Godfrey Getz, M.D., Ph.D.

Molecular Mechanisms Involved in Nutritional and Hormonal Control of Apolipoprotein Gene Expression; Site-specific Mutagenesis in Function of Lipoproteins, and Role of Apolipoproteins in Atherosclerosis and Alzheimer's Disease

Research Summary

Our laboratory focuses on the role of apoproteins E, A-I and SAA on the heterogeneity of lipoproteins and upon the process of atherogenesis. We are also interested in the role of the immune system on atherogenesis. The differential influences of apoprotein E isoforms on the evolution of experimental Alzheimer's disease are also a subject of our research.

Apopoprotein E is an important component of several lipoprotein classes and functions as a ligand for the clearance of VLDL and chylomicron remnants by the LDL receptor and its related receptor, LRP. Apoprotein A-I is the major apropretein of HDL and is responsible for the heterogeneity of HDL subclasses in human plasma. SAA is an acute phase protein which is produced at high levels by the liver in inflammatory states.
It exists in multiple isoforms which are highly conserved across mammalian species. To each of these aproproteins have been assigned multiple attributes - e.g. interaction with several cell surface receptors, promoting cholesterol efflux from cholesterol loaded cells, binding to matrix molecules, promotion of endothelial nitric oxide synthase, etc. We have available mouse models that lack each of these apoproteins which permits us to explore the function wild type and mutant versions of each protein in relation to atherogenesis and its reversal.

The immune system, innate and adaptive, has been strongly implicated in atherogenesis. We have available immune deficient animals that lack apoprotein E, or the LDL receptor that nevertheless develop significant atherosclerosis. We are in the process of complementing the immune deficient animals with single T or B cell subtypes to ascertain the role of each separate from their interaction with other cells of the adaptive immune system. This approach lends itself to the sequential complementation of immune deficient animals with cells of the immune system. Immune deficient animals have reduced plasma lipid levels, and the mechanism for this is unknown, and under investigation in our laboratory.
Finally apoprotein E exists as three common isoforms, E2, E3 and E4. The last, apoprotein E4, is a major risk factor for the development of Alzheimer's disease. We are examining the differential effects of apoprotein E3 and apoprotein E4 in a mouse model of Alzheimer's disease, both on the evolution and clearance of amyloid plaques.

Selected Papers

Cabana VG, Reardon CA, Feng N, Neath S, Lukens J, Getz GS. (2003). Serum paraoxonase: effect of the apolipoprotein composition of HDL and the acute phase response. J Lipid Res. 44(4):780-92.

Reardon CA, Blachowicz L, Lukens J, Nissenbaum M, Getz GS. (2003). Genetic background selectively influences innominate artery atherosclerosis: immune system deficiency as a probe. Arterioscler Thromb Vasc Biol. 23(8):1449-54.

Peng D, Song C, Reardon CA, Liao S, Getz GS. (2003). Lipoproteins produced by ApoE-/- astrocytes infected with adenovirus expressing human ApoE. J Neurochem. 86(6):1391-402.

Edelstein C, Pfaffinger D, Hinman J, Miller E, Lipkind G, Tsimikas S, Bergmark C, Getz GS, Witztum JL, Scanu AM. (2003). Lysine-phosphatidylcholine adducts in kringle V impart unique immunological and potential pro-inflammatory properties to human apolipoprotein(a). J Biol Chem. 278(52):52841-7.

VanderLaan PA, Reardon CA, Getz GS. (2004). Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler Thromb Vasc Biol. 24(1):12-22.

Cabana VG, Feng N, Reardon CA, Lukens J, Webb NR, de Beer FC, Getz GS. (2004). Influence of apoA-I and apoE on the formation of serum amyloid A-containing lipoproteins in vivo and in vitro. J Lipid Res. 45(2):317-25.

Reardon CA, Getz GS. (2004). Paraoxonase, a cardioprotective enzyme: continuing issues. Curr Opin Lipidol. 15(3):261-7

Reardon CA, Miller ER, Blachowicz L, Lukens J, Binder CJ, Witztum JL, Getz GS. (2004). Autoantibodies to OxLDL fail to alter the clearance of injected OxLDL in apolipoprotein E-deficient mice. J Lipid Res. 45(7):1347-54.

Getz GS. (2005). hgtThematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis.
J Lipid Res. 46(1):1-10.