Department of Cell Biology Faculty

New Genes Involoved in Lipoprotein Metabolism and Atherosclerosis

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 very interesting to study the underlyng 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 XC, Bruce C, Mar J, Lin M, Ji Y, Francone OL, Tall AR. Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels. J Clin Invest. 1999;103:907-14.

Kawano K, Qin SC, Lin M, Tall AR, Jiang XC. Cholesteryl ester transfer protein and phospholipid transfer protein have nonoverlapping functions in vivo. J Biol Chem. 2000;275:29477-81.

Jiang XC, Paultre F, Pearson TA, Reed RG, Francis CK, Lin M, Berglund L, Tall AR. Plasma sphingomyelin level as a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol. 2000;20:2614-8.

Jiang XC, Qin S, Qiao C, Kawano K, Lin M, Skold A, Xiao X, Tall AR. Apolipoprotein B secretion and atherosclerosis are decreased in mice with phospholipid-transfer protein deficiency. Nat Med. 2001;7:847-52. Erratum in: Nat Med 2001;7:973.

Jiang XC, Tall AR, Qin S, Lin M, Schneider M, Lalanne F, Deckert V, Desrumaux C, Athias A, Witztum JL, Lagrost L. Phospholipid transfer protein deficiency protects circulating lipoproteins from oxidation due to the enhanced accumulation of vitamin E. J Biol Chem. 2002;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. Phospholipid transfer protein is regulated by liver X receptors in vivo. J Biol Chem. 2002;277:39561-5.

Yang XP, Yan D, Qiao C, Liu RJ, Chen JG, Li J, Schneider M, Lagrost L, Xiao X, Jiang XC. Increased atherosclerotic lesions in apoE mice with plasma phospholipid transfer protein overexpression. Arterioscler Thromb Vasc Biol. 2003;23:1601-7.

Schlitt A, Bickel C, Thumma P, Blankenberg S, Rupprecht HJ, Meyer J, Jiang XC. High plasma phospholipid transfer protein levels as a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol. 2003;23:1857-62.

Jiang XC, Beyer TP, Li Z, Liu J, Quan W, Schmidt RJ, Zhang Y, Bensch WR, Eacho PI, Cao G. Enlargement of high density lipoprotein in mice via liver X receptor activation requires apolipoprotein E and is abolished by cholesteryl ester transfer protein expression. J Biol Chem. 2003;278:49072-8.

Yan D, Navab M, Bruce C, Fogelman AM, Jiang XC. PLTP deficiency improves the anti-inflammatory properties of HDL and reduces the ability of LDL to induce monocyte chemotactic activity. J Lipid Res. 2004;45:1852-8.

Hojjati MR, Li Z, Zhou H, Tang S, Huan C, Ooi E, Lu S, Jiang XC. Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice. J Biol Chem. 2005;280:10284-9.

Jiang XC, Li Z, Liu R, Yang XP, Pan M, Lagrost L, Fisher EA, Williams KJ 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. 2005;280:18336-40.

Dong J, Liu J, Lou B, Li Z, Ye X, Wu M, Jiang XC. Adenovirus-mediated overexpression of sphingomyelin synthases 1 and 2 increases the atherogenic potential in mice. J Lipid Res. 2006;47:1307-14.

 Zhou H, Li Z, Hojjati MR, Jang D, Beyer TP, Cao G, Tall AR, Jiang XC. Adipose tissue-specific CETP expression in mice: impact on plasma lipoprotein metabolism. J Lipid Res. 2006;47:2011-9.

Liu R, Hojjati MR, Devlin CM, Hansen IH, Jiang XC. Macrophage phospholipid transfer protein deficiency and ApoE secretion: impact on mouse plasma cholesterol levels and atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27:190-6.

Liu R, Iqbal J, Yeang C, Wang DQ, Hussain MM, Jiang XC. Phospholipid transfer protein-deficient mice absorb less cholesterol. Arterioscler Thromb Vasc Biol. 2007;27:2014-21.

Ding T, Li Z, Hailemariam T, Mukherjee S, Maxfield FR, Wu MP, Jiang XC. SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis. J Lipid Res. 2008;49:376-85.

Jiang XC. Generation of adipose tissue-specific transgenic mouse models. Methods Mol Biol. 2008;456:55-64.

Hailemariam TK, Huan C, Liu J, Li Z, Roman C, Kalbfeisch M, Bui HH, Peake DA, Kuo MS, Cao G, Wadgaonkar R, Jiang XC. Sphingomyelin synthase 2 deficiency attenuates NFkappaB activation. Arterioscler Thromb Vasc Biol. 2008;28:1519-26.

Schlitt A, Blankenberg S, Bickel C, Lackner KJ, Heine GH, Buerke M, Werdan K, Maegdefessel L, Raaz U, Rupprecht HJ, Munzel T, Jiang XC. PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene Study. J Lipid Res. 2009;50:723-9.

Li Z, Park TS, Li Y, Pan X, Iqbal J, Lu D, Tang W, Yu L, Goldberg IJ, Hussain MM, Jiang XC. Serine palmitoyltransferase (SPT) deficient mice absorb less cholesterol. Biochim Biophys Acta. 2009;1791:297-306.

Liu J, Zhang H, Li Z, Hailemariam TK, Chakraborty M, Qiu D, Bui HH, Peake DA, Kuo MS, Wadgaonkar R, Cao G, Jiang XC. Sphingomyelin Synthase 2 Is One of the Determinants for Plasma and Liver Sphingomyelin Levels in Mice. Arterioscler Thromb Vasc Biol. 2009; 105:295-303.

Cavusoglu E, Marmur JD, Chhabra S, Chopra V, Eng C, Jiang XC. Relation of baseline plasma phospholipid transfer protein (PLTP) activity to left ventricular systolic dysfunction in patients referred for coronary angiography. Atherosclerosis. 2009. In press.

Liu J, Huan C, Chakraborty M, Zhang H, Lu D, Kuo M, Cao G, Jiang XC. Macrophage Sphingomyelin Synthase 2 (SMS2) Deficiency Decreases Atherosclerosis in Mice. Cir. Res. 2009 in press.

Li Z, Li Y, Chakraborty M, Fan Y, Bui HH, Peake D.A, Kuo MS, Xiao X, Cao G, Jiang XC. Liver-specific deficiency of serine palmitoyltransferase (SPT) subunit 2 decreases plasma sphingomyelin and apolipoprotein E levels. J. Biol. Chem. 2009 In press.

List of Publications (Pub Med)