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Clinical Chemistry 43: 2379-2383, 1997;
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(Clinical Chemistry. 1997;43:2379-2383.)
© 1997 American Association for Clinical Chemistry, Inc.

Articles

Low plasma vitamin A concentrations in familial combined hyperlipidemia

Josep Ribalta, Agnes E. LaVille, Josefa Girona, Joan C. Vallvé and Lluís Masanaa

Unitat de Recerca de Lípids, Facultat de Medicina, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Sant Llorenç 21, 43201 Reus, Spain.
a Author for correspondence. Fax (+34-77) 75 93 22; e-mail jrv{at}fmcs.urv.es


   Abstract
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 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
As many as 20% of the survivors of acute myocardial infarction present with the heritable form of hyperlipidemia, termed familial combined hyperlipidemia (FCHL). Some of the genes reported to be involved in this disorder, such as those for lipoprotein lipase (LPL) and apolipoprotein (apo) C-III, are controlled by a peroxisome proliferator-activated receptor (PPAR)/retinoic acid receptor X (RXR) regulatory system, which is retinoic acid dependent. If, as we hypothesized, the availability of retinoic acid or its precursor retinol (vitamin A) could be altered in FCHL, this could help explain some aspects of the phenotypic expression of the disease. We therefore measured plasma retinol concentrations in 30 FCHL subjects and 56 controls. Plasma retinol concentrations in FCHL subjects were significantly lower than that of control subjects (1.96 ± 0.83 µmol/L vs 2.91 ± 1.23 µmol/L, respectively; P <0.0001). This novel finding of significantly decreased concentrations of plasma retinol in FCHL relative to control subjects gives support to the hypothesis that vitamin A might be involved in the expression of this disorder.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Familial combined hyperlipidemia (FCHL)1 (1) is the commonest genetic form of hyperlipidemia and is present in ~20% of myocardial infarction survivors (2). FCHL patients may present with hypercholesterolemia, hypertriglyceridemia, or both. Moreover, the FCHL phenotype may vary among family members and even in the individual patient over time (3). Although the etiology of this highly heterogeneous disorder is not well understood (4), several metabolic features such as VLDL, apolipoprotein (apo) B overproduction (5), small dense LDL particles (6), decreased lipoprotein lipase (LPL) activity [7, 8], and increased plasma apo C-III concentrations (9) have been described. Mutations in the LPL (10)(11) and apo C-III (12)(13) genes associated with decreased LPL activity or increased apo C-III concentrations are reported to be more frequent among FCHL subjects. The interaction between these genetic variants and environmental factors such as diet and obesity contribute to the individual expression of the FCHL phenotype. Hence, it is of considerable importance to identify the mechanisms by which these factors regulate gene expression.

The LPL and apo C-III genes, for example, are respectively stimulated and repressed by fibrate therapy and dietary fatty acids (14)(15)(16). More precisely, the metabolic perturbation induced by environmental stimuli leads to the activation of a class of proteins belonging to the nuclear receptor superfamily called peroxisome proliferator-activated receptors (PPARs) (17), which, by forming heterodimers with the 9-cis-retinoic acid receptor X (RXR), recognize response elements (RE) of the promoter region of the above-mentioned target genes and, hence, control their expression. Both elements of this signaling pathway, PPAR and RXR, need to be physiologically activated to promote a regulatory effect on the target genes. PPARs are activated by multiple stimuli directly resulting from the action of hypolipidemic agents (e.g., fibrates), diet, and lipid or glucose metabolism, whereas RXR is activated by retinoic acid (16)(17), an intracellular active form of dietary retinol (vitamin A). In this regulatory system, therefore, the physiological response to drug or diet-induced changes would directly depend on the availability of vitamin A. In view of the role that this signaling pathway has on the regulation of genes known to be involved in FCHL, we hypothesized that the availability (i.e., concentrations in plasma) of vitamin A might play a role in the expression of FCHL phenotype.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
fchl subjects
As part of a larger investigation into the inheritance of FCHL, 16 families diagnosed as having the disease were identified from the Lipid Clinic of the Hospital Universitari de Sant Joan in Reus (Spain). Diagnosis was based on the index patient's having had plasma concentrations of cholesterol and triglycerides >=6.4 mmol/L (2500 mg/L) and >=2.8 mmol/L (2500 mg/L), respectively, detected at any time in the clinical history and with at least one first-degree relative with a hyperlipidemic phenotype different from that of the proband. Among these families, all members with plasma cholesterol or triglycerides >=6.4 mmol/L and >=2.8 mmol/L, respectively, were assigned the FCHL phenotype (n = 30).

Biochemical analyses were conducted to rule out secondary causes of hyperlipidemia, and apo E genotyping was performed to exclude type III hyperlipidemia. Sixteen subjects were on lipid-lowering diets and had been taken off lipid-lowering medication for at least 2 months when recalled for the study. The rest (n = 14) were identified and recruited before any therapeutic intervention was initiated.

normolipidemic control subjects
Fifty-six clinically healthy individuals belonging to 12 normolipidemic families volunteered to participate and were included as controls in this study. These individuals were recruited from among the clinical and laboratory staff. Subjects undergoing lipid-lowering therapy or with secondary causes of hyperlipidemia were excluded. None of their families met the criteria to be classified as FCHL.

All patients and control subjects recruited into the study gave fully informed written consent and the protocol was approved by the Scientific and Ethical Committee of the Hospital Universitari de Sant Joan.

analytical methods
A 10-mL venous blood sample was withdrawn after an overnight fast of 12 h. One aliquot of the plasma was immediately frozen at -70 °C in opaque containers for batched vitamin A analyses; another aliquot was processed for lipoprotein profiling without delay.

Lipids and lipoproteins.
Triglycerides and cholesterol in plasma and lipoprotein fractions were measured with enzymatic kits (Boehringer Mannheim) adapted for use with a Cobas Mira centrifugal analyzer (Roche Pharmaceuticals); Precilip EL® and Precinorm® (Boehringer Mannheim) were the quality controls. The apolipoproteins were measured by immunoturbidimetry with specific antiserum purchased from Boehringer Mannheim (for apo A-I and apo B), Daiichi Chemicals (for apo C-II and apo C-III), and Incstar [for lipoprotein(a)].

Sequential preparative ultracentrifugation.
Lipoproteins were separated by sequential preparative ultracentrifugation (18) with a Kontron 45.6 fixed-angle rotor in a Centrikon 75 (Kontron Instruments). The lipoprotein fractions isolated were VLDL (d <1.006 kg/L), IDL (d = 1.006–1.019 kg/L), and LDL (d = 1.019–1.063 kg/L). Total HDL and HDL3 cholesterol were measured after precipitation of the apo B-containing lipoproteins with polyethylene glycol (Immuno AG). HDL2 cholesterol was calculated from the difference between total HDL and HDL3 cholesterol.

Vitamin A analyses.
Retinol in plasma was measured according to the method of Bieri et al. (19). Briefly, retinol was extracted from 100 µL of plasma into n-hexane, and 100 µL of a 1 µg/mL solution of all-trans-retinyl acetate in ethanol was added as internal standard. The samples were centrifuged and the hexane layer was evaporated under a stream of nitrogen. The reconstituted lipid residue was analyzed by HPLC with the Hewlett-Packard 1050 series system, in which the separation column was Spherisorb ODS 2 and the mobile phase was methanol:water (98:2 by vol). Absorbances were recorded on a UV-variable wavelength detector set at 325 nm.

statistical analyses
Analysis of variance was performed to compare the means of the lipid, lipoprotein, apolipoprotein, and retinol data adjusted for age, gender, and body mass index (BMI). The data with skewed distributions were log10-transformed. Differences in proportions were assessed by the Z test. Results are expressed as means ± SD. Statistical significance was accepted at the 0.05 level.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
analytical measurements
Those members of FCHL families with a hyperlipidemic phenotype (n = 30) and the group of healthy control subjects (n = 56) were comparable with respect to age, BMI, and male/female proportion (Table 1 ).


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  		Table 1. Biometric characteristics of the FCHL and control group of subjects.

Differences in lipids, lipoproteins, and apolipoproteins between groups were assessed on data adjusted for age, gender, and BMI and are summarized in Table 2 . Concentrations of cholesterol and triglycerides in plasma, VLDL, IDL, and LDL as well as plasma apos B, C-II, and C-III were greater in the FCHL group than in the control subjects.


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  		Table 2. Lipid, lipoprotein, and apolipoprotein values in the FCHL and control group of subjects.

Plasma retinol concentrations were significantly lower in FCHL individuals (1.96 ± 0.83 µmol/L; P <0.0001) than in control subjects (2.91 ± 1.23 µmol/L) (Fig. 1 ). There were no statistically significant differences between those FCHL subjects (n = 16) who were on a lipid-lowering diet (1.92 ± 0.72 µmol/L) and those (n = 14) who were not (1.61 ± 0.79 µmol/L). Thirteen affected subjects (43%; z = 2.169; P = 0.03) had plasma retinol concentrations below the mean - 1 SD value of the control group (1.87 µmol/L), but none was below the mean - 2 SD of the control values. Mean plasma concentrations of retinol obtained from 74 normolipidemic relatives of the studied FCHL patients (1.69 ± 1.17 µmol/L) were also significantly lower than those of controls (P <0.0001) but not lower than those of their affected relatives.



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  		Figure 1. Plasma retinol concentrations in the individual FCHL (n = 30) and control subjects (n = 56).

The horizontal lines indicate the mean plasma retinol concentration of each group.

correlation of plasma retinol with lipids and apolipoproteins
Correlation between plasma retinol concentrations and concentrations of lipids, lipoproteins, and apolipoproteins were evaluated in each group and are summarized in Table 3 . Among the control subjects, the results were significantly positively correlated between plasma retinol and: plasma cholesterol (r = 0.38; P = 0.003), plasma triglycerides (r = 0.23; P = 0.05), LDL cholesterol (r = 0.32; P = 0.01), and apo B (r = 0.42; P = 0.001). No significant correlation between plasma retinol and HDL cholesterol or apo A-I concentrations was detected in this group. Conversely, in the FCHL group, plasma retinol was positively and significantly correlated with HDL cholesterol (r = 0.44; P = 0.01) and apo A-I (r = 0.53; P = 0.002).


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  		Table 3. Plasma retinol correlation with lipid and apolipoprotein concentrations.1


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present report forms part of a wider investigation into the genotypic and phenotypic expression of FCHL. The hypothesis that vitamin A could be involved in the expression of FCHL was based on observations indicating that the increased synthesis of VLDL, which is characteristic of FCHL patients, is reversed by the action of fibrate therapy (20)(21). The mode of this action is stimulation of the expression of the triglyceride lipase enzyme and repression of the synthesis of its inhibitor, apo C-III (14)(16). Further, this regulatory effect occurs via the PPAR/RXR system, which depends on retinoic acid, the intracellular form of plasma vitamin A, to be physiologically active (16)(17). Because vitamin A is largely of dietary origin, this aspect could have some significance in the observed variation in the patterns of FCHL expression.

Our results indicating that plasma retinol concentrations were significantly lower in FCHL than in control subjects are intriguing, in that several phenomena associated with FCHL will now need to be explored.

Firstly, dietary intake of vitamin A could account for the 50% decrease in the circulating concentrations of retinol observed in FCHL subjects compared with controls (22)(23). This possibility, however, cannot be the case in the present study because plasma retinol concentrations were no different between those FCHL subjects who were on a lipid-lowering diet (regularly monitored in the Lipid Clinic) and those who were not. Moreover, preliminary results indicated that vitamin A concentrations were also less in normolipidemic members of FCHL families than in the control subjects. These two aspects suggest that low plasma vitamin A concentrations could be more a feature of FCHL than a consequence of dietary restriction. For example, lower vitamin A concentrations in these patients could be related to the increased prevalence of small, dense LDL particles, with a diminished content of specific antioxidants characteristic of this disorder (24). This is somewhat supported by the fact that vitamin A does not correlate with LDL but with HDL in these patients—possibly indicating that HDL acts as a more important antioxidant carrier than LDL in FCHL. Alterations of vitamin A absorption could affect the assembly, transport, and subsequent hepatic clearance of chylomicrons, the lipoprotein that delivers dietary vitamin A to the liver and is reported to have a delayed postprandial clearance in FCHL (9). In vivo lipoprotein kinetics performed with stable isotopes may help elucidate these aspects.

Secondly, the proposed hypothesis that vitamin A modulates the effect of the PPAR/RXR system on lipoprotein metabolism in response to fibrate or dietary therapy relies on the assumption that intracellular retinoic acid availability is dependent on the plasma concentration of its precursor, vitamin A. In the present study, vitamin A values in the FCHL subjects were not in the range that could be considered as a state of vitamin A deficiency (none of the subjects had plasma vitamin A concentrations below the mean - 2 SD of the control values) and, therefore, the extent to which the observed reductions could affect the intracellular availability of retinoic acid needs to be investigated—particularly in light of evidence indicating that vitamin A regulates the expression of apo A-I and C-III genes in a tissue-specific manner in rats (25).

Thirdly, controversy exists regarding the closeness of the relationship between retinoids and lipids: On one hand, hypertriglyceridemia has been reported to develop as a result of the therapeutic use of retinoids (26); on the other hand, epidemiological studies have demonstrated that long-term vitamin A intake does not produce clinically significant hypertriglyceridemia (27). Again, in vivo lipoprotein kinetics with the recently developed nonradioactive tracer methodologies, in conjunction with in vitro testing of this signaling pathway by means of gene expression assays, would resolve these questions—studies that are currently underway in our metabolic ward.

In conclusion, the novel observation of low vitamin A concentrations in subjects with FCHL is consistent with our hypothesis that vitamin A could be involved in the pathogenesis of this disorder. The cause of these low vitamin A concentrations requires prompt investigation also because of the reported anti-oxidant and, hence, anti-atherogenic characteristics of this nutrient.


   Acknowledgments
 
We thank Mercedes Heras and Silvia Olivé for their excellent technical support and Núria Plana, Pilar Sardà, Rosa Solà, and Carlos Alonso-Villaverde for their clinical assistance. This study has been supported, in part, by the Fundació Joan Abelló Pascual and the Ministerio de la Salud (DGICYT PM 92–0209).


   Footnotes
 
1 Nonstandard abbreviations: FCHL, familial combined hyperlipidemia; apo, apolipoprotein; LPL, lipoprotein lipase; PPAR, peroxisome proliferator-activated receptor; RXR, retinoic acid receptor X; BMI, body mass index.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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J. Ribalta, J. Girona, J. C. Vallvé, A. E. La Ville, M. Heras, and L. Masana
Vitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemia
J. Lipid Res., March 1, 1999; 40(3): 426 - 431.
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