miyake, and Daniel H. Hwang. Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem Pharmacol 72:62-69, 2006
• Hyung S. Youn, Joo Y. Lee, Shin I. Saitoh, Kensuke Miyake, 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
• Hyung S. Youn, Joo Y. Lee, Shin I. Saitoh, Kensuke Miyake, Keon W. Kang, Yong J. Choi, and Daniel H. Hwang. 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
• 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