Metabolomic analyses for atherosclerosis, diabetes, and obesity

Biomarker Research - Tập 1 Số 1 - 2013
Fuyong Du1, Anthony Virtue1, Hong Wang1, Xiaofeng Yang1
1Department of Pharmacology, Temple University School of Medicine Philadelphia, PA 19140 USA

Tóm tắt

Abstract

Insulin resistance associated with type 2 diabetes mellitus (T2DM), obesity, and atherosclerosis is a global health problem. A portfolio of abnormalities of metabolic and vascular homeostasis accompanies T2DM and obesity, which are believed to conspire to lead to accelerated atherosclerosis and premature death. The complexity of metabolic changes in the diseases presents challenges for a full understanding of the molecular pathways contributing to the development of these diseases. The recent advent of new technologies in this area termed “Metabolomics” may aid in comprehensive metabolic analysis of these diseases. Therefore, metabolomics has been extensively applied to the metabolites of T2DM, obesity, and atherosclerosis not only for the assessment of disease development and prognosis, but also for the biomarker discovery of disease diagnosis. Herein, we summarize the recent applications of metabolomics technology and the generated datasets in the metabolic profiling of these diseases, in particular, the applications of these technologies to these diseases at the cellular, animal models, and human disease levels. In addition, we also extensively discuss the mechanisms linking the metabolic profiling in insulin resistance, T2DM, obesity, and atherosclerosis, with a particular emphasis on potential roles of increased production of reactive oxygen species (ROS) and mitochondria dysfunctions.

Từ khóa


Tài liệu tham khảo

Goodacre R: Metabolic profiling: pathways in discovery. Drug Discov Today 2004, 9: 260–261. 10.1016/S1359-6446(04)03027-2

Goodacre R, Vaidyanathan S, Dunn WB, Harrigan GG, Kell DB: Metabolomics by numbers: acquiring and understanding global metabolite data. Trends Biotechnol 2004, 22: 245–252. 10.1016/j.tibtech.2004.03.007

Oliver SG, Winson MK, Kell DB, Baganz F: Systematic functional analysis of the yeast genome. Trends Biotechnol 1998, 16: 373–378. 10.1016/S0167-7799(98)01214-1

Scarfe GB, Wright B, Clayton E, Taylor S, Wilson ID, Lindon JC, Nicholson JK: 19 F-NMR and directly coupled HPLC-NMR-MS investigations into the metabolism of 2-bromo-4-trifluoromethylaniline in rat: a urinary excretion balance study without the use of radiolabelling. Xenobiotica 1998, 28: 373–388. 10.1080/004982598239489

Lindon JC, Holmes E, Nicholson JK: So what’s the deal with metabonomics? Anal Chem 2003, 75: 384A-391A.

Roberts LD, Souza AL, Gerszten RE, Clish CB: Targeted metabolomics. Curr Protoc Mol Biol 2012., Chapter 30: Unit 30 32 31–24

Wang C, Kong H, Guan Y, Yang J, Gu J, Yang S, Xu G: Plasma phospholipid metabolic profiling and biomarkers of type 2 diabetes mellitus based on high-performance liquid chromatography/electrospray mass spectrometry and multivariate statistical analysis. Anal Chem 2005, 77: 4108–4116. 10.1021/ac0481001

Festa A, Williams K, Hanley AJ, Otvos JD, Goff DC, Wagenknecht LE, Haffner SM: Nuclear magnetic resonance lipoprotein abnormalities in prediabetic subjects in the insulin resistance atherosclerosis study. Circulation 2005, 111: 3465–3472. 10.1161/CIRCULATIONAHA.104.512079

Roberts LD, Murray AJ, Menassa D, Ashmore T, Nicholls AW, Griffin JL: The contrasting roles of PPARdelta and PPARgamma in regulating the metabolic switch between oxidation and storage of fats in white adipose tissue. Genome Biol 2011,12(8):R75. 10.1186/gb-2011-12-8-r75

An J, Muoio DM, Shiota M, Fujimoto Y, Cline GW, Shulman GI, Koves TR, Stevens R, Millington D, Newgard CB: Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat Med 2004, 10: 268–274. 10.1038/nm995

Wakelam MJ, Pettitt TR, Postle AD: Lipidomic analysis of signaling pathways. Methods Enzymol 2007, 432: 233–246.

Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA: A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009, 9: 311–326. 10.1016/j.cmet.2009.02.002

Psychogios N, Hau DD, Peng J, Guo AC, Mandal R, Bouatra S, Sinelnikov I, Krishnamurthy R, Eisner R, Gautam B: The human serum metabolome. PLoS One 2011, 6: e16957. 10.1371/journal.pone.0016957

Atherton HJ, Bailey NJ, Zhang W, Taylor J, Major H, Shockcor J, Clarke K, Griffin JL: A combined 1H-NMR spectroscopy- and mass spectrometry-based metabolomic study of the PPAR-alpha null mutant mouse defines profound systemic changes in metabolism linked to the metabolic syndrome. Physiol Genomics 2006, 27: 178–186. 10.1152/physiolgenomics.00060.2006

Sabatine MS, Liu E, Morrow DA, Heller E, McCarroll R, Wiegand R, Berriz GF, Roth FP, Gerszten RE: Metabolomic identification of novel biomarkers of myocardial ischemia. Circulation 2005, 112: 3868–3875. 10.1161/CIRCULATIONAHA.105.569137

Brindle JT, Antti H, Holmes E, Tranter G, Nicholson JK, Bethell HW, Clarke S, Schofield PM, McKilligin E, Mosedale DE, Grainger DJ: Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nat Med 2002, 8: 1439–1444. 10.1038/nm1202-802

Brindle JT, Nicholson JK, Schofield PM, Grainger DJ, Holmes E: Application of chemometrics to 1H NMR spectroscopic data to investigate a relationship between human serum metabolic profiles and hypertension. Analyst 2003, 128: 32–36. 10.1039/b209155k

Kirschenlohr HL, Griffin JL, Clarke SC, Rhydwen R, Grace AA, Schofield PM, Brindle KM, Metcalfe JC: Proton NMR analysis of plasma is a weak predictor of coronary artery disease. Nat Med 2006, 12: 705–710. 10.1038/nm1432

Martinez-Pinna R, Barbas C, Blanco-Colio LM, Tunon J, Ramos-Mozo P, Lopez JA, Meilhac O, Michel JB, Egido J, Martin-Ventura JL: Proteomic and metabolomic profiles in atherothrombotic vascular disease. Curr Atheroscler Rep 2010, 12: 202–208. 10.1007/s11883-010-0102-y

Teul J, Ruperez FJ, Garcia A, Vaysse J, Balayssac S, Gilard V, Malet-Martino M, Martin-Ventura JL, Blanco-Colio LM, Tunon J: Improving metabolite knowledge in stable atherosclerosis patients by association and correlation of GC-MS and 1H NMR fingerprints. J Proteome Res 2009, 8: 5580–5589. 10.1021/pr900668v

Clish CB, Davidov E, Oresic M, Plasterer TN, Lavine G, Londo T, Meys M, Snell P, Stochaj W, Adourian A: Integrative biological analysis of the APOE*3-leiden transgenic mouse. OMICS 2004, 8: 3–13. 10.1089/153623104773547453

Mayr M, Chung YL, Mayr U, Yin X, Ly L, Troy H, Fredericks S, Hu Y, Griffiths JR, Xu Q: Proteomic and metabolomic analyses of atherosclerotic vessels from apolipoprotein E-deficient mice reveal alterations in inflammation, oxidative stress, and energy metabolism. Arterioscler Thromb Vasc Biol 2005, 25: 2135–2142. 10.1161/01.ATV.0000183928.25844.f6

Mayr U, Mayr M, Yin X, Begum S, Tarelli E, Wait R, Xu Q: Proteomic dataset of mouse aortic smooth muscle cells. Proteomics 2005, 5: 4546–4557. 10.1002/pmic.200402045

Kleemann R, Verschuren L, van Erk MJ, Nikolsky Y, Cnubben NH, Verheij ER, Smilde AK, Hendriks HF, Zadelaar S, Smith GJ: Atherosclerosis and liver inflammation induced by increased dietary cholesterol intake: a combined transcriptomics and metabolomics analysis. Genome Biol 2007, 8: R200. 10.1186/gb-2007-8-9-r200

Leo GC, Darrow AL: NMR-based metabolomics of urine for the atherosclerotic mouse model using apolipoprotein-E deficient mice. Magn Reson Chem 2009,47(Suppl 1):S20–25.

Zhang F, Jia Z, Gao P, Kong H, Li X, Chen J, Yang Q, Yin P, Wang J, Lu X: Metabonomics study of atherosclerosis rats by ultra fast liquid chromatography coupled with ion trap-time of flight mass spectrometry. Talanta 2009, 79: 836–844. 10.1016/j.talanta.2009.05.010

Shaham O, Wei R, Wang TJ, Ricciardi C, Lewis GD, Vasan RS, Carr SA, Thadhani R, Gerszten RE, Mootha VK: Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Mol Syst Biol 2008, 4: 214.

Lucio M, Fekete A, Weigert C, Wagele B, Zhao X, Chen J, Fritsche A, Haring HU, Schleicher ED, Xu G: Insulin sensitivity is reflected by characteristic metabolic fingerprints--a Fourier transform mass spectrometric non-targeted metabolomics approach. PLoS One 2010, 5: e13317. 10.1371/journal.pone.0013317

Lanza IR, Zhang S, Ward LE, Karakelides H, Raftery D, Nair KS: Quantitative metabolomics by H-NMR and LC-MS/MS confirms altered metabolic pathways in diabetes. PLoS One 2010, 5: e10538. 10.1371/journal.pone.0010538

Zhao X, Fritsche J, Wang J, Chen J, Rittig K, Schmitt-Kopplin P, Fritsche A, Haring HU, Schleicher ED, Xu G, Lehmann R: Metabonomic fingerprints of fasting plasma and spot urine reveal human pre-diabetic metabolic traits. Metabolomics 2010, 6: 362–374. 10.1007/s11306-010-0203-1

Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS, Jacques PF, Fernandez C: Metabolite profiles and the risk of developing diabetes. Nat Med 2011, 17: 448–453. 10.1038/nm.2307

Han LD, Xia JF, Liang QL, Wang Y, Wang YM, Hu P, Li P, Luo GA: Plasma esterified and non-esterified fatty acids metabolic profiling using gas chromatography-mass spectrometry and its application in the study of diabetic mellitus and diabetic nephropathy. Anal Chim Acta 2011, 689: 85–91. 10.1016/j.aca.2011.01.034

Bonzo JA, Patterson AD, Krausz KW, Gonzalez FJ: Metabolomics identifies novel Hnf1alpha-dependent physiological pathways in vivo. Mol Endocrinol 2010, 24: 2343–2355. 10.1210/me.2010-0130

Li LO, Hu YF, Wang L, Mitchell M, Berger A, Coleman RA: Early hepatic insulin resistance in mice: a metabolomics analysis. Mol Endocrinol 2010, 24: 657–666. 10.1210/me.2009-0152

Huang Q, Yin P, Wang J, Chen J, Kong H, Lu X, Xu G: Method for liver tissue metabolic profiling study and its application in type 2 diabetic rats based on ultra performance liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2011, 879: 961–967. 10.1016/j.jchromb.2011.03.009

Ugarte M, Brown M, Hollywood KA, Cooper GJ, Bishop PN, Dunn WB: Metabolomic analysis of rat serum in Streptozotocin-induced diabetes and after treatment with oral triethylenetetramine (TETA). Genome Med 2012, 4: 35. 10.1186/gm334

Ament Z, Masoodi M, Griffin JL: Applications of metabolomics for understanding the action of peroxisome proliferator-activated receptors (PPARs) in diabetes, obesity and cancer. Genome Med 2012, 4: 32. 10.1186/gm331

Kim JY, Park JY, Kim OY, Ham BM, Kim HJ, Kwon DY, Jang Y, Lee JH: Metabolic profiling of plasma in overweight/obese and lean men using ultra performance liquid chromatography and Q-TOF mass spectrometry (UPLC-Q-TOF MS). J Proteome Res 2010, 9: 4368–4375. 10.1021/pr100101p

Mihalik SJ, Michaliszyn SF, de las Heras J, Bacha F, Lee S, Chace DH, De Jesus VR, Vockley J, Arslanian SA: Metabolomic profiling of fatty acid and amino acid metabolism in youth with obesity and type 2 diabetes: evidence for enhanced mitochondrial oxidation. Diabetes Care 2012, 35: 605–611. 10.2337/DC11-1577

Adams SH: Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state. Adv Nutr 2012, 2: 445–456.

Das UN: Essential fatty acids: biochemistry, physiology and pathology. Biotechnol J 2006, 1: 420–439. 10.1002/biot.200600012

Shah SH, Hauser ER, Bain JR, Muehlbauer MJ, Haynes C, Stevens RD, Wenner BR, Dowdy ZE, Granger CB, Ginsburg GS: High heritability of metabolomic profiles in families burdened with premature cardiovascular disease. Mol Syst Biol 2009, 5: 258.

Zhao X, Peter A, Fritsche J, Elcnerova M, Fritsche A, Haring HU, Schleicher ED, Xu G, Lehmann R: Changes of the plasma metabolome during an oral glucose tolerance test: is there more than glucose to look at? Am J Physiol Endocrinol Metab 2009, 296: E384–393.

Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B: Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009, 89: 147–191. 10.1152/physrev.00010.2008

Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ: Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 1990, 86: 228–234. 10.1172/JCI114688

Clapp BR, Hingorani AD, Kharbanda RK, Mohamed-Ali V, Stephens JW, Vallance P, MacAllister RJ: Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress. Cardiovasc Res 2004, 64: 172–178. 10.1016/j.cardiores.2004.06.020

Tanner FC, Meier P, Greutert H, Champion C, Nabel EG, Luscher TF: Nitric oxide modulates expression of cell cycle regulatory proteins: a cytostatic strategy for inhibition of human vascular smooth muscle cell proliferation. Circulation 2000, 101: 1982–1989. 10.1161/01.CIR.101.16.1982

Monastyrskaya E, Folarin N, Malyshev I, Green C, Andreeva L: Application of the nitric oxide donor SNAP to cardiomyocytes in culture provides protection against oxidative stress. Nitric Oxide 2002, 7: 127–131. 10.1016/S1089-8603(02)00107-6

Schafer A, Wiesmann F, Neubauer S, Eigenthaler M, Bauersachs J, Channon KM: Rapid regulation of platelet activation in vivo by nitric oxide. Circulation 2004, 109: 1819–1822. 10.1161/01.CIR.0000126837.88743.DD

Schachinger V, Britten MB, Zeiher AM: Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000, 101: 1899–1906. 10.1161/01.CIR.101.16.1899

Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G: Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation 2004, 109: 2518–2523. 10.1161/01.CIR.0000128208.22378.E3

Williams IL, Chowienczyk PJ, Wheatcroft SB, Patel AG, Sherwood RA, Momin A, Shah AM, Kearney MT: Endothelial function and weight loss in obese humans. Obes Surg 2005, 15: 1055–1060. 10.1381/0960892054621134

Melikian N, Kearney MT, Thomas MR, De Bruyne B, Shah AM, MacCarthy PA: A simple thermodilution technique to assess coronary endothelium-dependent microvascular function in humans: validation and comparison with coronary flow reserve. Eur Heart J 2007, 28: 2188–2194. 10.1093/eurheartj/ehm269

Momin A, Melikian N, Wheatcroft SB, Grieve D, John LC, El Gamel A, Marrinan MT, Desai JB, Driver C, Sherwood R: The association between saphenous vein endothelial function, systemic inflammation, and statin therapy in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2007, 134: 335–341. 10.1016/j.jtcvs.2006.12.064

Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD: Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 1996, 97: 2601–2610. 10.1172/JCI118709

Laine H, Yki-Jarvinen H, Kirvela O, Tolvanen T, Raitakari M, Solin O, Haaparanta M, Knuuti J, Nuutila P: Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity. J Clin Invest 1998, 101: 1156–1162. 10.1172/JCI1065

Tack CJ, Ong MK, Lutterman JA, Smits P: Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia 1998, 41: 569–576. 10.1007/s001250050948

Westerbacka J, Vehkavaara S, Bergholm R, Wilkinson I, Cockcroft J, Yki-Jarvinen H: Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity. Diabetes 1999, 48: 821–827. 10.2337/diabetes.48.4.821

Williams IL, Wheatcroft SB, Shah AM, Kearney MT: Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans. Int J Obes Relat Metab Disord 2002, 26: 754–764.

Noronha BT, Li JM, Wheatcroft SB, Shah AM, Kearney MT: Inducible nitric oxide synthase has divergent effects on vascular and metabolic function in obesity. Diabetes 2005, 54: 1082–1089. 10.2337/diabetes.54.4.1082

Wheatcroft SB, Shah AM, Li JM, Duncan E, Noronha BT, Crossey PA, Kearney MT: Preserved glucoregulation but attenuation of the vascular actions of insulin in mice heterozygous for knockout of the insulin receptor. Diabetes 2004, 53: 2645–2652. 10.2337/diabetes.53.10.2645

Duncan ER, Walker SJ, Ezzat VA, Wheatcroft SB, Li JM, Shah AM, Kearney MT: Accelerated endothelial dysfunction in mild prediabetic insulin resistance: the early role of reactive oxygen species. Am J Physiol Endocrinol Metab 2007, 293: E1311–1319. 10.1152/ajpendo.00299.2007

Cai H, Harrison DG: Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000, 87: 840–844. 10.1161/01.RES.87.10.840

Houstis N, Rosen ED, Lander ES: Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006, 440: 944–948. 10.1038/nature04634

Bain JR, Stevens RD, Wenner BR, Ilkayeva O, Muoio DM, Newgard CB: Metabolomics applied to diabetes research: moving from information to knowledge. Diabetes 2009, 58: 2429–2443. 10.2337/db09-0580

Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S, Shah AM: NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 2006, 8: 691–728. 10.1089/ars.2006.8.691

Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ: Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 2000, 192: 1001–1014. 10.1084/jem.192.7.1001

Bernal-Mizrachi C, Gates AC, Weng S, Imamura T, Knutsen RH, DeSantis P, Coleman T, Townsend RR, Muglia LJ, Semenkovich CF: Vascular respiratory uncoupling increases blood pressure and atherosclerosis. Nature 2005, 435: 502–506. 10.1038/nature03527

Silver AE, Beske SD, Christou DD, Donato AJ, Moreau KL, Eskurza I, Gates PE, Seals DR: Overweight and obese humans demonstrate increased vascular endothelial NAD(P)H oxidase-p47(phox) expression and evidence of endothelial oxidative stress. Circulation 2007, 115: 627–637. 10.1161/CIRCULATIONAHA.106.657486

Steinberg HO, Baron AD: Vascular function, insulin resistance and fatty acids. Diabetologia 2002, 45: 623–634. 10.1007/s00125-002-0800-2

Duncan ER, Crossey PA, Walker S, Anilkumar N, Poston L, Douglas G, Ezzat VA, Wheatcroft SB, Shah AM, Kearney MT: Effect of endothelium-specific insulin resistance on endothelial function in vivo. Diabetes 2008, 57: 3307–3314. 10.2337/db07-1111

Fortuno A, San Jose G, Moreno MU, Beloqui O, Diez J, Zalba G: Phagocytic NADPH oxidase overactivity underlies oxidative stress in metabolic syndrome. Diabetes 2006, 55: 209–215. 10.2337/diabetes.55.01.06.db05-0751

Guzik TJ, Mussa S, Gastaldi D, Sadowski J, Ratnatunga C, Pillai R, Channon KM: Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 2002, 105: 1656–1662. 10.1161/01.CIR.0000012748.58444.08

Dworakowski R, Walker S, Momin A, Desai J, El-Gamel A, Wendler O, Kearney MT, Shah AM: Reduced nicotinamide adenine dinucleotide phosphate oxidase-derived superoxide and vascular endothelial dysfunction in human heart failure. J Am Coll Cardiol 2008, 51: 1349–1356. 10.1016/j.jacc.2007.12.033

Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I: Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004, 114: 1752–1761.

Fu P, Birukov KG: Oxidized phospholipids in control of inflammation and endothelial barrier. Transl Res 2009, 153: 166–176. 10.1016/j.trsl.2008.12.005

Schonfeld P, Wojtczak L: Fatty acids as modulators of the cellular production of reactive oxygen species. Free Radic Biol Med 2008, 45: 231–241. 10.1016/j.freeradbiomed.2008.04.029

Symons JD, McMillin SL, Riehle C, Tanner J, Palionyte M, Hillas E, Jones D, Cooksey RC, Birnbaum MJ, McClain DA: Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase in the regulation of endothelial function and blood pressure. Circ Res 2009, 104: 1085–1094. 10.1161/CIRCRESAHA.108.189316

Karman RJ, Gupta MP, Garcia JG, Hart CM: Exogenous fatty acids modulate the functional and cytotoxic responses of cultured pulmonary artery endothelial cells to oxidant stress. J Lab Clin Med 1997, 129: 548–556. 10.1016/S0022-2143(97)90009-3

Chinen I, Shimabukuro M, Yamakawa K, Higa N, Matsuzaki T, Noguchi K, Ueda S, Sakanashi M, Takasu N: Vascular lipotoxicity: endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese zucker diabetic fatty rats. Endocrinology 2007, 148: 160–165.

Du X, Edelstein D, Obici S, Higham N, Zou MH, Brownlee M: Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest 2006, 116: 1071–1080. 10.1172/JCI23354

Kim F, Tysseling KA, Rice J, Pham M, Haji L, Gallis BM, Baas AS, Paramsothy P, Giachelli CM, Corson MA, Raines EW: Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol 2005, 25: 989–994. 10.1161/01.ATV.0000160549.60980.a8

Maloney E, Sweet IR, Hockenbery DM, Pham M, Rizzo NO, Tateya S, Handa P, Schwartz MW, Kim F: Activation of NF-kappaB by palmitate in endothelial cells: a key role for NADPH oxidase-derived superoxide in response to TLR4 activation. Arterioscler Thromb Vasc Biol 2009, 29: 1370–1375. 10.1161/ATVBAHA.109.188813

Kim F, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler J, Hawn TR, Raines EW, Schwartz MW: Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 2007, 100: 1589–1596. 10.1161/CIRCRESAHA.106.142851