Structure and function of lecithin cholesterol acyl transferase: New insights from structural predictions and animal models

Current Opinion in Lipidology

Volumn 11, Issue 2, 2000, Pages 155-160

  Peelman, Frank ^a   Vandekerckhove, Joël ^b   Rosseneu, Maryvonne ^a  

^a GHENT UNIVERSITY   (Belgium)

^b DEPARTMENT OF PLANT SYSTEMS BIOLOGY   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

LIPID; PHOSPHATIDYLCHOLINE STEROL ACYLTRANSFERASE;

ATHEROSCLEROSIS; ENZYME SPECIFICITY; ENZYME STRUCTURE; GENE MUTATION; HUMAN; HYDROLYSIS; LIPID OXIDATION; LIPOPROTEIN METABOLISM; MOLECULAR MODEL; NONHUMAN; PATHOLOGY; PREDICTION; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; TRANSGENIC ANIMAL;

ANIMALS; ANIMALS, GENETICALLY MODIFIED; CARDIOVASCULAR DISEASES; LIPOPROTEINS, HDL; MICE; MODELS, MOLECULAR; MUTATION; PHOSPHATIDYLCHOLINE-STEROL O-ACYLTRANSFERASE; RABBITS;

ANIMALIA;

EID: 0034100270     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/00041433-200004000-00008     Document Type: Review

References (48)

1. 1 Glomset JA. The mechanism of the plasma cholesterol esterification reaction: plasma fatty acid transferase. Biochim Biophys Acta 1962; 65:128-135.
2. 2 Glomset JA, Assmann G, Gjone E, Norum KR. Lecithin:cholesterol acyltransferase deficiency and fish-eye disease. In: The metabolic and molecular bases of inherited disease. Scriver CR, Beaudet AL, Sly WS, Valle D (editors). New York: McGraw-Hill Book Co.; 1995. pp. 1933-1951.
3. 3 Jonas A. Regulation of lecithin cholesterol acyltransferase activity. Prog Lipid Res 1998; 37:209-234. The latest concepts about LCAT structure, function and contribution to lipoprotein metabolism are summarized and discussed in this extensive and well-documented review.
4. 4 Kuivenhoven JA, Pritchard H, Hill J, Frohlich J, Assmann G, Kastelein J. The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res 1997; 38:191-205.
5. 5 Hoeg JM, Santamarina FS, Berard AM, Cornhill JF, Herderick EE, Feldman SH, et al. Overexpression of lecithin:cholesterol acyltransferase in transgenic rabbits prevents diet-induced atherosclerosis. Proc Natl Acad Sci USA 1996; 93:11448-11453.
6. 6 Seguret MS, Latta MM, Castro G, Luc G, Fruchart JC, Rubin E, et al. Potential gene therapy for lecithin-cholesterol acyltransferase (LCAT)-deficient and hypoalphalipoproteinemic patients with adenovirus-mediated transfer of human LCAT gene. Circulation 1996; 94:2177-2184.
7. 7 Chisholm JW, Gebre AK, Parks JS. Characterization of C-terminal histidine-tagged human recombinant lecithin:cholesterol acyltransferase. J Lipid Res 1999; 40:1512-1519.
8. 8 Kosek AB, Durbin D, Jonas A. Binding affinity and reactivity of lecithin cholesterol acyltransferase with native lipoproteins. Biochem Biophys Res Commun 1999; 258:548-551.
9. 9 Jin L, Shieh JJ, Grabbe E, Adimoolam S, Durbin D, Jonas A. Surface plasmon resonance biosensor studies of human wild-type and mutant lecithin cholesterol acyltransferase interactions with lipoproteins. Biochemistry 1999; 38:15659-15665.
10. 10 Adimoolam S, Jin L, Grabbe E, Shieh JJ, Jonas A. Structural and functional properties of two mutants of lecithin-cholesterol acyltransferase (T123I and N228K). J Biol Chem 1998; 273:32561-32567. This paper is important because it represents the first expression of two recombinant LCAT mutants in sufficient amounts to enable physicochemical characterization, activity measurements and binding constants to different lipoprotein substrates. It demonstrates that, unlike lipases, LCAT dissociates from its substrates between catalytic cycles.
11. 11 Peelman F, Vanloo B, Perez-Mendez O, Decout A, Verschelde JL, Labeur C, et al. Characterization of functional residues in the interfacial recognition domain of lecithin cholesterol acyltransferase (LCAT). Protein Eng 1999; 12:71-78. Site-directed mutagenesis and activity measurements of LCAT mutants on monomeric and organized substrates, showed that residues 56-68 contribute to destabilization of a lipoprotein substrate and that W61 is important for substrate recognition.
12. 12 Perez-Mendez O, Vanloo B, Decout A, Goethals M, Peelman F, Vandekerckhove J, et al. Contribution of the hydrophobicity gradient of an amphipathic peptide to its mode of association with lipids. Eur J Biochem 1998; 256:570-579.
13. 13 Sparks DL, Frank PG, Braschi S, Neville TA, Marcel YL. Effect of apolipoprotein A-I lipidation on the formation and function of pre-beta and alpha-migrating LpA-I particles. Biochemistry 1999; 38:1727-1735.
14. 14 Huggins KW, Curtiss LK, Gebre AK, Parks JS. Effect of long chain polyunsaturated fatty acids in the sn-2 position of phosphatidylcholine on the interaction with recombinant high density lipoprotein apolipoprotein A-I. J Lipid Res 1998; 39:2423-2431.
15. 15 Subbaiah PV, Subramanian VS, Liu M. Trans unsaturated fatty acids inhibit lecithin:cholesterol acyltransferase and alter its positional specificity. J Lipid Res 1998; 39:1438-1447.
16. 16 Kanji SS, Kuohung W, Labaree DC, Hochberg RB. Regiospecific esterification of estrogens by lecithin:cholesterol acyltransferase. J Clin Endocrinol Metab 1999; 84:2481-2488. The authors compare the esterification specificty of LCAT for different sterols and show that, in contrast to most sterols which are esterified at the 3-beta-hydroxyl position, oestradiol is selectively esterified at the 17-beta-hydroxyl position by LCAT. This might be related to the antioxidant action of LCAT on LDL.
17. 17 Taniyama Y, Shibata S, Kita S, Horikoshi K, Fuse H, Shirafuji H, et al. Cloning and expression of a novel lysophospholipase which structurally resembles lecithin cholesterol acyltransferase. Biochem Biophys Res Commun 1999; 257:50-56.
18. 18 Peelman F, Verschelde JL, Vanloo B, Ampe C, Labeur C, Tavernier J, et al. Effects of natural mutations in lecithin:cholesterol acyltransferase on the enzyme structure and activity. J Lipid Res 1999; 40:59-69. Molecular modelling calculations, based upon the three-dimensional model built for wild-type LCAT (see Ref. [17]), were carried out for several natural LCAT mutants causing either FLD or FED. The results provide a structural interpretation for the impaired activity observed for mutants, and demonstrate that FLD and FED mutants cluster in different regions of the three-dimensional model.
19. 19 Peelman F, Vinaimont N, Verhee A, Vanloo B, Verschelde JL, Labeur C, et al. A proposed architecture for lecithin cholesterol acyl transferase (LCAT): identification of the catalytic triad and molecular modeling. Protein Sci 1998; 7:587-599. This is an important paper because it combines a structural approach, using structural homology calculations, together with site-directed mutagenesis and activity measurements on different substrates to identify the predicted catalytic residues of the enzyme. The results demonstrate that LCAT is a member of the α/β hydrolase family with a Ser/Asp/His catalytic triad and the same fold as lipases.
20. 20 Daum U, Leren TP, Langer C, Chirazi A, Cullen P, Pritchard PH, et al. Multiple dysfunctions of two apolipoprotein A-I variants, apoA-I(R160L)Oslo and apoA-I(P165R), that are associated with hypoalphalipoproteinemia in heterozygous carriers. J Lipid Res 1999; 40:486-494.
21. 21 Winder AF, Owen JS, Pritchard PH, Lloyd-Jones D, Vallance DT, White P, Wray R. A first British case of fish-eye disease presenting at age 75 years: a double heterozygote for defined and new mutations affecting LCAT structure and expression. J Clin Pathol 1999; 52:228-230.
22. 22 Teh EM, Chisholm JW, Dolphin PJ, Pouliquen Y, Savoldelli M, De Gennes JL, Benlian P. Classical LCAT deficiency resulting from a novel homozygous dinucleotide deletion in exon 4 of the human lecithin:cholesterol acyltransferase gene causing a frameshift and stop codon at residue 144. Atherosclerosis 1999; 146:141-151.
23. 23 Argyropoulos G, Jenkins A, Klein RL, Lyons T, Wagenhorst B, Marcovina SM, et al. Transmission of two novel mutations in a pedigree with familial lecithin:cholesterol acyltransferase deficiency: structure-function relationships and studies in a compound heterozygous proband. J Lipid Res 1998; 39:1870-1876.
24. 24 Brites FD, Fernandez KM, Zunino MJ, Vael MJ, Lardo M, Castro GR, Wikinski RL. Sindrome de deficiencia parcial de lecitina-colesterol aciltransferasa (LCAT). [Partial lecithin-cholesterol acyltransferase (LCAT) deficiency syndrome]. (in Spanish). Medicina (B. Aires) 1999; 59:89-92.
25. 25 Aouizerat BE, Allayee H, Cantor RM, Dallinga-Thie GM, Lanning CD, De Bruin TW, et al. Linkage of a candidate gene locus to familial combined hyperlipidemia:lecithin:cholesterol acyltransferase on 16q. Arterioscler Thromb Vasc Biol 1999; 19:2730-2736. This paper identifies the LCAT gene as a candidate contributor to familial combined hyperlipidaemia, together with the apolipoprotein AI/CIII/AIV gene locus.
26. 26 Mehlum A, Staels B, Duverger N, Tailleux A, Castro G, Fievet C, et al. Tissue-specific expression of the human gene for lecithin:cholesterol acyltransferase in transgenic mice alters blood lipids, lipoproteins and lipases towards a less atherogenic profile. Eur J Biochem 1995; 230:567-575.
27. 27 Brousseau ME, Hoeg JM. Transgenic rabbits as models for atherosclerosis research. J Lipid Res 1999; 40:365-375. This review discusses rabbit models of human lipoprotein disorders and the use of transgenic rabbits to provide new insights into the mechanisms responsible for the development of atherosclerosis. Results obtained with transgenic rabbits overexpressing LCAT are discussed at length.
28. 28 Berard AM, Foger B, Remaley A, Shamburek R, Vaisman BL, Talley G, et al. High plasma HDL concentrations associated with enhanced atherosclerosis in transgenic mice overexpressing lecithin-cholesteryl acyltransferase. Nat Med 1997; 3:744-749.
29. 29 Hoeg JM, Vaisman BL, Demosky Jr SJ, Meyn SM, Talley GD, Hoyt Jr RF, et al. Lecithin:cholesterol acyltransferase overexpression generates hyperalphalipoproteinemia and a nonatherogenic lipoprotein pattern in transgenic rabbits. J Biol Chem 1996; 271:4396-4402.
30. 30 Amar MJA, Shamburek RD, Foger B, Hoyt Jr RF, Wood DO, Santamarina-Fojo S, Brewer Jr HB. Adenovirus-mediated expression of LCAT in non-human primates leads to an antiatherogenic lipoprotein profile with increased HDL and decreased LDL. Circulation 1998; 98(17):1-35 Abstract 166.
31. 31 Brousseau ME, Santamarina-Fojo S, Vaisman BL, Applebaum-Bowden D, Berard AM, Talley GD, et al. Overexpression of human lecithin:cholesterol acyltransferase in cholesterol-fed rabbits: LDL metabolism and HDL metabolism are affected in a gene dose-dependent manner. J Lipid Res 1997; 38:2537-2547.
32. 32 Brousseau ME, Santamarina FS, Zech LA, Berard AM, Vaisman BL, Meyn SM, et al. Hyperalphalipoproteinemia in human lecithin cholesterol acyltransferase transgenic rabbits. In vivo apolipoprotein A-I catabolism is delayed in a gene dose-dependent manner. J Clin Invest 1996; 97:1844-1851.
33. 33 Mehlum A, Muri M, Hagve TA, Solberg LA, Prydz H. Mice overexpressing human lecithin:cholesterol acyltransferase are not protected against diet-induced atherosclerosis. APMIS 1997; 105:861-868.
34. 34 Foger B, Vaisman BL, Paigen B, Hoyt Jr RF, Brewer Jr HB, Santamarina-Fojo S. CETP modulates the development of aortic atherosclerosis in LCAT-transgenic mice. Circulation 1997; 96:1-110 Abstract 613.
35. 35 Ng DS, Francone OL, Forte TM, Zhang J, Haghpassand M, Rubin EM. Disruption of the murine lecithin:cholesterol acyltransferase gene causes impairment of adrenal lipid delivery and up-regulation of scavenger receptor class B type I. J Biol Chem 1997; 272:15777-15781.
36. 36 Sakai N, Vaisman BL, Koch CA, Hoyt RFJ, Meyn SM, Talley GD, et al. Targeted disruption of the mouse lecithin:cholesterol acyltransferase (LCAT) gene. Generation of a new animal model for human LCAT deficiency. J Biol Chem 1997; 272:7506-7510.
37. 37 Subramanian VS, Goyal J, Miwa M, Sugatami J, Akiyama M, Liu M, Subbaiah PV. Role of lecithin-cholesterol acyltransferase in the metabolism of oxidized phospholipids in plasma: studies with platelet-activating factor-acetyl hydrolase-deficient plasma. Biochim Biophys Acta 1999; 1439:95-109.
38. 38 Itabe H, Hosoya R, Karasawa K, Jimi S, Saku K, Takebayashi S, et al. Metabolism of oxidized phosphatidylcholines formed in oxidized low density lipoprotein by lecithin-cholesterol acyltransferase. J Biochem (Tokyo) 1999; 126:153-161.
39. 39 Goyal J, Wang K, Liu M, Subbaiah PV. Novel function of lecithin-cholesterol acyltransferase. Hydrolysis of oxidized polar phospholipids generated during lipoprotein oxidation. J Biol Chem 1997; 272:16231-16239.
40. 40 Vohl MC, Neville TA, Kumarathasan R, Braschi S, Sparks DL. A novel lecithin-cholesterol acyltransferase antioxidant activity prevents the formation of oxidized lipids during lipoprotein oxidation. Biochemistry 1999; 38:5976-5981.
41. 41 Bielicki JK, Forte TM. Evidence that lipid hydroperoxides inhibit plasma lecithin:cholesterol acyltransferase activity. J Lipid Res 1999; 40:948-954.
42. 42 Davit-Spraul A, Therond P, Leroy A, Palmade-Rieunier F, Rousset C, Moatti N, Legrand A. Inhibition of lecithin cholesterol acyltransferase by phosphatidylcholine hydroperoxides. FEBS Lett 1999; 447:106-110.
43. 43 Jimi S, Uesugi N, Saku K, Itabe H, Zhang B, Arakawa K, Takebayashi S. Possible induction of renal dysfunction in patients with lecithin:cholesterol acyltransferase deficiency by oxidized phosphatidylcholine in glomeruli. Arterioscler Thromb Vasc Biol 1999; 19:794-801. These authors show that LCAT deficiency patients have increased plasma oxidized phosphatidylcholine-modified LDL concentrations. Oxidized phosphatidylcholines are also found extracellularly in glomerular lesions, which might contribute to the renal insufficiency observed in patients.
44. 44 Forte TM, Oda MN, Knoff L, Frei B, Suh J, Harmony JA, et al. Targeted disruption of the murine lecithin:cholesterol acyltransferase gene is associated with reductions in plasma paraoxonase and platelet-activating factor acetylhydrolase activities but not in apolipoprotein J concentration. J Lipid Res 1999; 40:1276-1283. Targeted disruption of the LCAT gene in mice not only leads to the absence of LCAT, but also to a reduced concentration of paraoxonase and platelet activating factor, two other enzymes that protect against LDL oxidation.
45. 45 Riemens SC, Van Tol A, Sluiter WJ, Dullaart RP. Acute and chronic effects of a 24-hour intravenous triglyceride emulsion challenge on plasma lecithin:cholesterol acyltransferase, phospholipid transfer protein, and cholesteryl ester transfer protein activities. J Lipid Res 1999; 40:1459-1466.
46. 46 Riemens SC, Van Tol A, Stulp BK, Dullaart RP. Influence of insulin sensitivity and the TaqIB cholesteryl ester transfer protein gene polymorphism on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities and their response to hyperinsulinemia in non-diabetic men. J Lipid Res 1999; 40:1467-1474.
47. 47 Sakurai T, Akiyama H, Oka T, Sekita K, Yokono K, Goto T. Serum lipids status in patients with diabetic uremia on 10 years of maintenance hemodialysis. Kidney Int 1999; 71 (Suppl.):S216-S218.
48. 48 Collet X, Francone O, Besnard F, Fielding CJ. Secretion of lecithin:cholesterol acyltransferase by brain neuroglial cell lines. Biochem Biophys Res Commun 1999; 258:73-76. This paper demonstrates for the first time that LCAT is produced by neuroglial cells and that it might play a metabolic role in cholesterol homeostasis in the brain.