BADERC Welcome

Freeman, Mason, M.D

The Biology of Lipid Trafficking in Macrophages

The Freeman laboratory's research centers on the role of lipid transport mechanisms, particularly into and out of macrophages, and the contribution those processes make to human disease. The emphasis has historically been on atherosclerosis. Atherosclerosis manifests as coronary artery disease as well as peripheral vascular disease and these two vascular disorders account for much of the morbidity and mortality associated with diabetes. At the same time, diabetes is a major risk factor for the development of accelerated atherosclerosis. The macrophage plays a critical role in the initiation of atherosclerotic plaques and increasing evidence suggests that macrophages also contribute to complex lesion development and plaque rupture. Genetically engineered mice are employed by our laboratory to examine the role of macrophage receptors that bind modified forms of lipoproteins, leading to atherosclerotic foam cell formation. As glycated lipoproteins have also recently been demonstrated to bind to these macrophage scavenger receptors, their role in diabetic atherosclerosis may be significant. LDL receptor deficient and apo E deficient mice in the C57/BL6 background form atherosclerotic lesions in the proximal aorta that share many characteristics of human atheroma. Early foam cell lesions followed by the development of complex, calcific plaques are generated in these animals. Recent studies have been examining the following questions:

Is scavenger receptor uptake of modified lipoproteins essential for lesion formation and progression? This issue is addressed through the generation of mice lacking the two major scavenger receptors known to be expressed in atherosclerotic lesions (i.e., SR-A, and CD 36). Knock-outs for both receptors are in hand and our initial work has indicated that while the receptors are not required for foam cells to form in hyperlipidemic mice, they do appear to contribute to the inflammatory and apoptotic responses that are generated in the artery wall of the animals. We also recently identified an important role for the innate immunity signaling pathways that link through the toll receptor adaptor molecule known as MyD88 and work is ongoing to explore the role of these pathways in atherosclerosis. Finally, lipid egress mechanisms are being examined through a detailed structure/function analysis of ABCA1 and other members of the A class of ABC transporters and through this work we have identified major lipid transport functions that affect skin integrity and respiratory function.

Participation in the Diabetes Research Center enhances many aspects of our research, particularly the laboratory's ability to investigate signal transduction pathways that are involved in the activation of lesional macrophages.

References:

Ricci R, Sumara G, Sumara I, Rozenberg I, Kurrer M, Alexander Akhmedov A, Hersberger M, Eriksson U, Eberli1 FR, Becher B, Borén J, Chen M, Cybulsky MI, Moore KJ, Freeman MW, Wagner EF, Matter CM, and TF Lüscher. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science. 2004; 306:1558-1561.
Kim WS, Fitzgerald ML, Kang K, Okuhira K, Bell SA, Manning JJ, Koehn SL, Lu N, Moore KJ and MW Freeman. Abca7 null mice retain normal macrophage phosphatidylcholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels. J Biol Chem.2005; 280:3989-3995.
Jeyaseelan S, Chu HW, Young SK, Freeman MW and GS Worthen. Toll-like receptor 4, but not CD14, is necessary and sufficient to mediate LPS-induced pulmonary inflammation in mice. Infection and Immunity: 2005;73(3):1754-63.
Heller EA, Liu E, Tager AM, Sinha S, Robert JD, Koehn SL, Libby P, Aikawa ER, Chen JQ, Huang P, Freeman MW, Moore KJ, Luster AD, and RE Gerszten. Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment. Circulation. 2005;112:578-586.
Moore KJ, Kunjathoor VV, Koehn SL, Manning JJ, Tseng AA, Silver JM, McKee M and MW Freeman. Loss of scavenger receptor mediated lipid uptake via SR-A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice. J Clin Invest. 2005;115:2192-2201.
Okuhira K, Fitzgerald ML, Sarracino DA, Manning JJ, Bell SA, Goss JL, and MW Freeman. Purification of ABCA1 and associated binding proteins reveals the importance of b1-syntrophin in cholesterol efflux. J Biol Chem. 2005;280(47):39653-39664.
Kuo WP, Liu F, Trimarchi J, Punzo C, Lombardi M, Sarang J, Whipple ME, Maysuria M, Serikawa K, Lee SY, McCrann D, Kang J, Shearstone JR, Burke J, Park DJ, Wang X, Rector TL, Ricciardi-Castagnoli P, Perrin S, Choi S, Bumgarner R, Kim JH, Short GF 3rd, Freeman MW, Seed B, Jensen R, Church GM, Hovig E, Cepko CL, Park P, Ohno-Machado L, Jenssen TK. A sequence-oriented comparison of gene expression measurements across different hybridization-based technologies. Nature Biotechnology. 2006; 24(7):832-840.
Fitzgerald ML, Xavier R, Haley KJ, Welti R, Goss JL, Brown CE, Zhuang DZ, Bell SA, Lu N, McKee M, Seed B, and MW Freeman. ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol. J Lipid Res. 2007; 48:621-632.
DeFaria, DY, Freeman MW, Meigs JB, and RW Grant. Risk factors for coronary artery disease in patients with elevated high density lipoprotein cholesterol. Am J Cardiol 2007; 99 (1): 1-4.
Kiss RS, Kavaslar N, Okuhira KI, Freeman MW, Walter S, Milne RW, McPherson R, and YL Marcel. Genetic etiology of isolated low HDL syndrome. Incidence and heterogeneity of efflux defects. Arterioscler Thromb Vasc Biol. 2007; 27(5):1139-45
.
Tamehiro N, Zhou S, Okuhira K, Benita Y, Brown CE, Zhuang DZ, Latz E, Xavier RJ, Freeman MW, and ML Fitzgerald. SPTLC1 Binds ABCA1 to Negatively Regulate Trafficking and Cholesterol Efflux Activity of the Transporter. Biochemistry 2008;47:6138-6147.
Zuo Y, Zhuang DZ, Han R, Isaac G, Manning JJ, McKee M, Welti R, Brissette JL, Fitzgerald ML, and MW Freeman. ABCA12 maintains the epidermal lipid permeability barrier by facilitating formation of ceramide linoleic esters. J Biol. Chem 2008;283:36624-36635.
Manning-Tobin JJ, Moore KJ, Seimon TA, Bell SA, Sharuk M, Alvarez-Leite JI, de Winther MPJ, Tabas I, and MW Freeman. Loss of SR-A and CD 36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice. Arterioscler Thromb Vasc Biol. 2009; 29:19-26.






			Freeman, Mason, M.D The Biology of Lipid Trafficking in Macrophages The Freeman laboratory's research centers on the role of lipid transport mechanisms, particularly into and out of macrophages, and the contribution those processes make to human disease. The emphasis has historically been on atherosclerosis. Atherosclerosis manifests as coronary artery disease as well as peripheral vascular disease and these two vascular disorders account for much of the morbidity and mortality associated with diabetes. At the same time, diabetes is a major risk factor for the development of accelerated atherosclerosis. The macrophage plays a critical role in the initiation of atherosclerotic plaques and increasing evidence suggests that macrophages also contribute to complex lesion development and plaque rupture. Genetically engineered mice are employed by our laboratory to examine the role of macrophage receptors that bind modified forms of lipoproteins, leading to atherosclerotic foam cell formation. As glycated lipoproteins have also recently been demonstrated to bind to these macrophage scavenger receptors, their role in diabetic atherosclerosis may be significant. LDL receptor deficient and apo E deficient mice in the C57/BL6 background form atherosclerotic lesions in the proximal aorta that share many characteristics of human atheroma. Early foam cell lesions followed by the development of complex, calcific plaques are generated in these animals. Recent studies have been examining the following questions: Is scavenger receptor uptake of modified lipoproteins essential for lesion formation and progression? This issue is addressed through the generation of mice lacking the two major scavenger receptors known to be expressed in atherosclerotic lesions (i.e., SR-A, and CD 36). Knock-outs for both receptors are in hand and our initial work has indicated that while the receptors are not required for foam cells to form in hyperlipidemic mice, they do appear to contribute to the inflammatory and apoptotic responses that are generated in the artery wall of the animals. We also recently identified an important role for the innate immunity signaling pathways that link through the toll receptor adaptor molecule known as MyD88 and work is ongoing to explore the role of these pathways in atherosclerosis. Finally, lipid egress mechanisms are being examined through a detailed structure/function analysis of ABCA1 and other members of the A class of ABC transporters and through this work we have identified major lipid transport functions that affect skin integrity and respiratory function. Participation in the Diabetes Research Center enhances many aspects of our research, particularly the laboratory's ability to investigate signal transduction pathways that are involved in the activation of lesional macrophages. References: Ricci R, Sumara G, Sumara I, Rozenberg I, Kurrer M, Alexander Akhmedov A, Hersberger M, Eriksson U, Eberli1 FR, Becher B, Borén J, Chen M, Cybulsky MI, Moore KJ, Freeman MW, Wagner EF, Matter CM, and TF Lüscher. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science. 2004; 306:1558-1561. Kim WS, Fitzgerald ML, Kang K, Okuhira K, Bell SA, Manning JJ, Koehn SL, Lu N, Moore KJ and MW Freeman. Abca7 null mice retain normal macrophage phosphatidylcholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels. J Biol Chem.2005; 280:3989-3995. Jeyaseelan S, Chu HW, Young SK, Freeman MW and GS Worthen. Toll-like receptor 4, but not CD14, is necessary and sufficient to mediate LPS-induced pulmonary inflammation in mice. Infection and Immunity: 2005;73(3):1754-63. Heller EA, Liu E, Tager AM, Sinha S, Robert JD, Koehn SL, Libby P, Aikawa ER, Chen JQ, Huang P, Freeman MW, Moore KJ, Luster AD, and RE Gerszten. Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment. Circulation. 2005;112:578-586. Moore KJ, Kunjathoor VV, Koehn SL, Manning JJ, Tseng AA, Silver JM, McKee M and MW Freeman. Loss of scavenger receptor mediated lipid uptake via SR-A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice. J Clin Invest. 2005;115:2192-2201. Okuhira K, Fitzgerald ML, Sarracino DA, Manning JJ, Bell SA, Goss JL, and MW Freeman. Purification of ABCA1 and associated binding proteins reveals the importance of b1-syntrophin in cholesterol efflux. J Biol Chem. 2005;280(47):39653-39664. Kuo WP, Liu F, Trimarchi J, Punzo C, Lombardi M, Sarang J, Whipple ME, Maysuria M, Serikawa K, Lee SY, McCrann D, Kang J, Shearstone JR, Burke J, Park DJ, Wang X, Rector TL, Ricciardi-Castagnoli P, Perrin S, Choi S, Bumgarner R, Kim JH, Short GF 3rd, Freeman MW, Seed B, Jensen R, Church GM, Hovig E, Cepko CL, Park P, Ohno-Machado L, Jenssen TK. A sequence-oriented comparison of gene expression measurements across different hybridization-based technologies. Nature Biotechnology. 2006; 24(7):832-840. Fitzgerald ML, Xavier R, Haley KJ, Welti R, Goss JL, Brown CE, Zhuang DZ, Bell SA, Lu N, McKee M, Seed B, and MW Freeman. ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol. J Lipid Res. 2007; 48:621-632. DeFaria, DY, Freeman MW, Meigs JB, and RW Grant. Risk factors for coronary artery disease in patients with elevated high density lipoprotein cholesterol. Am J Cardiol 2007; 99 (1): 1-4. Kiss RS, Kavaslar N, Okuhira KI, Freeman MW, Walter S, Milne RW, McPherson R, and YL Marcel. Genetic etiology of isolated low HDL syndrome. Incidence and heterogeneity of efflux defects. Arterioscler Thromb Vasc Biol. 2007; 27(5):1139-45 . Tamehiro N, Zhou S, Okuhira K, Benita Y, Brown CE, Zhuang DZ, Latz E, Xavier RJ, Freeman MW, and ML Fitzgerald. SPTLC1 Binds ABCA1 to Negatively Regulate Trafficking and Cholesterol Efflux Activity of the Transporter. Biochemistry 2008;47:6138-6147. Zuo Y, Zhuang DZ, Han R, Isaac G, Manning JJ, McKee M, Welti R, Brissette JL, Fitzgerald ML, and MW Freeman. ABCA12 maintains the epidermal lipid permeability barrier by facilitating formation of ceramide linoleic esters. J Biol. Chem 2008;283:36624-36635. Manning-Tobin JJ, Moore KJ, Seimon TA, Bell SA, Sharuk M, Alvarez-Leite JI, de Winther MPJ, Tabas I, and MW Freeman. Loss of SR-A and CD 36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice. Arterioscler Thromb Vasc Biol. 2009; 29:19-26.