Increased scavenger receptor class B type I-mediated cellular cholesterol efflux and antioxidant capacity in the sera of glycogen storage disease type Ia patients

doi:10.1016/j.ymgme.2006.05.002

Molecular Genetics and Metabolism

Volume 89, Issue 3, November 2006, Pages 233-238

https://doi.org/10.1016/j.ymgme.2006.05.002 Get rights and content

Abstract

Glycogen storage disease type Ia (GSD-Ia) is characterized by hypercholesterolemia, hypertriglyceridemia, decreased cholesterol in high density lipoprotein and increased cholesterol in low and very low density lipoprotein fractions. Despite this pro-atherogenic lipid profile, GSD-Ia patients are not at elevated risk for atherosclerosis. Studies have shown that reverse cholesterol transport and antioxidant capacity can be protective against atherosclerosis. In this study, we show that sera from GSD-Ia patients are more efficient than sera from control subjects in promoting the scavenger receptor class B type I (SR-BI)-mediated cellular cholesterol efflux, a key component in reverse cholesterol transport. The major determinants of the SR-BI-mediated cholesterol efflux are serum phospholipid (PL) and HDL-PL. Phospholipid and that ratio of HDL-PL to HDL are increased in GSD-Ia patients. We further show that sera from GSD-Ia patients have increased total antioxidant capacity compared to controls and this increase correlates with elevated levels of uric acid, a powerful plasma antioxidant. Taken together, the results suggest that the increase in SR-BI-mediated cellular cholesterol efflux and antioxidant capacity in the sera of GSD-Ia patients may contribute to protection against premature atherosclerosis.

Introduction

Glycogen storage disease type Ia (GSD-Ia, MIM232200), also known as von Gierke disease, is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α), the enzyme that catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the terminal step of glyconeogenesis and glycogenolysis [1], [2]. Patients with GSD-Ia are unable to maintain glucose homeostasis and manifest a pro-atherogenic lipid profile characterized by hypercholesterolemia, hypertriglyceridemia, reduced cholesterol in high density lipoprotein (HDL), and increased cholesterol in low density lipoprotein (LDL) and very low density lipoprotein (VLDL) fractions [3], [4]. The hyperlipidemic phenotype in GSD-Ia responds only partially to dietary therapies [4], [5]. Fortunately, these patients do not exhibit an increased risk for either endothelial vascular dysfunctions [6] or the development of atherosclerosis [7]. It is unclear why GSD-Ia patients are seemingly protected against premature atherosclerosis, despite their lipid profile.

Reverse cholesterol transport is a key step in maintaining cellular cholesterol homeostasis. It involves the transfer of excess free cholesterol from peripheral cells to an acceptor, such as HDL, or lipid-rich apolipoproteins, which then transports it to the liver for excretion into the bile (reviewed in [8], [9]). One principle mechanism of the first step, the efflux of unesterified cholesterol from extrahepatic cells and transfer to a cholesterol acceptor, is the scavenger receptor class B type I (SR-BI) which mediates a bidirectional exchange of cholesterol between the cell and cholesterol acceptors [10], [11]. The direction of the net flux depends on the cholesterol gradient. Studies have shown that phospholipid (PL) is the major component of HDL that modulates the SR-B1-mediated cellular cholesterol efflux and HDL-PL levels best reflect the capacity of serum to accept cellular cholesterol mediated by SR-BI [12], [13].

Oxidative stress and LDL oxidation have also been implicated in the development of atherosclerosis. In mammals, a complex antioxidant system has evolved to counteract the reactive oxygen species and reduce oxidative damage (reviewed in [14]). These include enzymes that degrade free radicals, antioxidants that act as free radical scavengers [14], and the low molecular mass plasma antioxidants such as uric acid [15], [16]. GSD-Ia patients manifest hyperuricemia and it was shown that the sera of these patients have elevated levels of total radical trapping ability [17].

In this study, we investigate cellular cholesterol efflux and antioxidant capacity in the sera of GSD-Ia patients. We show that the sera of GSD-Ia patients are more efficient than those from control subjects in promoting the SR-B1-mediated cellular cholesterol efflux and GSD-Ia sera have an increased total antioxidant capacity. Taken together these finding provides one possible clue why GSD-Ia patients are protected against premature atherosclerosis.

Section snippets

Patients

Twenty-one metabolically compensated GSD-Ia patients ranging from age 2 to 37 years and their age- and sex-matched healthy control subjects were studied. All patients were diagnosed biochemically and confirmed by mutation analysis. The study was approved by the Clinical Investigation Committee of Children’s Hospital Boston, and informed consent was obtained prior to enrollment in this study.

Lipid and phospholipid analyses

Serum cholesterol was analyzed using kits obtained from Thermo Electron (Louisville, CO) and

The metabolically compensated GSD-Ia patients manifest a pro-atherogenic lipid profile

Twenty-one metabolically compensated GSD-Ia patients ranging from 2 to 37 years and 21 age- and sex-matched control subjects were studied. Despite intensive dietary therapy, GSD-Ia patients continue to suffer from hypercholesterolemia and hypertriglyceridemia and serum VLDL levels in GSD-Ia patients increased 4.3-fold, compared to the control subjects (Fig. 1A). The ratios of cholesterol/HDL, HDL/LDL, and HDL/VLDL also vary with the cholesterol/HDL ratio increasing 169%, the HDL/LDL and

Discussion

GSD-Ia patients manifest a pro-atherogenic lipid profile [3], [4] but are not at elevated risk for atherosclerosis [6], [7]. There are two primary mechanisms that might be anticipated to protect these patients from premature atherosclerosis—reverse cholesterol transport and antioxidant capacity.

Reverse cholesterol transport, which recycles cholesterol from peripheral tissues to the liver, is important in preventing the formation of foam cells from macrophages and preventing the formation of

Acknowledgments

The authors gratefully acknowledge Dr. G.H. Rothblat for gift of Fu5AH cell lines, Pfizer for the gift of the ACAT inhibitor CP113,818, and Ms. Catherine Correia for technical assistance. The patient samples were obtained through the Clinical Research Center at Children’s Hospital Boston which was supported by a grant from the Public Health Service Division of Research Resources (NIH M01RR02172). D.A.W. was supported by a K23 grant from NCRR (RR017560).

References (34)

E. Levy et al.
Circulating lipids and lipoproteins in glycogen storage disease type I with nocturnal intragastric feeding
J. Lipid. Res.
(1988)
P.J. Lee et al.
Hyperlipidaemia does not impair vascular endothelial function in glycogen storage disease type 1a
Atherosclerosis
(1994)
C.J. Fielding et al.
Cellular cholesterol efflux
Biochim. Biophys. Acta
(2001)
B. Jian et al.
Scavenger receptor class B type I as a mediator of cellular cholesterol efflux to lipoproteins and phospholipid acceptors
J. Biol. Chem.
(1998)
P.G. Yancey et al.
In vivo modulation of HDL phospholipid has opposing effects on SR-BI- and ABCA1-mediated cholesterol efflux
J. Lipid. Res.
(2004)
K. Nyyssonen et al.
Ascorbate and urate are the strongest determinants of plasma antioxidative capacity and serum lipid resistance to oxidation in Finnish men
Atherosclerosis
(1997)
V. Schlotte et al.
Effect of uric acid and chemical analogues on oxidation of human low density lipoprotein in vitro
Free Radic. Biol. Med.
(1998)
Y. Ji et al.
Scavenger receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux
J. Biol. Chem.
(1997)
A.D. Nguyen et al.
Increased cellular cholesterol efflux in glycogen storage disease type Ia mice: a potential mechanism that protects against premature atherosclerosis
FEBS Lett.
(2005)
S. Stan et al.
Apo A-IV: an update on regulation and physiologic functions
Biochim. Biophys. Acta
(2003)

J.Y. Chou et al.

Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex

Curr. Mol. Med.

(2002)

Y.-T. Chen

Glycogen storage diseases

E. Levy et al.

Plasma and lipoprotein fatty acid composition in glycogen storage disease type I

Lipids

(1987)

J. Fernandes et al.

Gastric drip feeding in patients with glycogen storage disease type I: its effects on growth and plasma lipids and apolipoproteins

Pediatr. Res.

(1989)

F.L. Ubels et al.

Is glycogen storage disease 1a associated with atherosclerosis?

Eur. J. Pediatr.

(2002)

P.G. Yancey et al.

Importance of different pathways of cellular cholesterol efflux

Arterioscler. Thromb. Vasc. Biol.

(2003)

M.A. Connelly et al.

Scavenger receptor BI: a scavenger receptor with a mission to transport high density lipoprotein lipids

Curr. Opin. Lipidol.

(2004)

Cited by (12)

Glycogen storage disease type I patients with hyperlipidemia have no signs of early vascular dysfunction and premature atherosclerosis
2021, Nutrition, Metabolism and Cardiovascular Diseases
Citation Excerpt :
For high quality and reproducibility, the IMT measurements in our study were performed according to the Mannheim consensus which recommends standardized methods including ECG-triggering and automatic contour identification to guarantee better reproducibility of data [46]. Several mechanisms have been postulated to be protective against cardiovascular disease in GSD I, among them decreased platelet aggregation, increased antioxidant defense, increased levels of apolipoprotein E, decreased susceptibility of LDL to oxidation, elevated levels of adiponectin, hypoinsulinemia, and reverse cholesterol transport [15,47–49]. Although patients with GSD I exhibit a bleeding diathesis when in poor metabolic control or during acute illness, platelet aggregation usually normalizes with improved metabolic control [15].
Glycogen storage disease type I (GSD I) is associated with hyperlipidemia, a known risk factor for premature atherosclerosis. Few studies have addressed endothelial dysfunction in patients with GSD I, and these studies yielded controversial results.
We investigated vascular dysfunction in a cohort of 32 patients with GSD I (26 GSD Ia, 6 GSD Ib, mean age 20.7 (4.8–47.5) years) compared to 32 age-, gender-, and BMI-matched healthy controls using non-invasive techniques such as quantification of carotid intima media thickness, retinal vessel analysis and 24 h-blood pressure measurements. In addition, early biomarkers of inflammatory and oxidative endothelial stress were assessed in blood. Although GSD I patients had a clearly proatherogenic lipid profile, increased oxidative stress, higher levels of high sensitivity C-reactive protein and increased lipoprotein associated phospholipase A2 activity, functional and structural parameters including carotid intima media thickness and retinal vessel diameters did not indicate premature atherosclerosis in this patient cohort. Blood pressure values and pulse wave velocity were comparable in patients and healthy controls, while central blood pressure and augmentation index were higher in GSD patients.
Our data suggest that GSD I is not associated with early vascular dysfunction up to the age of at least 20 years. Further studies are needed to elucidate the possibly protective mechanisms that prevent early atherosclerosis is GSD I. Longer follow-up studies are required to assess the long-term risk of vascular disease with increased oxidative stress being present in GSD I patients.
An association among iron, copper, zinc, and selenium, and antioxidative status in dyslipidemic pediatric patients with glycogen storage disease types IA and III
2010, Journal of Trace Elements in Medicine and Biology
Dyslipidemia in patients with glycogen storage disease types Ia (GSD Ia) and III (GSD III) does not lead to premature atherosclerosis. The aim of this study was to investigate the association among serum copper (Cu), zinc (Zn), iron (Fe), and selenium (Se) concentrations, and their carrier proteins: ceruloplasmin, albumin, and related antioxidant enzyme activities [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), paraoxonase (PON), and arylesterase (ARYL)] in 20 GSD Ia and 14 III patients compared to age and sex matched 20 healthy subjects. Erythrocyte oxidative stress was measured by erythrocyte thiobarbituric acid reactive substances (eTBARSs). Hypertriglyceridemia [333 (36–890) mg/dL] in GSD Ia and hypercholesterolemia with elevated LDL-cholesterol [188 (91–313) mg/dL] and decreased HDL-cholesterol [32(23–58) mg/dL] levels in GSD III were found. Serum Cu, Fe, and Zn showed no significant differences between groups. However, Se 60 (54–94), 81 (57–127) μg/L, ceruloplasmin 21 (10–90), 27 (23–65) μg/L, and albumin 2.4 (1.7–5.1), 2.8 (1.8–4.06) g/dL levels were decreased in GSD Ia and III groups, respectively, in comparison with the controls [Se 110 (60–136) μg/L, ceruloplasmin 72 (32–94) μg/L, and albumin 4.4 (4–4.8) g/dL)]. In spite of high oxidative stress in erythrocyte detected by elevated eTBARS/Hb levels in GSD group [674.8 (454.6–948.2) for GSD Ia, 636.3 (460.9–842.1) for GSD III, and 525.6 (449.2–612.6)], the activities of CAT, SOD, ARYL, and PON in GSD patients were not different from the controls. GPx activity was decreased in GSD Ia [3.7 (1.8–7.1) U/mL] and GSD III [4.2 (2.2–8.6) U/mL] compared with healthy controls [7.1 (2.9–16.2) U/mL].
In conclusion, this study supplied the data for trace elements, their carrier, and antioxidative enzymes in the patients with GSD Ia and III. The trace elements and anti-oxidative enzyme levels in GSD patients failed to explain the atherosclerotic escape phenomenon reported in these patients.
A monocentric pilot study of an antioxidative defense and hsCRP in pediatric patients with glycogen storage disease type IA and III
2009, Nutrition, Metabolism and Cardiovascular Diseases
Citation Excerpt :
The idea that imbalance of oxidative stress and antioxidative defense leads to vascular complications of atherosclerosis shows the areas that need to be widely investigated: antioxidant capacity and reverse cholesterol transport. The former, an increased cellular cholesterol efflux in GSD Ia, was favorably demonstrated by Nguyen et al.22 The data on elevated antioxidative defense total radical trapping ability parameter (TRAP) in GSD Ia were reported by Wittenstein et al.21 Our results showing elevated FRAP and TEAC levels in GSD Ia patients support the concept of increased antioxidative defense. The major contributor to total antioxidant activity in GSD Ia, according to the results of Wittenstein et al., was urate.
Patients with glycogen storage disease type Ia (GSD Ia) and III (GSD III) do not develop premature atherosclerosis despite hyperlipidemia. The aim of the study was to investigate the oxidative–antioxidative conditions and high sensitivity C-reactive protein (hsCRP) levels in patients with glycogen storage disease type Ia and III.
We measured lipid profile and lipid peroxidation products in comparison with hsCRP and antioxidative status: trolox equivalent antioxidant capacity, total antioxidant activity, proteinaceous antioxidant enzymes (catalase, superoxide dismutase, paraoxonase, arylesterase), aqueous antioxidants (vitamin C, uric acid, bilirubin, total protein) and lipid-soluble antioxidants (alpha-tocopherol, beta-carotene). The study included 50 individuals: 22 with GSD Ia, 9 with GSD III, and 19 healthy subjects.
GSD Ia patients showed a marked hypertriglyceridemia, whereas GSD III patients demonstrated hypercholesterolemia with elevated LDL-cholesterol and decreased HDL-cholesterol levels. Lipid peroxidation levels increased in both GSD groups. The antioxidant activity elevated in GSD Ia group. No significant differences were found in the activities of antioxidant enzymes. Uric acid and alpha-tocopherol levels increased, however, vitamin C and beta-carotene reduced in both GSD groups. The hsCRP levels did not differ among the groups.
In summary our study revealed normal levels of hsCRP in spite of the dyslipidemic status in both GSD patients. The increased plasma antioxidative defense in GSD Ia might be attributed not only to the elevated uric acid but also to the supplemented vitamin E levels. These findings should motivate further investigations in the area of atherosclerotic escape of GSDs.
Vascular Dysfunction in Glycogen Storage Disease Type I
2009, Journal of Pediatrics
Citation Excerpt :
The mechanisms differ between species. In mice, preliminary studies demonstrate that both SRB1 and ABCA1 transporters are increased in contrast to human beings in whom only SRB1 is increased.5 The effect of multiple cardiovascular risk factors on vascular function may be attenuated by increased reverse cholesterol transport.
To determine cardiovascular disease risk in a larger cohort of patients with glycogen storage disease (GSD) I through the use of noninvasive measures of arterial function and anatomy.
Carotid intima media thickness (IMT), radial artery tonometry, and brachial artery reactivity were performed in 28 patients with GSD I (13F/15M, mean age 23 years) and 23 control subjects (19F/4M, mean age 23 years).
The primary outcome measure, mean left distal IMT was greater in the GSD cohort (0.500 ± 0.055 mm) than in the control group (0.457 ± 0.039 mm) (P = .002, adjusted for age, sex, and body mass index). Mean augmentation index measured by radial artery tonometry was higher in the GSD cohort (16.4% ± 14.0%) than in the control group (2.4% ± 8.7%) (P < .001). No significant difference was observed between mean brachial artery reactivity in the GSD cohort (6.3% ± 4.9% change) versus control subjects (6.6% ± 5.1% change) (P = .46).
GSD I is associated with arterial dysfunction evident by increased IMT and augmentation index. Patients with GSD I may be at increased risk for cardiovascular disease.
Natural history of hepatic glycogen storage diseases
2008, Presse Medicale
Les glycogénoses avec atteinte hépatique sont des maladies héréditaires rares du métabolisme du glycogène.
Les progrès concernant les traitements et la surveillance des malades atteints de glycogénoses hépatiques ont permis aujourd’hui à des enfants d’atteindre l’âge adulte alors qu’il y a quelques décennies, ces mêmes enfants mouraient avant l’âge de 10 ans.
Il est donc important de connaître l’histoire naturelle actuelle de ces malades, afin d’en tirer les leçons qui permettent une amélioration constante de leur prise en charge et de leurs soins durant l’enfance, mais également d’insister d’emblée sur l’importance de la poursuite des soins lorsque ces enfants deviennent adultes et sur la nécessaire collaboration entre pédiatres spécialistes d’une part, et médecins d’adultes d’autre part.
Hepatic glycogen storage diseases are rare inherited conditions affecting glycogen metabolism.
During the last twenty years, medical progress has allowed children who used to die before they reached the age of ten years to reach adulthood.
It is important to know the natural history and long-term outcome of these patients to improve their treatment during childhood.
To reach this goal, collaboration between pediatric specialists and those who treat adults is essential.
Glycogen storage disorder
2014, Medical Forum Monthly

View all citing articles on Scopus

View full text