Lipid transfer proteins (LTP) and atherosclerosis.
This review deals with four lipid transfer proteins (LTP): three are involved in cholesteryl ester (CE) synthesis or transport, the fourth deals with plasma phospholipid (PL) transfer. Experimental models of atherosclerosis, clinical and epidemiological studies provided information as to the relationship of these LTP(s) to atherosclerosis, which is the main focus of this review. Thus, inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) 1 and 2 decreases cholesterol absorption, plasma cholesterol and aortic cholesterol esterification in the aorta. The discovery that tamoxifen is a potent ACAT inhibitor explained the plasma cholesterol lowering of the drug. The use of ACAT inhibition in humans is under current investigation. As low cholesteryl ester transfer protein (CETP) activity is connected with high HDL-C, several CETP inhibitors were tried in rabbits, with variable results. A new CETP inhibitor, Torcetrapib, was tested in humans and there was a 50-100% increase in HDL-C. Lecithin cholesterol acyl-transferase (LCAT) influences oxidative stress, which can be lowered by transient LCAT gene transfer in LCAT-/- mice. Phospholipid transfer protein (PLTP) deficiency reduced apo B production in apo E-/- mice, as well as oxidative stress in four models of mouse atherosclerosis. In conclusion, the ability to increase HDL-C so markedly by inhibitors of CETP introduces us into a new era in prevention and treatment of coronary heart disease (CHD).
Stein
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Department of Experimental Medicine and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Stein
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D000042:Absorption; D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors; D016021:Epidemiologic Studies; D018014:Gene Transfer Techniques; D006023:Glycoproteins / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D018384:Oxidative Stress; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000097587:Sterol O-Acyltransferase 2
D002352:Carrier Proteins; D002784:Cholesterol; D053480:Cholesterol Ester Transfer Proteins; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D008565:Membrane Proteins; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D049294:Phospholipid Transfer Proteins; D011804:Quinolines; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C506642:CETP protein, human; C483909:torcetrapib; C493492:sterol O-acyltransferase 1