In western societies atherosclerosis is the main cause of death. One of my lab scientific interests is to use and create mice models (transgenic, gene knock-out) for the studies of sphingolipid metabolism and atherosclerosis. The association of lipid abnormalities and atherosclerosis is well established. Case-control and prospective epidemiological studies have shown a direct correlation between atherosclerosis and serum levels of total cholesterol and low density lipoprotein cholesterol (LDL-C, "bad cholesterol"), and an inverse relationship between atherosclerosis and high density lipoprotein cholesterol (HDL-C, "good cholesterol") levels. However, compared to plasma cholesterol measurements, much less attention has been given to the relationship between sphingolipid and atherosclerosis.
It has long been known that sphingomyelin (SM) accumulates in human and animal atheroma, and that the major source is plasma lipoproteins. Plasma SM levels are increased in human familial hyperlipidemias, especially in familial hypercholesterolemia, and also in animal models of atherosclerosis. The concentration of SM relative to total phospholipids (principally PC and SM), i.e. SM/(SM+PC), is an important determinant of the susceptibility of lipoprotein SM to SMase. These findings suggest that plasma SM levels and the relative SM concentration might be risk factors for atherosclerosis.
Another scientific interest in my lab is to use transgenic approach to perform functional studies of two plasma lipid transfer proteins, phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP). It is known that both lipid transfer proteins play very important roles in lipoprotein metabolism and atherosclerosis. PLTP mediates transfer of phospholipids between very low density (VLDL) and HDL during their intravascular metabolism. PLTP gene knock-out mice showed an anti-atherosclerosis phenotype. CETP mediates transfer cholesteryl ester from HDL to VLDL and LDL. Human CETP deficiency showed a dramatic increase of HDL, and human CETP transgenic mice showed significant decrease of HDL. Inhibition of CETP in rabbit showed an anti-athersclerosis phenotype. It will be of very interesting to study the underlied mechanisms of both lipid transfer proteins in terms of lipoprotein metabolism and atherosclerosis.
My lab is also interested in searching for new genes involved in lipoprotein metabolism and atherosclerosis and for new drugs involved in the treatment of atherosclerosis.
SELECTED RECENT PUBLICATIONS
Jiang, X.C., D’Armianto, J., Mallampalli, R., Mar, J., Yan, S.F., and Lin, M. Expression of plasma phospholipid transfer protein mRNA in normal and emphysematous lungs and regulation by hypoxia. (1998) J. Biol.Chem. 273,15714-15718.
Jeong, T.S., Schissel, S.L., Tabas, I., Pownall, H., Tall, A.R., and Jiang, X.C. (1998). Increased sphingomyelin content of plasma lipoproteins in apolipoprotein E knock-out mice: reflects combined production and catabolic defects and enhances reactivity with mammalian sphingomyelinase. J.Clin.Invest. 101,905-912.
Jiang, X.C., Bruce, C., Mar, J., Lin, M., Ji, Y., Francone, O., and Tall, A. (1999) Targeted mutation of plasma phospholipid transfer protein gene markedly reduces HDL level. J. Clin. Invest. 103, 907-914.
Kawano, K., Qin, S., Lin, M., Tall, A.R. and Jiang, X.C. (2000) Cholesteryl ester transfer protein and phospholipid transfer protein have non-overlapping function in vivo. J. Biol. Chem. 275, 29477-29481.
Jiang, X.C., Paules, F., Berglund, L., Pearson, T.A., Reed, B., Francis, C.K., Lin, M., and Tall, A.R. (2000) Plasma sphingomyelin level as a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol. 20,2614-2618.
Jiang, X.C., Qin, S., Kawano, K., Lin, M., Xiao, X., and Tall, A.R.(2001) Decreased apoB production and reduced atherosclerosis in mice with phospholipid transfer protein deficiency. Nature Medicine. 7, 847-852.
Jiang, X.C. Tall, A.R. Qin, S., Lin, M., Schneider, M., Lalanne, F., Deckert, V., Desrumaux, C., Witztum, J., and Lagrost,L. (2002) Phospholipid transfer protein (PLTP) deficiency protects circulating lipoproteins from oxidation due to the enhanced accumulation of vitamin E. J. Biol. Chem. 277:31850-6.
Cao G, Beyer TP, Yang XP, Schmidt RJ, Zhang Y, Bensch WR, Kauffman RF, Gao H, Ryan TP, Liang Y, Eacho PI, Jiang XC. (2002) Phospholipid transfer protein is regulated by liver x receptors in vivo. J Biol Chem. 277:39561-5.
Schlitt, A., Bickel, C., Thumma, P., Blankenberg, S., Rupprecht, H., Meyer, J., and Jiang, X.C. High Plasma Phospholipid Transfer Protein Level as a Risk Factor for Coronary Artery Disease. Arterioscler Thromb Vasc Biol. (2003) 23:1857-62.
Yang, X.P., Yan, D., Qiao, C., Liu, R.J., Li, G., Schneider, M., Lagrost, L., Xiao, X., and Jiang, X.C. (2003) Increased atherosclerotic lesion and lipoprotein oxidizability in apoE knock out mice overexpression plasma PLTP. Arterioscler Thromb Vasc Biol. (2003) 23:1601-7.
Jiang, X.C, Beyer, T.P., Li. Z, Liu, J., Schmidt R.J., Zhang, Y., Bensch, W.R., Eacho, P and Cao, G. A. Enlargement of HDL in mice via LXR activation requires apoE and is abolished by CETP expression. (2003) J. Biol. Chem. 278,49072-9.
Yan, D., Navab, M., Bruce, C., Fogelman, A., and Jiang, X.C. (2004) Phospholipid Transfer Protein Deficiency Improves the Anti-inflammatory Properties of High Density Lipoprotein and Reduces the Ability of Low Density Lipoprotein to Induce Monocyte Chemotactic Activity. J. Lipid Res. 2004, 45:1852-8
Schlitt, A., Reza, M., Lackner, K., Yan, D., Blankenberg, S., Fischer, C., Meyer, J., Rupprecht, H.J., and Jiang, X.C. (2005) Serum sphingomyelin is related to clearance of remnant like particles - new insights into the proatherogenic potency of sphingomyelin. J. Lipid Res. 46:196-200.
Hojjati, M., Li, Z., Zhou, H., Tang, S., Huan, C., Ooi, E., Lu, S., and Jiang, X.C. (2005) Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice. J Biol Chem. 280:10284-9.
Jiang, X.C., Li, Z., Liu, R., Yang, X.P., Pan, M., Lagrost, L., Fisher, E.A., and Williams, K.J. (2005) Phospholipid transfer protein deficiency impairs apolipoprotein-B secretion from hepatocytes by stimulating a proteolytic pathway through a relative deficiency of vitamin E and an increase in intracellular oxidants. J. Biol. Chem. 280:18336-40.
Hojjati, M.R., and Jiang, X.C. (2006) Rapid, specific and sensitive measurements of plasma sphingomyelin and phosphatidylcholine. J Lipid Res. 47:673-6.
Dong, J., Liu, J., Lou, B., Li, Z., Ye, X., Wu, M., and Jiang, X.C. (2006) Adenovirus-mediated overexpression of sphingomyelin synthase 1 and 2 increases the atherogenic potential in mice. J Lipid Res. 47:1307-14.
Zhou, H., Li, Z., Hojjati, M.R., Jang, D., Beyer, T.P., Cao, G., Tall, A.R., and Jiang, X.C. (2006) Adipose tissue specific CETP expression in mice: impact on lipoprotein metabolism. J Lipid Res. 47:2011-9.
Liu, R., Hojjati, M.R., Davlin, C.M., Hansen, I.H., and Jiang, X.C. (2007) Macrophage Phospholipid Transfer Protein Deficiency and ApoE Secretion: Impact on Mouse Plasma Cholesterol Levels and Atherosclerosis. Arterioscler Thromb Vasc Biol. 27:190-6.
Liu, R., Iqbal, J., Yeang, C., Wang, D.Q.H., Hussain, M., and Jiang, X.C. (2007) Phospholipid transfer protein deficient mice absorb less cholesterol. Arterioscler Thromb Vasc Biol. In press.