Fitzgerald Laboratory: Michael Fitzgerald, PhD
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The Fitzgerald Laboratory research centers on cardiovascular disease, cholesterol metabolism and innate immunity. This effort is anchored by investigation of the efflux transporter ABCA1, which exports cholesterol and phospholipid from cells in the first step of HDL biogenesis. HDL is a lipoprotein whose blood level is inversely correlated with cardiovascular disease. Tangier patients with ABCA1 mutations develop premature vascular disease, peripheral neuropathies and lack circulating HDL. ABCA1 poly-morphisms are also of diagnostic interest, since they exert a strong influence on HDL levels in the general population.
Additionally, we investigate how HIV infection and antiretroviral treatment can alter HDL function and cardiovascular disease risk. Here the Fitzgerald Laboratory has developed methods to profile HDL from HIV positive individuals using mass spectrometry methods to quantitate protein and lipid content in this athero-protective lipoprotein. Additional work has analyzed how the HIV Nef protein reprograms macrophage lipid metabolism to maximize virion envelope production. Importantly, we have found that activation of the LXR nuclear hormone receptor strongly inhibits viremia in a humanized mouse model of HIV disease.
Finally, we are analyzing the mechanisms by which formation of cholesterol crystals in the artery wall can incite inflammatory processes through molecular pathways that involve a cellular multi-protein complex termed the “inflammasome”. This collaborative work with the laboratory of Eicke Latz has suggested cyclodextrin, a carrier molecule for hydrophobic drugs, has potential to be repurposed as an anti-atherosclerotic therapy that, in part, reprograms macrophage LXR transcriptional networks.
HDL prevention of cholesterol crystal inflammation in HIV disease
Contact PI: Fitzgerald ML; mPI: Latz, E
9/1/12 - 6/30/17
This basic and translational grant explores the relationship between HIV infection, anti-retroviral therapy, and the ability of HDL to prevent vessel wall cholesterol crystal inflammation.
HIV disease and cholesterol metabolism
Co-PI: Fitzgerald ML; Contact PI: Bukrinsky, M
This grant explores the role that HIV infection and antiretroviral drug therapy play in causing dyslipidemia and increased risk of cardiovascular disease in HIV positive individual. The role of the Fitzgerald lab is to develop a HDL proteomic and lipid profiling procedure to monitor changes in HDL composition during the acute infection period and subsequent drug treatment phase.
Zimmer S, Grebe A, Bakke S, Bode N, Halvorsen B, Ulas T, Skjelland M, Nardo D, Labzin L, Kerksiek A, Hempe C, Heneka M, Hawxhurst V, Fitzgerald ML, Trebicka J, Gustafsson J, Westerterp M, Tall AR, Wright S, Espevik T, Schultze J, Nickenig G, Lütjohann D, Latz E. Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. 2016, Science Translation Medicine, Apr 6; 8(333):333 PMID: 27053774
Sakae N, Liu C, Shinohara M, Frisch-Daiello J, Ma L, Yamazaki Y, Tachibana M, Younkin L, Aishe K, Carrasquillo M, Zou F, Sevlever D, Bisceglio G, Gan M, Fol R, Knight P, Wang M, Han X, Fryer J, Fitzgerald ML, Ohyagi Y, Younkin S, Bu G, Kanekiyo T. ABCA7 deficiency accelerates amyloid-β generation and Alzheimer’s neuronal pathology. 2016 Neuroscience, Mar 30; 36(13):3848-59. PMID:27030769
Tamehiro N, Park MH, Hawxhurst V, Nagpal K, Adams ME, Zannis VI, Golenbock DT, Fitzgerald ML. LXR agonism upregulates the macrophage ABCA1/Syntrophin protein complex that can bind ApoA-I and stabilized ABCA1 protein, but complex loss does not inhibit lipid efflux. Biochemistry. 2015 Nov 24; 54(46):6931-41 PMID: 26506427
Siegel MO, Borkowska AG, Dubrovsky L, Roth M, Welti R, Roberts AD, Parenti DM, Simon GL, Sviridov D, Simmens S, Bukrinsky M, Fitzgerald ML. HIV infection induces structural and functional changes in high density lipoproteins. Atherosclerosis. 2015 Nov; 243(1):19-29. PMID: 26343868
Ramezani A, Dubrovsky L, Pushkarsky T, Sviridov D, Karandish S, Raj DS, Fitzgerald ML, Bukrinsky M. Stimulation of Liver X Receptor Has Potent Anti-HIV Effects in a Humanized Mouse Model of HIV Infection. J Pharmacol Exp Ther. 2015 Sep; 354(3):376-83. PMID:26126533
Midtbø LK, Borkowska AG, Bernhard A, Rønnevik AK, Lock EJ, Fitzgerald ML, Torstensen BE, Liaset B, Brattelid T, Pedersen TL, Newman JW, Kristiansen K, Madsen L. Intake of farmed Atlantic salmon fed soybean oil increases hepatic levels of arachidonic acid-derived oxylipins and ceramides in mice. J Nutr Biochem. 2015 Jun; 26(6):585-95. PMID: 25776459
Jennelle L, Hunegnaw R, Dubrovsky L, Pushkarsky T, Fitzgerald ML, Sviridov D, Popratiloff A, Brichacek B, Bukrinsky M. HIV-1 Protein Nef Inhibits Activity of ATP Binding Cassette Transporter A1 by Targeting Endoplasmic Reticulum Chaperone Calnexin. J Biol Chem. 2014 Aug 28. [Epub ahead of print] PMID:25170080
Zanni MV, Kelesidis T, Fitzgerald ML, Lo J, Abbara S, Wai B, Marmarelis E, Hernandez NJ, Yang OO, Currier JS, Grinspoon SK. HDL redox activity is increased in HIV-infected men in association with macrophage activation and noncalcified coronary atherosclerotic plaque.Antivir Ther. 2014 Feb 17. PMID: 24535655
Haller JF, Cavallaro P, Hernandez NJ, Dolat L, Soscia SJ, Welti R, Grabowski GA, Fitzgerald ML, Freeman MW. Endogenous β-glucocerebrosidase activity in Abca12-/-epidermis elevates ceramide levels after topical lipid application but does not restore barrier function. J Lipid Res. 2014 Mar;55(3):493-503. Epub 2013 Nov 30. PMID:24293640
De Nardo D, Labzin LI, Kono H, Seki R, Schmidt SV, Beyer M, Xu D, Zimmer S, Lahrmann C, Schildberg FA, Vogelhuber J, Kraut M, Ulas T, Kerksiek A, Krebs W, Bode N, Grebe A, Fitzgerald ML, Hernandez NJ, Williams BR, Knolle P, Kneilling M, Röcken M, Lütjohann D, Wright SD, Schultze JL, Latz E. High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3.Nat Immunology. 2014 Feb; 15(2):152-60. Epub 2013 Dec 8, PMID: 24317040
Cui HL, Grant A, Mukhamedova N, Pushkarsky T, Jennelle L, Dubrovsky L, Gaus K, Fitzgerald ML, Sviridov D, Bukrinsky M HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux.J Lipid Res. 2012 Jan 19. PMCID: PMC3307646.
Tanaka N, Abe-Dohmae S, Iwamoto N, Fitzgerald ML, Yokoyama S. HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7. Atherosclerosis. 2011 Aug; 217(2):407-14. Epub 2011 Jun 23. PMCID: PMC3150192.
Mujawar Z, Tamehiro N, Grant A, Sviridov D, Bukrinsky M, Fitzgerald ML. Mutation of the ATP Cassette Binding Transporter A1 (ABCA1) C-Terminus Disrupts HIV-1 Nef Binding but Does Not Block the Nef Enhancement of ABCA1 Protein Degradation. Biochemistry. 2010 Sep 28; 49(38):8338-49.PMCID: PMC2932757.
Rayner KJ, Suárez Y, Dávalos A, Parathath S, Tamehiro N, Fitzgerald ML, Fisher EA, Moore KJ, Fernández-Hernando C. miR-33 coordinates genes regulating cholesterol homeostasis. Science. 2010 Jun 18;328 (5985):1570-3. PMCID:PMC3114628
Tanaka N, Abe-Dohmae S, Iwamoto N, Fitzgerald ML, Yokoyama S. Helical apolipoproteins of high-density lipoprotein enhance phagocytosis by stabilizing ATP-binding cassette transporter A7. J Lipid Res. 2010 Sep; 51(9):2591-9. PMCID: PMC2918442.
Okuhira K, Fitzgerald ML, Tamehiro T, Ohoka N, Suzuki K, Sawada J, Naito M, Nishimaki-Mogami T. Binding of PDZ-RhoGEF to ATP-Binding Cassette Transporter A1 (ABCA1) Induces Cholesterol Efflux through RhoA Activation and Prevention of Transporter Degradation.J Biol Chem. 2010, In Press
Asztalos B, Mujawar A, Morrow M, Grant A, Pushkarsky T, Wanke C, Shannon R, Geyer M, Kirchhoff F, Sviridov D, Fitzgerald ML, Bukrinsky M, Mansfield K. Circulating Nef Induces Dyslipidemia in SIV-Infected Macaques by Suppressing Cholesterol Efflux. J Infectious Diseases. 2010, 15;202 (4):614. PMCID: PMC3114628.
Tamehiro N, Mujawar Z, Zhou S, Zhuang DZ, Hornemann T, von Eckardstein A, Fitzgerald ML. Cell polarity factor Par3 binds SPTLC1 and modulates monocyte serine palmitoyltransferase activity and chemotaxis. J Biol Chem. 2009 Sep 11; 284(37):24881-90. Epub 2009 Jul 10. PMCID: PMC2605993
Zuo, Z., Zhuang, D., Han, R., Isaac, G., Manning, J., McKee, M., Welti, R., Brissette, J., Fitzgerald, ML, and Freeman, MW. ABCA12 maintains the epidermal lipid permeability barrier by facilitating formation of ceramide linoleic esters. J Biol Chem. 2008 Dec 26; 283(52):36624-35. Epub 2008 Oct 27 PMCID: PMC2605993
Tamehiro N, Zhou S, Okuhira K, Benita Y, Brown CE, Zhuang DZ, Latz E, Hornemann T, von Eckardstein A, Xavier RJ, Freeman MW, Fitzgerald ML. SPTLC1 Binds ABCA1 to Negatively Regulate Trafficking and Cholesterol Efflux Activity of the Transporter. Biochemistry, 2008 Jun 10; 47(23):6138-47. Epub 2008 May 17. PMCID: PMC2504083
Fitzgerald ML, Xavier R, Haley KJ, Welti R, Goss JL, Brown CE, Zhuang DZ, Bell SA, Lu N, McKee M, Seed B, Freeman MW. ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant and depletion of lung phosphatidylglycerol. J Lipid Res. 2007, 48:621-632. [Epub ahead of print 2006 Dec 1]
Huang ZH, Fitzgerald ML, Mazzone T. Distinct Cellular Loci for the ABCA1-Dependent and ABCA1-Independent Lipid Efflux Mediated by Endogenous Apolipoprotein E Expression. Arterioscler Thromb Vasc Biol. 2006 Jan; 26(1):157-62
Okuhira KI*, Fitzgerald ML*, Sarracino DA, Manning JJ, Bell SA, Goss JL, Freeman MW. Purification of ABCA1 and associated binding proteins reveals the importance of beta 1-syntrophin in cholesterol efflux. J Biol Chem. 2005 Nov 25; 280(47):39653-64. *Co-First Authors
Kim WS*, Fitzgerald ML*, Kang K, Okuhira KI, Bell SA, Manning JJ, Koehn SL, Lu N, Moore KJ, Freeman MW. Abca7 null mice retain normal macrophage phosphatidylcholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels. J Biol Chem. 2005 Feb 4; 280(5):3989-95.
Fukuchi J, Hiipakka RA, Kokontis JM, Hsu S, Ko AL, Fitzgerald ML, Liao S. Androgenic suppression of ATP-binding cassette transporter A1 expression in LNCaP human prostate cancer cells. Cancer Res. 2004 Nov 1; 64(21):7682-5.
Fitzgerald ML, Okuhira KI, Short GF 3rd, Manning JJ, Bell SA, Freeman MW. ABCA1 contains a novel C-terminal VFVNFA motif that is required for its cholesterol efflux and apoA-I binding activities. J Biol Chem. 2004;279:48477-485, Sep 3 [Epub ahead of print]
Nieland TJ, Chroni A, Fitzgerald ML, Maliga Z, Zannis VI, Kirchhausen T, Krieger M. Cross-inhibition of SR-BI- and ABCA1-mediated cholesterol transport by the small molecules BLT-4 and glyburide. J Lipid Res. 2004 Jul; 45(7):1256-65. Epub 2004 Apr 21 PMID: 15102890.
Chroni A, Liu T, Fitzgerald ML, Freeman MW, Zannis VI. Cross-Linking and Lipid Efflux Properties of APOA-I Mutants Suggest Direct Association between APOA-I Helices and ABCA1. Biochemistry 2004 Feb 24; 43(7):2126-39.
Fitzgerald ML, Morris AL, Chorni A, Mendez AJ, Zannis VI, Freeman MW. ABCA1 and amphipathic apolipoproteins form high affinity molecular complexes required for cholesterol efflux. J Lipid Res, 2004 Feb; 45(2):287-94. Epub 2003
Fukumoto H, Deng A, Irizarry MC, Fitzgerald ML, Rebeck GW. Induction of the cholesterol transporter ABCA1 in central nervous system cells by liver X receptor agonists increases secreted Abeta levels. J Biol Chem. 2002; 277(50):48508-13.
Fitzgerald ML, Morris AL, Rhee JS, Andersson LP, Mendez AJ, Freeman MW. Naturally Occurring Mutations in the Largest Extracellular Loops of ABCA1 Can Disrupt Its Direct Interaction with Apolipoprotein A-I. J Biol Chem 2002 Sep 6; 277(36):33178-87 PMID: 12084722.
Fitzgerald ML, Mendez AJ, Moore KJ, Andersson LP, Panjeton HA, and MW Freeman. (2001) ABCA1 contains an N-terminal signal-anchor sequence that translocates the protein’s first hydrophilic domain to the exoplasmic space. J. of Biol. Chem. 276: 15137-15145 PMID: 11328826.
Moore KJ, Rosen ED, Fitzgerald ML, Randow F, Andersson LP, Altshuler D, Milstone DSPP, Mortensen RM, Spiegelman BM, Freeman, MW (2001) The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nature Medicine 2001 Jan; 7(1):41-7. PMID: 11135614.
Fitzgerald ML, Moore KJ, Freeman MW, Reed GL. Lipopolysaccharide induces Scavenger Receptor-A expression in mouse macrophages: a divergent regulatory mechanism relative to human macrophages. J Immunol 2000; 164(5):2692-700.
Fitzgerald ML, Reed GL. Rab6 is phosphorylated in thrombin-activated platelets by a protein kinase C-dependent mechanism: effects on GTP/GDP binding and cellular distribution. Biochem J. 1999; 342:353-60.
Reed GL, Houng A, Fitzgerald ML. Platelet secretory protein, a human unc-18c homologue that interacts with syntaxin 4 and is phosphorylated in activated cells: implication for triggered secretion in platelets. Blood 1999; 93:2617-26.
Vora A, McCord M, Fitzgerald ML, Inman R, Grandgenett D. Efficient concerted integration of retrovirus-like DNA in vitro by avian myeloblastosis virus integrase. Nucleic Acids Res. 1994; 22:4454-61.
Fitzgerald ML, Grandgenett D. Retroviral integration: in vitro host site selection by avian myeloblastosis virus integrase. J Virol., 1994; 68:4314-21.
Grandgenett D, Inman R, Vora A, Fitzgerald ML. Comparison of DNA binding and integration half-site selection by avian myeloblastosis virus integrase. J Virol. 1993; 67:2628-36.
Fitzgerald ML, Vora A, Zeh B, Grandgenett, D. Concerted integration of viral DNA termini by purified avian myeloblastosis virus integrase. J Virol. 1992; 66:6257-63.
Fitzgerald ML, Vora A, Grandgenett D. Development of an acid-soluble assay for measuring retrovirus integrase 3'-OH terminal nuclease activity. Anal Biochem. 1991; 196:19-23.
Vora A, Fitzgerald ML, Grandgenett D. Removal of 3'-OH-terminal nucleotides from blunt-ended long terminal repeat termini by the avian retrovirus integration protein. J Virol. 1990; 64:5656-59.
Michael Fitzgerald, PhD is an Assistant Professor of Medicine at Harvard Medical School and a faculty member in the Lipid Metabolism Unit of the Department of Medicine at Massachusetts General Hospital. Learn more about him and the rest of the research group here.