Lipid Trafficking in Macrophages and Novel Diabetes Therapeutics
The Freeman laboratory’s basic science 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. Our lab also identified an important role for innate immunity signaling pathways that link through the toll receptor adaptor molecule known as MyD88 the role of these pathways has become an important focus on recent atherosclerosis research. 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. This work in turn has led us to explore the functional role of HDL in cholesterol deposition in artery walls, particularly as it relates to cholesterol crystal formation and the possible triggering of innate immune pathways via crystal induced inflammatory signaling.
Much of our work in recent years has shifted into the new translational research center at MGH that Dr. Freeman now directs. Of relevance to the DRC is that we have generated a novel anti-diabetic drug, a member of the SGLT-2 class of glucose transport inhibitors, and this molecule is now in phase 3 development. Our team has been responsible for the design and development of the molecule, funded via a virtual biotech company called Theracos. This effort is directly and specifically targeted at the treatment of patients with diabetes mellitus.
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.
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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. PMCID: PMC2666043
7. Haller JF, Cavallaro P, Hernandez NJ, Dolat L, Soscia SJ, Welti R, Grabowski GA, Fitzgerald ML and MW Freeman. Endogenous B-glucocerebrosidase activity in Abca 12 -\- epidermis elevates ceramide levels after topical lipid application but does not restore barrier function. J Lipid Res. 2014, 55:493-503. PMCID: PMC3934733 [Available on 2015/3/1]