Daniel Hwang is a Research Molecular Biologist at the Western Human Nutrition Research Center (WHNRC) and adjunct professor at the Department of Nutrition, UC Davis. Dr. Hwang obtained his B.S. degree in Pharmacy (1967) and Masters in Public Health (1969) from SeoulNationalUniversity. He earned his Ph.D. degree in nutrition from ColoradoStateUniversity(1974). From 1974 to 1977, he was a postdoctoral fellow at CornellUniversity. In 1978, he joined faculty as an assistant professor in Human Nutrition at LouisianaStateUniversity. He moved to the Pennington Biomedical Research Center, Louisiana State University(1988), and was named as John S, McIlhenny professor(2000), and received the Osborne Mendel Award from the American Society for Nutrition (2011). He served as NIH study section member (1994-1998), and editorial board member for the Journal of Biological Chemistry (2004-2006).
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. Currently, Dr. Hwang's group is conducting translation studies to understand how postprandial inflammation is modulated by the different types of food using a single meal experimental design.
•• Proposed the conceptual framework for the mechanism by which fatty acids modulate receptor-mediated signaling pathways and the expression of target genes (Am. J. Clin. Nutr. 70:545, 1999; Ann. Rev. Nutr. 20:431, 2000).
•• Demonstrated that NFkB transcription factor is the required component in the signaling pathways leading to the production of the inducible cyclooxygenase (COX-2) (Biochem Pharmacol 54:87, 1997; J Biol Chem 275:34035, 2000). Cyclooxygenase is the key enzyme responsible for the production of prostanoids in the body, and is over-produced in tumor and inflammatory tissues. Inhibiting this enzyme to suppress the production of prostanoids by non-steroidal anti-inflammatory drugs reduces the risk of cancer and other inflammatory diseases. This suggests that dietary factors that can inhibit the expression of cyclooxygenase should give similar beneficial effects.
•• Demonstrated for the first time that saturated fatty acids stimulate, but polyunsaturated fatty acids (PUFAs), particularly n-3 PUFAs, inhibit Toll-like receptor (TLR) signaling pathways and the expression of target genes including COX-2 (J Biol. Chem 2001, 2003; J Lipid Res. 2005; J Biol. Chem 2004). This finding provided a conceptual foundation that dietary fatty acids can differentially modulate TLR-mediated inflammation and consequent chronic diseases. Studies by many other investigators have verified that dietary saturated fatty acids can activate TLR4 and lead to the induction of insulin resistance using TLR4 knockout or mutant mice.
•• Demonstrated that saturated and n-3 PUFAs reciprocally modulate dendritic cell functions and T-lymphocyte activation as a functional consequence of reciprocal modulation of TLR-signaling pathways and target gene expression (J Immunology 2005).
•• Demonstrated 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 reciprocally modulated by saturated and n-3 PUFAs (J. Biol. Chem 2007).
•• Demonstrated that saturated fatty acid lauric acid induces dimerization and recruitment of TLR4 into lipid rafts in a reactive oxygen species-dependent manner, whereas, n-3 polyunsaturated fatty acid docosahexaenoic acid inhibits the processes (J BIol Chem 2009).
•• Elucidated the mechanism by which saturated fatty acids activate TLR2 and induce inflammasome-mediated IL-1? release in human monocytes. Palmitic acid induces the dimerization of TLR2 with TLR1 as determined by the time resolved-fluorescence resonance energy transfer assay (J Immunology 2013).
•• In a translation study with human volunteers, it was demonstrated that the concentration of plasma free fatty acids is one of the major determinants affecting the plasma concentration of proinflammatory cytokines (target gene products of TLRs) after a moderately high fat meal (manuscript submitted).
These findings define a new paradigm in understanding the mechanism by which dietary fatty acids and certain plant polyphenols differentially modify risks of many chronic diseases, and implicate a new dietary strategy to delay the progression of inflammatory chronic disease resulting from dysregulated activation of pattern recognition receptors.
Kikumi D. Ono-Moore, Ryan G. Snodgrass, Shurong Huang, Shamsher Singh, Tammy L. Freytag, Dustin J. Burnett, Ellen L. Bonnel, Leslie R. Woodhouse, Susan J. Zunino, Joo Young Lee, John C. Rutledge, and Daniel H. Hwang. Postprandial Inflammatory Responses and Plasma Free Fatty Acids: Effects of Blueberry Intake (submitted)
Rutkowsky JM, Knotts TA, Ono-Moore KD, McCoin CS, Huang S, Schneider D, Singh S, Adams SH, Hwang DH. Acylcarnitines activate proinflammatory signaling pathways. Am J Physiol Endocrinol Metab. 2014; 306(12):E1378-87.
Snodgrass RG, Huang S, Choi IW, Rutledge JC, Hwang DH. Inflammasome-mediated secretion of IL-1? in human monocytes through TLR2 activation; modulation by dietary fatty acids. J Immunol. 2013; 191(8):4337-47.
Huang S, Rutkowsky JM, Snodgrass RG, Ono-Moore KD, Schneider DA, Newman JW, Adams SH, Hwang DH. Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J Lipid Res. 2012; 53(9):2002-13.
Dawson K, Zhao L, Adkins Y, Vemuri M, Rodriguez RL, Gregg JP, Kelley DS, Hwang DH. Modulation of blood cell gene expression by DHA supplementation in hypertriglyceridemic men. J Nutr Biochem. 2012; 23(6):616-21.
Zhao L, Hu P, Zhou Y, Purohit J, Hwang D. NOD1 activation induces proinflammatory gene expression and insulin resistance in 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab. 2011; 301(4):E587-98. (Highlighted by Editorial Focus, July 19, 2011) .
Zhao L, Lee JY, Hwang DH. Inhibition of pattern recognition receptor-mediated inflammation by bioactive phytochemicals: A review of recent research. (in press, Epub, July 18, 2011, J Nutritional Biochem).
Lee JY, Zhao L, Hwang DH. Modulation of pattern recognition receptor-mediated inflammation and risk of chronic diseases by dietary fatty acids. Nutr Rev. 2010; 68: 38-61.
Youn HS, Kim YS, Park ZY, Kim SY, Choi NY, Joung SM, Seo JA, Lim KM, Kwak MK, Hwang DH, Lee JY. Sulforaphane suppresses oligomerization of tlr4 in a thiol-dependent manner. J Immunol. 2010; 184: 411-9.
Hwang DH, Ogawa Y, Schaeffler A. A staturated fatty acid-induced activation of toll-like receptors is fatty acid-specific effect. Arteriosclerosis, Thrombosis, and Vascular Biology (online puplication, October 23, 2009). 2009.
Wong SW, Kwon MJ, Choi AM, Kim HP, Nakahira K, Hwang DH. Fatty acids modulate toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J Biol Chem. 2009; 284: 27384-92.
Adams SH, Hoppel CL, Lok KH, Zhao L, Wong SW, Minkler PE, Hwang DH, Newman JW, Garvey WT. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic african-american women. J Nutr. 2009; 139: 1073-81.
Lee JK, Kim SY, Kim YS, Lee WH, Hwang DH, Lee JY. Suppression of the trif-dependent signaling pathway of toll-like receptors by luteolin. Biochem Pharmacol. 2009; 77: 1391-400.
Dasu MR, Devaraj S, Zhao L, Hwang DH, Jialal I. High glucose induces toll-like receptor expression in human monocytes: Mechanism of activation. Diabetes. 2008; 57: 3090-8.
Huang S, Zhao L, Kim K, Lee DS, Hwang DH. Inhibition of nod2 signaling and target gene expression by curcumin. Mol Pharmacol. 2008; 74: 274-81.
Zhao L, Lee JY, Hwang DH. The phosphatidylinositol 3-kinase/akt pathway negatively regulates nod2-mediated nf-kappab pathway. Biochem Pharmacol. 2008; 75: 1515-25.
Youn HS, Lee JK, Choi YJ, Saitoh SI, Miyake K, Hwang DH, Lee JY. Cinnamaldehyde suppresses toll-like receptor 4 activation mediated through the inhibition of receptor oligomerization. Biochem Pharmacol. 2008; 75: 494-502.
Youn HS, Lim HJ, Lee HJ, Hwang D, Yang M, Jeon R, Ryu JH. Garlic (allium sativum) extract inhibits lipopolysaccharide-induced toll-like receptor 4 dimerization. Biosci Biotechnol Biochem. 2008; 72: 368-75.
Zhao L, Kwon MJ, Huang S, Lee JY, Fukase K, Inohara N, Hwang DH. Differential modulation of nods signaling pathways by fatty acids in human colonic epithelial hct116 cells. J Biol Chem. 2007; 282: 11618-28.
Lee JK, Hwang DH, Lee JY. Toll-like receptors in the pathogenesis of inflammatory diseases. Journal of Organ Dysfunction. 2009; 5: 119 - 28.
Youn HS, Lee JY, Saitoh SI, Miyake K, Kang KW, Choi YJ, Hwang DH. Suppression of myd88- and trif-dependent signaling pathways of toll-like receptor by (-)-epigallocatechin-3-gallate, a polyphenol component of green tea. Biochem Pharmacol. 2006; 72: 850-9.
Youn HS, Lee JY, Saitoh SI, Miyake K, Hwang DH. Auranofin, as an anti-rheumatic gold compound, suppresses lps-induced homodimerization of tlr4. Biochem Biophys Res Commun. 2006; 350: 866-71.
Youn HS, Saitoh SI, Miyake K, Hwang DH. Inhibition of homodimerization of toll-like receptor 4 by curcumin. Biochem Pharmacol. 2006; 72: 62-9.
Lemay DG, Hwang DH. Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics. J Lipid Res. 2006; 47: 1583-7.
Sung YM, He G, Hwang DH, Fischer SM. Overexpression of the prostaglandin e2 receptor ep2 results in enhanced skin tumor development. Oncogene. 2006; 25: 5507-16.
Lee JY, Hwang DH. The modulation of inflammatory gene expression by lipids: Mediation through toll-like receptors. Mol Cells. 2006; 21: 174-85.
Lee JYL, C.A., Young, H.A., Lemay,D., Youn,H.S., Rhee, S.H., Sohn, K.H., Jang, B., Ye,J., Chung, J.H., 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 2005; 70: 1231-40.
Youn HS, Lee JY, Fitzgerald KA, Young HA, Akira S, Hwang DH. Specific inhibition of myd88-independent signaling pathways of tlr3 and tlr4 by resveratrol: Molecular targets are tbk1 and rip1 in trif complex. J Immunol. 2005; 175: 3339-46.
WeatherillAR, Lee JY, Zhao L, Lemay DG, Youn HS, Hwang DH. Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through tlr4. J Immunol. 2005; 174: 5390-7.
Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3t3-l1 adipocytes. Mol Endocrinol. 2004; 18: 2024-34.
Lee JY, Zhao L, Youn HS, WeatherillAR, Tapping R, Feng L, Lee WH, Fitzgerald KA, Hwang DH. Saturated fatty acid activates but polyunsaturated fatty acid inhibits toll-like receptor 2 dimerized with toll-like receptor 6 or 1. J Biol Chem. 2004; 279: 16971-9.
Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, Sizemore N, Hwang DH. 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. 2003; 278: 37041-51.
Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G, Hwang DH. Differential modulation of toll-like receptors by fatty acids: Preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res. 2003; 44: 479-86.
Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa b kinase complex. J Biol Chem. 2002; 277: 48115-21.
Lee JY, Hwang DH. Docosahexaenoic acid suppresses the activity of peroxisome proliferator-activated receptors in a colon tumor cell line. Biochem Biophys Res Commun. 2002; 298: 667-74.
Han JA, Kim JI, Ongusaha PP, Hwang DH, Ballou LR, Mahale A, Aaronson SA, Lee SW. P53-mediated induction of cox-2 counteracts p53- or genotoxic stress-induced apoptosis. EMBO J. 2002; 21: 5635-44.
Bray GA, Lovejoy JC, Smith SR, DeLany JP, Lefevre M, Hwang D, Ryan DH, York DA. The influence of different fats and fatty acids on obesity, insulin resistance and inflammation. J Nutr. 2002; 132: 2488-91.
Hwang DH, Fung V, Dannenberg AJ. National cancer institute workshop on chemopreventive properties of nonsteroidal anti-inflammatory drugs: Role of cox-dependent and -independent mechanisms. Neoplasia. 2002; 4: 91-7.
Paik JH, Lee JY, 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 2002; 57: 503-08.
Hwang D. Modulation of the expression of cyclooxygenase-2 by fatty acids mediated through toll-like receptor 4-derived signaling pathways. FASEB J. 2001; 15: 2556-64.
Lee JY, Sohn KH, Rhee SH, Hwang D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through toll-like receptor 4. J Biol Chem. 2001; 276: 16683-9.
Boudreau MD, Sohn KH, Rhee SH, Lee SW, Hunt JD, Hwang DH. 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. 2001; 61: 1386-91.
Hwang D. Fatty acids and immune responses--a new perspective in searching for clues to mechanism. Annu Rev Nutr. 2000; 20: 431-56.
Rhee SH, Hwang D. Murine toll-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of nf kappa b and expression of the inducible cyclooxygenase. J Biol Chem. 2000; 275: 34035-40.
Lefevre M, Lovejoy JC, DeFelice SM, Keener JW, BrayGA, Ryan DH, Hwang DH, Greenway FL. Common apolipoprotein a-iv variants are associated with differences in body mass index levels and percentage body fat. Int J Obes Relat Metab Disord. 2000; 24: 945-53.
Paik JH, Ju JH, Lee JY, Boudreau MD, Hwang DH. Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase. Mediation through different signaling pathways. J Biol Chem. 2000; 275: 28173-9.
Hwang D, Chanmugam P, Boudreau M, Sohn KH, Stone K, Pryor WA. Activation and inactivation of cyclo-oxygenase in rat alveolar macrophages by aqueous cigarette tar extracts. Free Radic Biol Med. 1999; 27: 673-82.
Hwang D, Rhee SH. Receptor-mediated signaling pathways: Potential targets of modulation by dietary fatty acids. Am J Clin Nutr. 1999; 70: 545-56.
Hwang D, Scollard D, Byrne J, Levine E. Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J Natl Cancer Inst. 1998; 90: 455-60.
Wu D, Mura C, Beharka AA, Han SN, Paulson KE, Hwang D, Meydani SN. Age-associated increase in pge2 synthesis and cox activity in murine macrophages is reversed by vitamin e. Am J Physiol. 1998; 275: C661-8.
Hayek MG, Mura C, Wu D, Beharka AA, Han SN, Paulson KE, Hwang D, Meydani SN. Enhanced expression of inducible cyclooxygenase with age in murine macrophages. J Immunol. 1997; 159: 2445-51.
Adams LB, Gillis TP, Hwang DH, Krahenbuhl JL. Effects of essential fatty acid deficiency on prostaglandin e2 production and cell-mediated immunity in a mouse model of leprosy. Infect Immun. 1997; 65: 1152-7.
Hwang DH, Chanmugam PS, Ryan DH, Boudreau MD, Windhauser MM, Tulley RT, Brooks ER, Bray GA. Does vegetable oil attenuate the beneficial effects of fish oil in reducing risk factors for cardiovascular disease? Am J Clin Nutr. 1997; 66: 89-96.
Hwang D, JangBC, Yu G, Boudreau M. Expression of mitogen-inducible cyclooxygenase induced by lipopolysaccharide: Mediation through both mitogen-activated protein kinase and nf-kappab signaling pathways in macrophages. Biochem Pharmacol. 1997; 54: 87-96.
Feng L, JangBC, 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. 1997; 407: 281-8.
Hwang D, Fischer NH, Jang BC, Tak H, Kim JK, Lee W. 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 Commun. 1996; 226: 810-8.
Feng L, Xia Y, Garcia GE, Hwang D, Wilson CB. Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-alpha, and lipopolysaccharide. J Clin Invest. 1995; 95: 1669-75.
Chanmugam P, Feng L, Liou S, Jang BC, Boudreau M, Yu G, Lee JH, Kwon HJ, Beppu T, Yoshida M, et al. 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. 1995; 270: 5418-26.
Jacobs AL, Hwang D, Julian J, Carson DD. Regulated expression of prostaglandin endoperoxide synthase-2 by uterine stroma. Endocrinology. 1994; 135: 1807-15.
Feng L, Sun W, Xia Y, Tang WW, Chanmugam P, Soyoola E, Wilson CB, Hwang D. Cloning two isoforms of rat cyclooxygenase: Differential regulation of their expression. Arch Biochem Biophys. 1993; 307: 361-8.
Lee SH, Soyoola E, Chanmugam P, Hart S, Sun W, Zhong H, Liou S, Simmons D, Hwang D. Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. J Biol Chem. 1992; 267: 25934-8.