- (859) 218-1705 (Office)
- (859) 217-1798 (Lab)
- (859) 257-3235 (Fax)
- Saha Cardiovascular Research Center
- 741 South Limestone
- BBSRB B251
- Lexington, KY 40536-0509
- 1990. 3-1996. 2: B.S. & M.S. College of Pharmacy, Seoul National University, Seoul, South Korea.
- 2000. 8-2002. 7: Graduate coursework for Ph.D. of Pharmacology, University of Missouri School of Medicine, Columbia, MO.
- 2002. 8-2006. 5: Ph.D. of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA.
- 2006. 5-2011. 8: Postdoctoral Fellow, Pathology & Laboratory Medicine, Human Genetics, UCLA School of Medicine, Los Angeles, CA.
- 2011. 9-2013. 5: Assistant Researcher, Department of Pathology & Laboratory Medicine, UCLA School of Medicine, Los Angeles, CA.
- 2013. 6-present: Assistant Professor (Regular Title, Tenure-Track), Saha Cardiovascular Research Center, Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, KY.
The elevation of apoB-containing lipoproteins (VLDL and LDL) in the bloodstream is a risk factor for the development of atherosclerosis. My first research goal is to identify the mechanism of the development of hyperlipidemia and hypertriglyceridemia-associated cardiovascular diseases and find therapeutic targets to prevent or delay the progress of the conditions. Hyperlipidemia-induced oxidative stress and the accumulation of oxidized phospholipids in the vessel wall are critical events for the development of chronic inflammatory diseases like atherosclerosis and aneurysm. These vascular diseases are accompanied by proinflammatory cytokine overexpression and infiltration of monocytes and macrophages into the vessel wall. Oxidized phospholipids, as represented by Ox-PAPC, strongly activate vascular endothelial cells for the expression of proinflammatory and prothrombotic gene expressions. First, we test the hypothesis that the oxidized phospholipids employ both receptor and non-receptor cytosolic signaling and epigenetic modification for the induction of proinflammatory and prothrombotic gene expressions in the vascular endothelial cells. For the study, we employ in vitro vascular endothelial cell system and in vivo mouse hyperlipidemic model systems (LDLR or ApoE null) with biochemical and (epi)genetics approaches to find a key regulatory pathway and pharmacological target.
Obesity is a key risk factor for the development of metabolic syndrome including insulin resistance, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD). As a second lab project, we study the role of hepatic heparin-binding epidermal growth factor-like growth factor (HB-EGF) signaling in regulating the hepatic in the metabolic syndrome development. We mainly focus on the function of the HB-EGF expressed on the liver sinusoidal endothelial cells (LSECs) in the regulation of the VLDL production in the neighbor hepatocytes and induction of inflammatory cell accumulation in the liver tissue. We also study the HB-EGF role in the activation of the hepatic stellate cells, which produce fibrosis phenotypes in the development of the non-alcoholic steatohepatitis (NASH). The expression of HB-EGF was upregulated in the adipose tissues under obesity, and the factor is a representative mediator for the sustained EGFR transactivation under various stress-inducing factors like lipid peroxidation products in the tissue of oxidative stress. We hypothesize that the HB-EGF signaling in the LSECs is an unappreciated regulator of hepatic lipoprotein (VLDL) production/secretion and a potential target for lipid-lowering in circulation and hepatic inflammation. In a preliminary study, the HB-EGF targeting antisense oligonucleotide (ASO), which is mainly distributed in the LSECs, showed a remarkable suppression of circulatory triglyceride and cholesterol and the development of atherosclerosis and aneurysm in the vascular wall. We also newly observed that the HB-EGF targeting improved insulin sensitivity in the obese mouse model. In further studies, we will identify the cellular and molecular mechanism of HB-EGF signaling for the increase of assembly/secretion of VLDL in the liver and evaluate the HB-EGF targeting to prevent metabolic syndrome phenotypes. We employ liver- and adipose-specific HB-EGF knockout mouse systems and liver cell system for this study. We also test the effects of HB-EGF signaling and targeting in the development and progress of phenotypes of fatty liver disease and hepatic inflammation.
American Heart Association, 17GRNT33700302 (PI: Sangderk Lee) 07/2017-06/2019
Deciphering the regulatory mechanism of hepatic VLDL production by heparin-binding EGF-like growth factor (HB-EGF).
Heparin-binding EGF-like growth factor (HB-EGF) antisense oligonucleotide protected against hyperlipidemia-associated atherosclerosis.
Kim S, Graham MJ, Lee RG, Yang L, Kim S, Subramanian V, Layne JD, Cai L, Temel RE, Shih D, Lusis AJ, Berliner JA, Lee S.
Nutr Metab Cardiovasc Dis. 2019 Mar;29(3):306-315. doi: 10.1016/j.numecd.2018.12.006. Epub 2019 Jan 9.
Targeting hepatic heparin-binding EGF-like growth factor (HB-EGF) induces anti-hyperlipidemia leading to reduction of angiotensin II-induced aneurysm development.
Kim S, Yang L, Kim S, Lee RG, Graham MJ, Berliner JA, Lusis AJ, Cai L, Temel RE, Rateri DL, Lee S.
PLoS One. 2017 Aug 9;12(8):e0182566. doi: 10.1371/journal.pone.0182566. eCollection 2017.
Fatty acid epoxyisoprostane E2 stimulates an oxidative stress response in endothelial cells.
Yan X, Lee S, Gugiu BG, Koroniak L, Jung ME, Berliner J, Cheng J, Li R.
Biochem Biophys Res Commun. 2014 Jan 31;444(1):69-74. doi: 10.1016/j.bbrc.2014.01.016. Epub 2014 Jan 14.
An epoxyisoprostane is a major regulator of endothelial cell function.
Zhong W, Springstead JR, Al-Mubarak R, Lee S, Li R, Emert B, Berliner JA, Jung ME.
J Med Chem. 2013 Nov 14;56(21):8521-32. doi: 10.1021/jm400959q. Epub 2013 Oct 31.
Role of phospholipid oxidation products in atherosclerosis.
Lee S, Birukov KG, Romanoski CE, Springstead JR, Lusis AJ, Berliner JA.
Circ Res. 2012 Aug 31;111(6):778-99. doi: 10.1161/CIRCRESAHA.111.256859. Review.
Evidence for the importance of OxPAPC interaction with cysteines in regulating endothelial cell function.
Springstead JR, Gugiu BG, Lee S, Cha S, Watson AD, Berliner JA.
J Lipid Res. 2012 Jul;53(7):1304-15. doi: 10.1194/jlr.M025320. Epub 2012 May 1.
Metalloproteinase processing of HBEGF is a proximal event in the response of human aortic endothelial cells to oxidized phospholipids.
Lee S, Springstead JR, Parks BW, Romanoski CE, Palvolgyi R, Ho T, Nguyen P, Lusis AJ, Berliner JA.
Arterioscler Thromb Vasc Biol. 2012 May;32(5):1246-54. doi: 10.1161/ATVBAHA.111.241257. Epub 2012 Mar 8.
A role for VEGFR2 activation in endothelial responses caused by barrier disruptive OxPAPC concentrations.
Birukova AA, Lee S, Starosta V, Wu T, Ho T, Kim J, Berliner JA, Birukov KG.
PLoS One. 2012;7(1):e30957. doi: 10.1371/journal.pone.0030957. Epub 2012 Jan 31.
Paraoxonase-2 modulates stress response of endothelial cells to oxidized phospholipids and a bacterial quorum-sensing molecule.
Kim JB, Xia YR, Romanoski CE, Lee S, Meng Y, Shi YS, Bourquard N, Gong KW, Port Z, Grijalva V, Reddy ST, Berliner JA, Lusis AJ, Shih DM.
Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2624-33. doi: 10.1161/ATVBAHA.111.232827.
Network for activation of human endothelial cells by oxidized phospholipids: a critical role of heme oxygenase 1.
Romanoski CE, Che N, Yin F, Mai N, Pouldar D, Civelek M, Pan C, Lee S, Vakili L, Yang WP, Kayne P, Mungrue IN, Araujo JA, Berliner JA, Lusis AJ.
Circ Res. 2011 Aug 19;109(5):e27-41. doi: 10.1161/CIRCRESAHA.111.241869. Epub 2011 Jul 7.
Systems genetics analysis of gene-by-environment interactions in human cells.
Romanoski CE, Lee S, Kim MJ, Ingram-Drake L, Plaisier CL, Yordanova R, Tilford C, Guan B, He A, Gargalovic PS, Kirchgessner TG, Berliner JA, Lusis AJ.
Am J Hum Genet. 2010 Mar 12;86(3):399-410. doi: 10.1016/j.ajhg.2010.02.002. Epub 2010 Feb 18.
A role for NADPH oxidase 4 in the activation of vascular endothelial cells by oxidized phospholipids.
Lee S, Gharavi NM, Honda H, Chang I, Kim B, Jen N, Li R, Zimman A, Berliner JA.
Free Radic Biol Med. 2009 Jul 15;47(2):145-51. doi: 10.1016/j.freeradbiomed.2009.04.013. Epub 2009 Apr 16.
Ox-PAPC activation of PMET system increases expression of heme oxygenase-1 in the human aortic endothelial cell.
Lee S, Li R, Kim B, Palvolgyi R, Ho T, Yang QZ, Xu J, Szeto WL, Honda H, Berliner JA.
J Lipid Res. 2009 Feb;50(2):265-74. doi: 10.1194/jlr.M800317-JLR200. Epub 2008 Aug 29.
Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors.
Cui P, Tomsig JL, McCalmont WF, Lee S, Becker CJ, Lynch KR, Macdonald TL.
Bioorg Med Chem Lett. 2007 Mar 15;17(6):1634-40. Epub 2007 Jan 13.
OKL38 is an oxidative stress response gene stimulated by oxidized phospholipids.
Li R, Chen W, Yanes R, Lee S, Berliner JA.
J Lipid Res. 2007 Mar;48(3):709-15. Epub 2006 Dec 27.
Crystal structure analysis of phosphatidylcholine-GM2-activator product complexes: evidence for hydrolase activity.
Wright CS, Mi LZ, Lee S, Rastinejad F.
Biochemistry. 2005 Oct 18;44(41):13510-21.
Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720.
Kharel Y, Lee S, Snyder AH, Sheasley-O'neill SL, Morris MA, Setiady Y, Zhu R, Zigler MA, Burcin TL, Ley K, Tung KS, Engelhard VH, Macdonald TL, Pearson-White S, Lynch KR.
J Biol Chem. 2005 Nov 4;280(44):36865-72. Epub 2005 Aug 10.
Brown recluse spider (Loxosceles reclusa) venom phospholipase D (PLD) generates lysophosphatidic acid (LPA).
Lee S, Lynch KR.
Biochem J. 2005 Oct 15;391(Pt 2):317-23.
- Kim, S.; Graham, MJ ; Lee, RG ; Yang, L.; Kim, S.; Subramanian, V.; Layne, JD ; Cai, L.; Temel, RE ; Shih, D ; Lusis, AJ ; Berliner, JA ; Lee, S. "Heparin-binding EGF-like growth factor (HB-EGF) antisense oligonucleotide protected against hyperlipidemia-associated atherosclerosis." Nutrition, metabolism, and cardiovascular diseases : NMCD 29, 3 (2019): 306-315. [PubMed Link] | [ Full text ]