title: Functional lecithin: cholesterol acyltransferase is not required for efficient atheroprotection in humans.
abstract: BACKGROUND
  Mutations in the LCAT gene cause lecithin:cholesterol acyltransferase (LCAT) deficiency, a very rare metabolic disorder with 2 hypoalphalipoproteinemia syndromes: classic familial LCAT deficiency (Online Mendelian Inheritance in Man No. 245900), characterized by complete lack of enzyme activity, and fish-eye disease (Online Mendelian Inheritance in Man No. 136120), with a partially defective enzyme. Theoretically, hypoalphalipoproteinemia cases with LCAT deficiency should be at increased cardiovascular risk because of high-density lipoprotein deficiency and defective reverse cholesterol transport.
  
  
  RESULTS
  The extent of preclinical atherosclerosis was assessed in 40 carriers of LCAT gene mutations from 13 Italian families and 80 healthy controls by measuring carotid intima-media thickness (IMT). The average and maximum IMT values in the carriers were 0.07 and 0.21 mm smaller than in controls (P=0.0003 and P=0.0027), respectively. Moreover, the inheritance of a mutated LCAT genotype had a remarkable gene-dose-dependent effect in reducing carotid IMT (P=0.0003 for average IMT; P=0.001 for maximum IMT). Finally, no significant difference in carotid IMT was found between carriers of LCAT gene mutations that cause total or partial LCAT deficiency (ie, familial LCAT deficiency or fish-eye disease).
  
  
  CONCLUSIONS
  Genetically determined low LCAT activity in Italian families is not associated with enhanced preclinical atherosclerosis despite low high-density lipoprotein cholesterol levels. This finding challenges the notion that LCAT is required for effective atheroprotection and suggests that elevating LCAT expression or activity is not a promising therapeutic strategy to reduce cardiovascular risk.
authors.affiliation: Center E. Grossi Paoletti, Department of Pharmacological Sciences, Università degli Studi di Milano, 20133 Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Calabresi
authors.forename: Damiano
authors.initials: D
authors.lastname: Baldassarre
authors.forename: Samuela
authors.initials: S
authors.lastname: Castelnuovo
authors.forename: Paola
authors.initials: P
authors.lastname: Conca
authors.forename: Letizia
authors.initials: L
authors.lastname: Bocchi
authors.forename: Chiara
authors.initials: C
authors.lastname: Candini
authors.forename: Beatrice
authors.initials: B
authors.lastname: Frigerio
authors.forename: Mauro
authors.initials: M
authors.lastname: Amato
authors.forename: Cesare R
authors.initials: CR
authors.lastname: Sirtori
authors.forename: Paola
authors.initials: P
authors.lastname: Alessandrini
authors.forename: Marcello
authors.initials: M
authors.lastname: Arca
authors.forename: Giuliano
authors.initials: G
authors.lastname: Boscutti
authors.forename: Luigi
authors.initials: L
authors.lastname: Cattin
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
authors.forename: Tiziana
authors.initials: T
authors.lastname: Sampietro
authors.forename: Gaetano
authors.initials: G
authors.lastname: Vaudo
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Veglia
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.forename: Guido
authors.initials: G
authors.lastname: Franceschini
mesh_terms: D000328:Adult; D000483:Alleles; D050197:Atherosclerosis / Q000453:epidemiology / Q000503:physiopathology* / Q000517:prevention & control*; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007558:Italy; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics* / Q000502:physiology*; D012307:Risk Factors; D017539:Tunica Intima / Q000000981:diagnostic imaging; D017540:Tunica Media / Q000000981:diagnostic imaging; D014463:Ultrasonography
chemical_list: D008076:Cholesterol, HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase