doi: 10.1161/CIRCULATIONAHA.108.818143
(Circulation. 2009;120:628-635.)
© 2009 American Heart Association, Inc.
Vascular Medicine |
Functional Lecithin: Cholesterol Acyltransferase Is Not Required for Efficient Atheroprotection in Humans
From the Center E. Grossi Paoletti, Department of Pharmacological Sciences, Università degli Studi di Milano, Milano (L.C., D.B., S.C., P.C., B.F., C.R.S., G.F.); Monzino Cardiologic Institute, Istituto Di Ricovero e Cura a Carattere Scientifico, Milano (D.B., M.A., F.V.); Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena (L.B., C.C., S.C.); Department of Internal Medicine, S. Giovanni e Paolo Hospital, Venezia (P.A.); Department of Clinical and Applied Medical Therapy, University of Roma "La Sapienza," Roma (M.A.); Department of Nephrology, Ospedale di Gorizia, Gorizia (G.B.); Metabolic Unit, Department of Internal Medicine, Ospedali Riuniti and University of Trieste, Trieste (L.C.); Department of Biomedical Sciences, University of Foggia, Foggia (L.G.); Institute of Clinical Physiology, CNR, Pisa (T.S.); and Internal Medicine, Angiology, and Atherosclerosis, Department of Clinical and Experimental Medicine, University of Perugia, Perugia (G.V.), Italy.
Correspondence to Guido Franceschini, PhD, Center E. Grossi Paoletti, Department of Pharmacological Sciences, Via Balzaretti 9, 20133 Milano, Italy. E-mail guido.franceschini{at}unimi.it
Received January 3, 2009; accepted May 22, 2009.
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.
Methods and 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.
CLINICAL PERSPECTIVE
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