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Annals of Clinical & Laboratory Science 35:290-296 (2005)
© 2005 Association of Clinical Scientists

Relationships of Soluble APO-1 (Fas/CD95) Concentrations, Obesity, and Serum Lipid Parameters in Healthy Adults

Jong Weon Choi1 and Soon Ki Kim2
1 Department of Laboratory Medicine, and 2 Department of Pediatrics, College of Medicine, Inha University, Inchon, South Korea

Address correspondence to Jong Weon Choi, M.D., Ph.D., Department of Laboratory Medicine, Inha University Hospital, 7-206, 3-ga, Shinheung-dong, Jung-gu, Inchon, 400-711, South Korea; tel 82 32 890 2503; fax 82 32 890 2529; e-mail jwchoi{at}inha.ac.kr.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To investigate the relationships of apoptosis with obesity and lipid parameters, we measured serum soluble APO-1 (sAPO-1) concentrations, body mass index (BMI), and serum lipid profiles in 176 healthy adults. Serum sAPO-1 levels were measured by enzyme immunoassay. There were no significant differences in mean sAPO-1 concentrations between men and women, nor between subjects with and without obesity. However, women with high-density lipoprotein cholesterol (HDL-C) <50.2 mg/dl exhibited significantly higher sAPO-1 concentrations than those with HDL-C >50.2 mg/dl (ie, 45.6 ± 10.4 pg/ml vs 31.5 ± 11.3 pg/ml, p <0.05). Serum sAPO-1 concentrations averaged 46.8 ± 10.7 pg/ml in women with serum triglyceride >137.4 mg/dl, which was significantly above the mean value (32.6 ± 12.0 pg/ml, p <0.05) in those with serum triglyceride <137.4 mg/dl. Men with elevated sAPO-1 concentrations showed significantly higher waist-to-hip ratio (WHR) and total body fat (TBF) compared to those with diminished sAPO-1 levels, although no differences were noted in mean values of lipid profiles between the 2 groups of men. Serum sAPO-1 concentrations correlated significantly with HDL-C (r = – 0.41, p <0.05) and triglyceride (r = 0.35, p <0.05) in women and WHR (r = 0.25, p <0.05) and TBF (r = 0.21, p <0.05) in men. In conclusion, serum sAPO-1 appears to have an important relationship to serum lipid levels and body adiposity in healthy adults.

(received 20 March 2005; accepted 16 April 2005)

Keywords: serum soluble APO-1, obesity, serum lipids, total body fat, body mass index


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Apoptosis is the most common form of eukaryotic cell death and is found during tumor regression and embryonic development. Apoptosis is an important process in the process of selection and elimination of autoreactive B and T cells and therefore a prerequisite for the homeostasis of the immune system [1]. Apoptosis can be seen as a surveillance system, which removes genetically compromised cells, thereby preventing carcinogenic transformation of the normal mucosa. Inefficient removal of genetically compromised cells from colorectal mucosa is one of the plausible pathways of tumorigenesis [2].

The APO-1 molecule (also designated Fas/ CD95) is a glycosylated membrane-anchored protein and belongs to the tumor necrosis factor (TNF) receptor family. APO-1 is an important membrane death receptor responsible for induction of apoptosis. APO-1 is expressed on a variety of normal human tissues and many different tumor cells [3]. Triggering of APO-1 by its ligand or by certain anti-APO-1 antibodies results in rapid induction of apoptosis in susceptible cells [4]. Activation of APO-1 can be non-specifically achieved by ultraviolet radiation, cytotoxic drugs, or reactive oxygen species [5–7]. On the other hand, blockade of APO-1-mediated apoptosis results in an increased incidence of squamous cell carcinoma [8]. A soluble form of APO-1 (sAPO-1) is produced through proteolytic cleavage of membrane-bound receptors or by alternative splicing [9]. The biological importance of sAPO-1 is being extensively studied, but most studies are focused on autoimmune diseases in connection with T-cell activity, hematopoietic malignancy, and solid tumors [10,11].

Investigators have demonstrated that cholesterol depletion from cell membranes causes APO-1 activation [12]. Despite intense research, data concerning the changes in sAPO-1 concentrations in healthy subjects are limited, especially in relation to obesity and serum lipids. In the present study, we tested whether serum sAPO-1 concentrations are significantly correlated with total body fat (TBF), body mass index (BMI), and serum lipid concentrations. We also investigated whether or not serum sAPO-1 concentrations are influenced by age or gender in apparently healthy persons.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
A total of 176 adults (91 men and 85 women) with a median age of 58 yr (range 47–69 yr) were investigated by measurements of serum sAPO-1 concentrations and serum lipid profiles, including total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Four anthropometric parameters were measured in all subjects. The anthropometric indices were body weight, height, waist-to-hip ratio (WHR), and BMI (in kg/m2). The reference interval of BMI was defined as 18.5 to 22.9 kg/m2, overweight as 23.0 BMI<25.0 kg/m 2, and obesity as a BMI 25.0 kg/m 2, which was based on WHO criteria for Asian populations [13]. Total body fat (TBF) and lean body mass were assessed using an 8-polar tactile-electrode impedance-meter, the body composition analyzer (InBody 3.0, Biospace, Seoul, Korea).

To minimize the influence of age, hormonal effects, and smoking on apoptotic activity, nonsmoking postmenopausal women and age-matched men were enrolled in this study. Subjects who had smoked <10 packs of cigarettes during their lifetimes were defined as nonsmokers. The women were judged to have reached menopause if they had not menstruated for >12 mo prior to the investigation. Subjects with evidence of inflammatory diseases (n = 3) or drug administration (n = 4), such as hormonal replacement therapy and vitamin supplementation, were excluded from this study because episodes of infection or hormone administration may have an impact on sAPO-1 and lipid levels. The subjects were all Korean who showed no significant differences in racial composition and socioeconomic status among the groups. The study was approved by the Committee of Ethics of the Inha University Hospital, and informed consent was obtained from all subjects.

After the subjects fasted for >12 hr, venous blood was drawn into an evacuated serum separator tube. Serum sAPO-1 concentrations were measured by an enzyme immunoassay using human sAPO-1/Fas BMS245 kits (Bender MedSystems, Vienna, Austria). Lipid profiles were assayed with an automatic chemical analyzer (Hitachi 747, Hitachi, Tokyo, Japan) within 4 hr after collection. Serum triglyceride, total cholesterol, HDL-C, and LDL-C concentrations were analyzed by enzymatic colorimetric methods using triglyceride GPO-PAP reagents (Roche Diagnostics GmbH, Mannheim, Germany), SICDIA L T-CHO reagents (Eiken Chemical Industries, Tokyo, Japan), Cholestest-HDL reagents (Daiichi Chemicals, Tokyo, Japan), and Cholestest-LDL reagents (Daiichi Chemicals), respectively.

To test for differences in serum APO-1 concentrations in relation to age and gender, subjects were assigned to 1 of 5 groups: men and women age <50 yr (median age, 48 yr, n = 26), 50–55 yr (median age, 52 yr, n = 41), 56–60 yr (median age, 56 yr, n = 43), 61–65 yr (median age, 64 yr, n = 37), and > 65 yr (median age, 67 yr, n = 29), respectively. The subjects were also divided by gender into 2 groups: women with sAPO-1 <37.9 pg/ml (n = 47) and sAPO-1 37.9 pg/ml (n = 38); men with sAPO-1 <42.9 pg/ml (n = 49) and sAPO-1 42.9 pg/ml (n = 42), which are the mean sAPO-1 concentrations of men and women, respectively. To evaluate more strictly, men with sAPO-1 <25.1 pg/ml (20th percentile, n = 18) were compared to those with sAPO-1 >65.4 pg/ml (80th percentile, n = 18). A non-parametric test (Wilcoxon rank-sum test) was used to test the statistical significance of inter-group differences. Correlation coefficients were calculated by the Spearman method. All p values <0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Mean values of serum sAPO-1 concentrations in relation to the subjects’ age and gender are listed in Table 1Go. No significant differences were observed in sAPO-1 concentrations between males and females, although men showed slightly higher sAPO-1 levels than women. The serum sAPO-1 concentrations seemed to increase gradually with age in subjects 60 yr and to decr ease in subjects >61 yr of age, but no statistically significant differences were found.


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  		Table 1. Mean values of sAPO-1 concentrations in relation to age and gender in healthy Korean adults (mean ± SD; median).
 
As shown in Table 2Go, serum HDL-C and triglyceride concentrations averaged 44.6 ± 9.2 mg/ dl and 172.8 ± 65.1 mg/dl in women with sAPO-1 concentrations 37.9 pg/ml, which differ ed significantly from those with sAPO-1 concentrations <37.9 pg/ml (54.1 ± 11.3 mg/dl and 116.9 ± 49.2 mg/dl, p <0.05, respectively). In men, there were no significant differences in serum lipid concentrations between subjects with sAPO-1 <42.9 pg/ ml and sAPO-1 42.9 pg/ml (data not sho wn), nor between subjects with sAPO-1 <25.1 pg/ml (20th percentile) and sAPO-1 >65.4 pg/ml (80th percentile) (Table 3Go).


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  		Table 2. Anthropometric variables and lipid parameters in relation to sAPO-1 concentrations in female subjects.
 

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  		Table 3. Anthropometric variables and lipid parameters in relation to sAPO-1 concentrations in male subjects.
 
No significant differences in sAPO-1 concentrations were noted between the subjects with obesity (BMI 25.0 kg/m 2) and those with healthy weight (BMI <23.0 kg/m2) (Table 4Go). However, men with sAPO-1 concentrations >65.4 pg/ml displayed significantly higher TBF and WHR than those with sAPO-1 <25.1 pg/ml (17.0 ± 3.9 kg and 0.93 ± 0.04 vs 13.5 ± 3.7 kg and 0.88 ± 0.03, p <0.05, respectively). Serum sAPO-1 concentrations were also significantly higher in women with HDL-C <50.2 mg/dl and serum triglyceride 137.4 mg/dl compared to those with HDL-C 50.2 mg/dl and serum triglyceride <137.4 mg/dl (45.6 ± 10.4 pg/ ml and 46.8 ± 10.7 pg/ml vs 31.5 ± 11.3 pg/ml and 32.6 ± 12.0 pg/ml, p <0.05).


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  		Table 4. Serum sAPO-1 concentrations in relation to mean values of HDL-C, triglyceride, body mass index, and waist-to-hip ratio in male and female subjects.
 
Relationships of subjects’ gender, age, anthropometric variables, and serum lipid parameters to their serum sAPO-1 concentrations are summarized in Table 5Go. Serum sAPO-1 concentrations had weak but significant correlations with blood lipid levels and TBF. Correlation coefficients of anthropometric variables vs sAPO-1 were higher in men than in women for WHR (r = 0.25 vs 0.23) and TBF (r = 0.21 vs 0.11), but those of lipid parameters vs sAPO-1 were higher in women than in men for HDL-C (r = - 0.41 vs - 0.24) and triglyceride (r = 0.35 vs 0.11).


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  		Table 5. Correlation coefficients of anthropometric parameters and serum lipid profiles vs serum sAPO-1 concentrations in 176 subjects (for abbreviations, see Table 2Go).
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we investigated the relationships of sAPO-1 concentrations with obesity, total fat mass, and serum lipid profiles. We found that sAPO-1 levels are closely associated with body adiposity and lipid parameters in healthy adults, especially HDL-C and triglyceride in women and TBF and WHR in men. Men showed slightly higher sAPO-1 concentrations compared to age-matched women, but this trend was not statistically significant. Among the subjects, sAPO-1 concentrations were the lowest in persons <50 yr and were highest in those 56–60 yr of age; however, no statistically significant differences were observed between these 2 groups. These data suggest that the subject’s age or gender does not significantly influence serum sAPO-1 concentrations in healthy adults.

Obesity is a condition of abnormally increased body fat, resulting from increased energy intake relative to energy expenditure. Epidemiological studies have shown that obesity is directly associated with risk of cancer at several sites, including colon, breast, and endometrium [14]. These associations with cancer risk are explained by alterations in many cytokines, which can lead to distortion of the normal balance between apoptosis and cell proliferation [15]. Interferon-gamma enhances expression of the APO-1 cell surface protein, and TNF-alpha plays an important role in multiple aspects of adipose tissue biology in obesity [16,17]. In the present study, to investigate the changes in sAPO-1 concentrations in relation to obesity, subjects with increased BMI were compared to those with decreased or adequate BMI. We did not find any significant differences in sAPO-1 concentrations between the subjects with or without obesity. However, men with moderately increased sAPO-1 concentrations displayed significantly higher TBF and WHR than those with diminished sAPO-1 levels. Further, sAPO-1 concentrations were correlated significantly with TBF and WHR but were not correlated with body weight or BMI. These results imply that sAPO-1 is more strongly associated with body adiposity and body fat distribution than with the severity of obesity.

Cholesterol is a component of the plasma membranes of eukaryotic cells and is an essential regulator of membrane fluidity, permeability, and receptor function [18]. Membrane cholesterol depletion blocks ligand-induced apoptosis and prevents APO-1 clustering in response to antibody stimulation [19]. Large amounts of cholesterol in keratinocyte membrane can alter APO-1 function by changing the biophysical properties of the membrane or inducing conformational changes in the receptor [20].

In the current study, we could not measure cholesterol contents in cell membrane but tried to investigate the association of serum lipid levels and sAPO-1, because the serum lipids are related to membrane lipid composition in some types of cells [21]. Serum triglyceride concentrations were significantly higher in women with increased sAPO-1 levels compared to those with decreased sAPO-1 concentrations. Women with elevated HDL-C showed significantly lower sAPO-1 levels compared to those with diminished HDL-C. On the other hand, in men, there were no significant differences in serum lipid concentrations between subjects with and without increase in sAPO-1 levels. The serum sAPO-1 concentrations had weak but significant correlations with serum lipid levels and TBF, and the correlation coefficients among the parameters were higher in women than in men. These results suggest that sAPO-1 level has an important relationship to serum lipid levels and that the relationship is stronger in women than in men.

Our data for relationships between sAPO-1 and lipid profiles are in partial agreement with the results of a previous study, which demonstrated that experimental hypercholesterolemia induces apoptosis in an animal model [22,23]. A group of investigators found that prolonged diet-induced hypercholesterolemia in the pig causes rapid cellular turnover [24]. Chen et al [25] reported that a highly electronegative, mildly oxidized LDL subfraction, which is present in human hypercholesterolemic plasma, induced apoptosis in cultured vascular endothelial cells. Norata et al [26] demonstrated that oxidized LDL was cytotoxic to a variety of cells and induced apoptosis of smooth muscle cells, fibroblasts, macrophages, and endothelial cells in vitro.

In our study, sAPO-1 levels showed no significant correlations with LDL-C concentrations, although sAPO-1 had significant relationships with total cholesterol, triglyceride, and HDL-C. These discrepancies may reflect the different characteristics of human vascular endothelium and experimental animal cells. The inconsistencies may also reflect the differences in the methods for detecting apoptosis in vivo vs in vitro.

Apoptosis is a mode of cell death in which single cells are deleted in the midst of living tissue. Apoptosis accounts for the physiologic death of cells in the course of normal tissue turnover. APO-1-mediated cell death plays an important role in the regulation of the immune system, systemic inflammatory responses, and ischemic injury [27]. Considering that sAPO-1 is released from damaged cells [28], the elevated serum sAPO-1 levels that were observed in some elderly persons with increased serum total cholesterol concentration or elevated TBF suggest that increased serum lipid levels or body adiposity may be related to apoptosis or systemic tissue damage.

In conclusion, serum sAPO-1 concentrations showed significant correlations with TBF and WHR in men and with serum total cholesterol, HDL-C, and triglyceride levels in women, suggesting that the expression of sAPO-1 is associated with adiposity and lipid metabolism. The serum sAPO-1 level does not seem to vary according to subjects’ ages, but the relationship between sAPO-1 and serum lipid concentrations shows gender-dependent differences.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Reference Intervals of Serum Soluble APO-1 (Fas/CD95) Concentrations in Healthy Adults.
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