Functional lecithin: cholesterol acyltransferase is not required for efficient atheroprotection in humans.
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.
Calabresi
Laura
L
Center E. Grossi Paoletti, Department of Pharmacological Sciences, Università degli Studi di Milano, 20133 Milano, Italy.
Baldassarre
Damiano
D
Castelnuovo
Samuela
S
Conca
Paola
P
Bocchi
Letizia
L
Candini
Chiara
C
Frigerio
Beatrice
B
Amato
Mauro
M
Sirtori
Cesare R
CR
Alessandrini
Paola
P
Arca
Marcello
M
Boscutti
Giuliano
G
Cattin
Luigi
L
Gesualdo
Loreto
L
Sampietro
Tiziana
T
Vaudo
Gaetano
G
Veglia
Fabrizio
F
Calandra
Sebastiano
S
Franceschini
Guido
G
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
D008076:Cholesterol, HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase