Cholesterol trafficking-related serum lipoprotein functions in children with cholesteryl ester storage disease.
OBJECTIVE
Serum lipoproteins influence cell cholesterol content by delivering and removing cholesterol to/from cells, functions mainly exerted by LDL and HDL, respectively. Especially in the case of HDL, structure and composition are crucial for function, beyond serum levels. Cholesteryl ester storage disease (CESD) is caused by LIPA gene mutations and reduced activity of lysosomal acid lipase (LAL), the enzyme responsible for hydrolysis of cholesteryl esters and TG. CESD patients typically present dyslipidaemia, liver damage and premature atherosclerosis. The objective of this work was to evaluate serum HDL cholesterol efflux capacity (CEC) and serum cholesterol loading capacity (CLC) in CESD pediatric patients and to study lipoprotein qualitative modifications.


METHODS
HDL CEC was evaluated by radioisotopic techniques, serum CLC was measured by a fluorimetric assay, HDL subclasses were determined by two-dimensional electrophoresis.


RESULTS
CESD patients (n = 3) displayed on average increased LDL cholesterol (+163%; p = 0.019), TG (+203; p = 0.012), phospholipids (+40%; p = 0.024) and lower HDL cholesterol (-57%; p = 0.012) compared to controls (n = 9). CESD HDL CEC was impaired both as a whole (average reduction of 26%; p < 0.0001) and with respect to specific membrane cholesterol transporters (-23% for aqueous diffusion; p = 0.005; -32% for ABCA1-efflux; p = 0.0002; -60% for SR-BI-efflux; p < 0.0001; -42% for ABCG1-efflux p = 0.0003). A marked reduction in the pre-β HDL concentration (-69%; p = 0.012) was detected. Finally, CESD serum CLC was significantly increased (+21%; p = 0.0007).


CONCLUSIONS
These new data demonstrate that the pro-atherogenic modifications of serum include disturbances in lipoprotein functions involved in cell cholesterol homeostasis occurring from very early age in CESD patients.
Department of Pharmacy, University of Parma, Parma, Italy.
Francesca
F
Zimetti
Department of Pharmacy, University of Parma, Parma, Italy. Electronic address: elda.favari@unipr.it.
Elda
E
Favari
Department of Health Science and Pediatrics, University of Torino, Torino, Italy.
Paola
P
Cagliero
Department of Pharmacy, University of Parma, Parma, Italy.
Maria Pia
MP
Adorni
Department of Pharmacy, University of Parma, Parma, Italy.
Nicoletta
N
Ronda
Department of Medical Sciences, University of Torino, Torino, Italy.
Renato
R
Bonardi
Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Monica
M
Gomaraschi
Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Laura
L
Calabresi
Department of Pharmacy, University of Parma, Parma, Italy.
Franco
F
Bernini
Department of Health Science and Pediatrics, University of Torino, Torino, Italy.
Ornella
O
Guardamagna
D050197:Atherosclerosis / Q000097:blood* / Q000150:complications; D001692:Biological Transport; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000097:blood; D015217:Cholesterol Ester Storage Disease / Q000097:blood* / Q000150:complications; D008076:Cholesterol, HDL / Q000097:blood; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005470:Fluorometry; D005487:Foam Cells / Q000166:cytology; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood; D008297:Male; D012307:Risk Factors
D008076:Cholesterol, HDL; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D002784:Cholesterol
Atherosclerosis; Cholesterol efflux capacity; Cholesterol loading capacity; Cholesteryl ester storage disease; HDL; Lipoproteins; Lysosomal acid lipase