Mary G. Sorci-Thomas, PhD
My lab group has been interested in elucidating the role that high density lipoprotein (HDL) apo A-I plays in preventing coronary heart disease. Studies have shown that plasma HDL apo A-I plays a "protective function" and mitigates the effects of high levels of atherogenic lipoproteins through its ability to accept, organize and transport cholesterol out of the artery wall to the liver for uptake and excretion into bile. This "reverse cholesterol transport pathway" is highly dependent upon apo A-I's ability to bind lipids and form nascent HDL particles that circulate in plasma. If concentrations of HDL apo A-I particles are low or if their uptake by the liver is reduced or blocked, then increased plasma cholesterol levels can trigger an inflammatory responses leading to heart disease and stroke.
Interrelationship Between Autoimmunity and Atherosclerosis
One ongoing project in my lab has been to investigate the role of HDL apo A-I concentrations in reducing the development of autoimmunity and atherosclerosis. Since the immune system is a complex system with multiple layers of regulation to prevent reactions against self-antigens, or autoimmune disorders, it is possible that accumulation of cholesterol may alter cellular function to a point at which peripheral self-tolerance is lost. We have been particularly interested in the role of T cell activation and effector T cell response in autoimmunity and atherosclerosis. HDL apo A-I appears to be linked to autoimmunity, since individuals with decreased levels of HDL apo A-I are more likely to develop autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. In hypercholesterolemic mice lacking HDL apo A-I an autoimmune phenotype develops in response to the consumption of a cholesterol containing diet. These mice show heightened lymph node immune cell activation, proliferation and severe skin lesions. Interestingly these mice also show an increased population of T regulatory cells which are designed to modulate T cell activation. These results suggest that the Treg response under low HDL apo A-I conditions may lead to defective regulation of tolerance in these mice. A cartoon of this hypothesis is shown in Figure 1.
Figure 1. Autoimmunity and the Activation of Peripheral T Cells and their Impact on the Progression of Atherosclerosis. Recent studies have shown that the adaptive immune system is involved in the development of atherosclerosis. One model involves the entry of LDL into tissue where it can be modified or oxidized, termed (OxLDL). Ox LDL may act as candidate antigens in peripheral tissue, such as skin (left panel) as well as in the vasculature (right panel). The exact location of initial antigen presentation is atherosclerosis is not known, but macrophages and DCs acquire and process antigens for presentation (APC) to T cells in peripheral lymph nodes. Continuous trafficking of immune cells between the inflamed artery and the lymph node may be necessary to mount an adaptive immune response. DC maturation by self-altered molecules may be regulated by T regulatory cells (Treg) that suppress immune activation and maintain tolerance. In some cases, Tregs do not suppress APC activation leading to mature APC and a pathogenic immune response which can induce either a Th1 or Th2 pathogenic responses.
Formation of Nascent HDL
Another important area of research currently being studied in my lab concerns the formation of nascent HDL (nHDL) apo A-I particles. Since the concentration of HDL apo A-I varies greatly within the human population we are interested in determining the mechanism explaining how nascent HDL particles are formed. One approach we are using is to investigate the composition of the particles formed following the interaction between apo A-I and the ATP binding cassette transporter A1 (ABCA1) which transports cholesterol out of the cell onto the outer leaflet of the cellular membrane. To our surprise we have found that the lipid compositions of nHDL as determined by LC-MS/MS contain a large amount of sphingomyelin and suggest that lipid rafts may significantly contribute to the ABCA1 mediated formation of newly formed nascent HDL apo A-I particles. In addition, we are also using mass spectrometry techniques to determine the conformation of apo A-I on this small lipid containing particles. These molecular studies are useful in solving the structure of lipid bound proteins which are responsible for activating important plasma enzymes such as the lecithin:cholesterol acyltransferase (LCAT) as shown in Figure 2.
Figure 2. Molecular Models Depicting the Activation of Lecithin:Cholesterol Acyltransferase (LCAT) by High Density Lipoprotein (HDL) Apo A-I. Molecular models of the plasma enzyme LCAT (yellow atoms) and the lipoprotein HDL containing two molecules of apo A-I (green, orange, white and purple atoms) are shown before docking at helix 6 of one monomer of apo A-I (purple atoms). Helix 6 residues of apo A-I correspond to amino acids #143-164, shown in purple, flanked by helices 5 and 7, shown in orange, while all other apo A-I amino acids are shown in green. The LCAT region corresponding to amino acids #121 to 136, has been highlighted with blue atoms and indicates where LCAT binds HDL (blue arrow points to this region). The model of LCAT contains amino acids #9 through 420 of the pro-form of LCAT and is available at ModBase (http://modbase.compbio.ucsf.edu) with the primary database link P04180. The structure was rendered with MacPyMOL (http://www.pymol.org).
Link to PubMed Database