Advertisement

CETP activity variation in mice does not affect two major HDL antiatherogenic properties: Macrophage-specific reverse cholesterol transport and LDL antioxidant protection

      Abstract

      CETP inhibition increases HDL cholesterol levels and presumably could contribute to human atheroprotection via increasing macrophage-specific reverse cholesterol transport (RCT) and antioxidant properties of HDL. However, the impact of CETP activity variation on these two antiatherogenic functions of HDL remain unknown. In this study, we assessed the effects of overexpressing CETP in transgenic (Tg) mice on macrophage-specific RCT and HDL ability to protect against LDL oxidative modification. [3H]cholesterol-labeled macrophages were injected intraperitoneally into mice maintained on a chow diet or an atherogenic diet, after which the appearance of [3H]cholesterol in plasma, liver and feces over 48 h was determined. The degree of protection of oxidative modification of LDL coincubated with HDL was evaluated by measuring relative electrophoretic mobility and dichlorofluorescein fluorescence. CETP-Tg mice presented decreased radiolabeled HDL-bound [3H]cholesterol 24 and 48 h after the label injection. However, the magnitude of macrophage-derived [3H]cholesterol in liver and feces did not differ between CETP-Tg and control mice on either diet. Similar results were found when [3H]cholesterol-labeled endogenous peritoneal macrophages were injected into the CETP-Tg and control mice. Further, the injection of endogenous macrophages from CETP-Tg mice did not alter macrophage RCT in control mice. HDL from CETP-Tg and control mice protected LDL from oxidative modification similarly, and paraoxonase 1, platelet activated factor acetyl-hydrolase and lecithin-cholesterol acyl transferase activities of transgenic mice did not differ from those of control mice. In conclusion, CETP overexpression in transgenic mice does not affect RCT from macrophages to feces in vivo or the protection conferred by HDL against LDL oxidative modification.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Gordon D.J.
        • Rifkind B.M.
        High-density lipoprotein—the clinical implications of recent studies.
        N Engl J Med. 1989; 321: 1311-1316
        • Tall A.R.
        Plasma cholesteryl ester transfer protein.
        J Lipid Res. 1993; 34: 1255-1274
        • de Grooth G.J.
        • Klerkx A.H.
        • Stroes E.S.
        • et al.
        A review of CETP and its relation to atherosclerosis.
        J Lipid Res. 2004; 45: 1967-1974
        • Forrester J.S.
        • Makkar R.
        • Shah P.K.
        Increasing high-density lipoprotein cholesterol in dyslipidemia by cholesteryl ester transfer protein inhibition: an update for clinicians.
        Circulation. 2005; 111: 1847-1854
        • Klerkx A.H.
        • El Harchaoui K.
        • van der Steeg W.A.
        • et al.
        Cholesteryl ester transfer protein (CETP) inhibition beyond raising high-density lipoprotein cholesterol levels. pathways by which modulation of cetp activity may alter atherogenesis.
        Arterioscler Thromb Vasc Biol. 2006; 26: 706-715
        • Agellon L.B.
        • Walsh A.
        • Hayek T.
        • et al.
        Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice.
        J Biol Chem. 1991; 266: 10796-10801
        • Marotti K.R.
        • Castle C.K.
        • Murray R.W.
        • et al.
        The role of cholesteryl ester transfer protein in primate apolipoprotein A-I metabolism. Insights from studies with transgenic mice.
        Arterioscler Thromb. 1992; 12: 736-744
        • Escola-Gil J.C.
        • Calpe-Berdiel L.
        • Palomer X.
        • et al.
        Antiatherogenic role of high-density lipoproteins: insights from genetically engineered-mice.
        Front Biosci. 2006; 11: 1328-1348
        • Marotti K.R.
        • Castle C.K.
        • Boyle T.P.
        • et al.
        Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein.
        Nature. 1993; 364: 73-75
        • Hayek T.
        • Masucci-Magoulas L.
        • Jiang X.
        • et al.
        Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene.
        J Clin Invest. 1995; 96: 2071-2074
        • Plump A.S.
        • Masucci-Magoulas L.
        • Bruce C.
        • et al.
        Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1105-1110
        • Escola-Gil J.C.
        • Julve J.
        • Marzal-Casacuberta A.
        • et al.
        ApoA-II expression in CETP transgenic mice increases VLDL production and impairs VLDL clearance.
        J Lipid Res. 2001; 42: 241-248
        • Westerterp M.
        • van der Hoogt C.C.
        • de Haan W.
        • et al.
        Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice.
        Arterioscler Thromb Vasc Biol. 2006; 26: 2552-2559
        • Foger B.
        • Chase M.
        • Amar M.J.
        • et al.
        Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice.
        J Biol Chem. 1999; 274: 36912-36920
        • MacLean P.S.
        • Bower J.F.
        • Vadlamudi S.
        • et al.
        Cholesteryl ester transfer protein expression prevents diet-induced atherosclerotic lesions in male db/db mice.
        Arterioscler Thromb Vasc Biol. 2003; 23: 1412-1415
        • Linsel-Nitschke P.
        • Tall A.R.
        HDL as a target in the treatment of atherosclerotic cardiovascular disease.
        Nat Rev Drug Discov. 2005; 4: 193-205
        • Osono Y.
        • Woollett L.A.
        • Marotti K.R.
        • et al.
        Centripetal cholesterol flux from extrahepatic organs to the liver is independent of the concentration of high density lipoprotein-cholesterol in plasma.
        Proc Natl Acad Sci USA. 1996; 93: 4114-4119
        • Alam K.
        • Meidell R.S.
        • Spady D.K.
        Effect of up-regulating individual steps in the reverse cholesterol transport pathway on reverse cholesterol transport in normolipidemic mice.
        J Biol Chem. 2001; 276: 15641-15649
        • Harada L.M.
        • Amigo L.
        • Cazita P.M.
        • et al.
        CETP expression enhances liver HDL-cholesteryl ester uptake but does not alter VLDL and biliary lipid secretion.
        Atherosclerosis. 2007; 191: 313-318
        • Brousseau M.E.
        • Diffenderfer M.R.
        • Millar J.S.
        • et al.
        Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1057-1064
        • Zhang Y.
        • Zanotti I.
        • Reilly M.P.
        • et al.
        Overexpression of apolipoprotein A-I promotes reverse transport of cholesterol from macrophages to feces in vivo.
        Circulation. 2003; 108: 661-663
        • Rotllan N.
        • Ribas V.
        • Calpe-Berdiel L.
        • et al.
        Overexpression of human apolipoprotein A-II in transgenic mice does not impair macrophage-specific reverse cholesterol transport in vivo.
        Arterioscler Thromb Vasc Biol. 2005; 25: e128-e132
        • Calpe-Berdiel L.
        • Rotllan N.
        • Palomer X.
        • et al.
        Direct evidence in vivo of impaired macrophage-specific reverse cholesterol transport in ATP-binding cassette transporter A1-deficient mice.
        Biochim Biophys Acta. 2005; 1738: 6-9
        • Moore R.E.
        • Navab M.
        • Millar J.S.
        • et al.
        Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation.
        Circ Res. 2005; 97: 763-771
        • Noto H.
        • Kawamura M.
        • Hashimoto Y.
        • et al.
        Modulation of HDL metabolism by probucol in complete cholesteryl ester transfer protein deficiency.
        Atherosclerosis. 2003; 171: 131-136
        • Bisoendial R.J.
        • Hovingh G.K.
        • El Harchaoui K.
        • et al.
        Consequences of cholesteryl ester transfer protein inhibition in patients with familial hypoalphalipoproteinemia.
        Arterioscler Thromb Vasc Biol. 2005; 25: e133-e134
        • Zhang B.
        • Fan P.
        • Shimoji E.
        • et al.
        Inhibition of cholesteryl ester transfer protein activity by JTT-705 increases apolipoprotein E-containing high-density lipoprotein and favorably affects the function and enzyme composition of high-density lipoprotein in rabbits.
        Arterioscler Thromb Vasc Biol. 2004; 24: 1910-1915
        • Huang Z.
        • Inazu A.
        • Nohara A.
        • et al.
        Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia.
        Clin Sci (Lond). 2002; 103: 587-594
        • Trocho C.
        • Escola-Gil J.C.
        • Ribas V.
        • et al.
        Phenytoin treatment reduces atherosclerosis in mice through mechanisms independent of plasma HDL-cholesterol concentration.
        Atherosclerosis. 2004; 174: 275-285
        • Ribas V.
        • Sanchez-Quesada J.L.
        • Anton R.
        • et al.
        Human apolipoprotein A-II enrichment displaces paraoxonase from HDL and impairs its antioxidant properties: a new mechanism linking HDL protein composition and antiatherogenic potential.
        Circ Res. 2004; 95: 789-797
        • Calpe-Berdiel L.
        • Escola-Gil J.C.
        • Ribas V.
        • et al.
        Changes in intestinal and liver global gene expression in response to a phytosterol-enriched diet.
        Atherosclerosis. 2005; 181: 75-85
        • Marzal-Casacuberta A.
        • Blanco-Vaca F.
        • Ishida B.Y.
        • et al.
        Functional lecithin:cholesterol acyltransferase deficiency and high density lipoprotein deficiency in transgenic mice overexpressing human apolipoprotein A-II.
        J Biol Chem. 1996; 271: 6720-6728
        • Serrat-Serrat J.
        • Ordonez-Llanos J.
        • Serra-Grima R.
        • et al.
        Marathon runners presented lower serum cholesteryl ester transfer activity than sedentary subjects.
        Atherosclerosis. 1993; 101: 43-49
        • Stein O.
        • Dabach Y.
        • Hollander G.
        • et al.
        Reverse cholesterol transport in mice expressing simian cholesteryl ester transfer protein.
        Atherosclerosis. 2002; 164: 73-78
        • Cuchel M.
        • Rader D.J.
        Macrophage reverse cholesterol transport: key to the regression of atherosclerosis?.
        Circulation. 2006; 113: 2548-2555
        • Rader D.J.
        Molecular regulation of HDL metabolism and function: implications for novel therapies.
        J Clin Invest. 2006; 116: 3090-3100
        • Masson D.
        • Staels B.
        • Gautier T.
        • et al.
        Cholesteryl ester transfer protein modulates the effect of liver X receptor agonists on cholesterol transport and excretion in the mouse.
        J Lipid Res. 2004; 45: 543-550
        • Van Eck M.
        • Ye D.
        • Hildebrand R.B.
        • et al.
        Important role for bone marrow-derived cholesteryl ester transfer protein in lipoprotein cholesterol redistribution and atherosclerotic lesion development in LDL receptor knockout mice.
        Circ Res. 2007; 100: 678-685
        • Zhang Y.
        • Da Silva J.R.
        • Reilly M.
        • et al.
        Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo.
        J Clin Invest. 2005; 115: 2870-2874
        • Gauthier A.
        • Lau P.
        • Zha X.
        • et al.
        Cholesteryl ester transfer protein directly mediates selective uptake of high density lipoprotein cholesteryl esters by the liver.
        Arterioscler Thromb Vasc Biol. 2005; 25: 2177-2184
        • Cazita P.M.
        • Berti J.A.
        • Aoki C.
        • et al.
        Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice.
        J Lipid Res. 2003; 44: 33-40
        • Chiang J.Y.
        Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms.
        J Hepatol. 2004; 40: 539-551
        • Luo Y.
        • Tall A.R.
        Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element.
        J Clin Invest. 2000; 105: 513-520
        • Blanco-Vaca F.
        • Escola-Gil J.C.
        • Martin-Campos J.M.
        • et al.
        Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein.
        J Lipid Res. 2001; 42: 1727-1739
        • Chiba H.
        • Akita H.
        • Kotani K.
        • et al.
        Complete cholesteryl ester transfer protein deficiency increases oxidized-LDL in plasma.
        Rinsho Byori. 1997; 45: 55-57