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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 2 853-858
Copyright © 2002 by The Endocrine Society

Other Original Articles

Increased Fasting Plasma Acylation-Stimulating Protein Concentrations in Nephrotic Syndrome

Metin Ozata, Cagatay Oktenli, Mustafa Gulec, Taner Ozgurtas, Fatih Bulucu, Kayser Caglar, Necati Bingol, Abdulgaffar Vural and I. Caglayan Ozdemir

Departments of Endocrinology and Metabolism (M.O., I.C.O.), Internal Medicine (C.O., M.G., F.B.), Biochemistry (T.O.), and Nephrology (K.C., A.V.), Gulhane School of Medicine, Etlik-Ankara and Bayindir Medical Center (N.B.), TR-06018 Sogutozu-Ankara, Turkey

Address all correspondence and requests for reprints to: Metin Ozata, M.D., Department of Endocrinology and Metabolism, Gülhane School of Medicine, TR-06018 Etlik/Ankara, Turkey. E-mail: mozata{at}gata.edu.tr

Abstract

Acylation-stimulating protein (ASP) is an adipocyte-derived protein that has recently been suggested to play an important role in the regulation of lipoprotein metabolism and triglyceride (TG) storage. ASP also appears to have a role in the regulation of energy balance. In addition to its role as a hormonal regulator of body weight and energy expenditure, leptin is now implicated as a regulatory molecule in lipid metabolism. However, little is known about the alterations in fasting plasma ASP and leptin concentrations in the nephrotic syndrome. As hyperlipidemia is one of the most striking manifestations of the nephrotic syndrome, we have investigated fasting plasma ASP and leptin levels and their relation to lipid levels in this syndrome.

Twenty-five patients with untreated nephrotic syndrome and 25 age-, sex-, and body mass index-matched healthy controls were included in the study. Fasting plasma lipoproteins, TG, total cholesterol, lipoprotein(a), apolipoprotein AI (apoAI), apoB, urinary protein, plasma albumin, third component of complement (C3), ASP, and leptin levels were measured in both groups.

Total cholesterol, TG, low and very low density lipoproteins, lipoprotein(a), apoB, and urinary protein levels were increased in the patient group, whereas plasma albumin, high density lipoprotein cholesterol, and apoAI levels were decreased compared with those in the control group (P < 0.001). Plasma ASP levels were significantly higher in the patient group compared with the control subjects (133.72 ± 65.14 vs. 29.93 ± 12.68 nmol/liter; P < 0.001), whereas leptin (2.69 ± 2.06 vs. 3.99 ± 2.99 ng/ml; P = 0.118) and C3 (1.01 ± 0.25 vs. 1.06 ± 0.23 g/liter; P = 0.662) levels were not significantly different between the two groups. Plasma leptin levels were correlated with body mass index in both nephrotic patients (rs = 0.86; P < 0.001) and controls (rs = 0.98; P < 0.001), but were not correlated with the other parameters. Fasting ASP concentrations showed no correlation with body mass index, proteinuria, plasma albumin, leptin, or any lipid parameter in either group, but C3 levels (in patient group: rs = 0.92; P < 0.001; in control group: rs = 0.68; P < 0.001).

Our findings showed that plasma ASP levels were significantly elevated, whereas leptin levels were normal in the nephrotic syndrome. Increased ASP levels in the setting of dyslipidemia in the nephrotic syndrome raise the possibility of an ASP receptor defect in adipocytes, which also suggests the existence of so-called ASP resistance. Moreover, it is possible that ASP activity is maximal, but cannot keep up with increased rates of lipid production by the liver. Thus, further studies are needed to elucidate the mechanism or source (adipocytes, the liver, or both) of elevated ASP concentrations in the nephrotic syndrome.

ACYLATION-STIMULATING protein (ASP) is an adipocyte-derived protein that has recently been suggested to play an important role in the regulation of lipoprotein metabolism and triglyceride (TG) storage (1). ASP also appears to have a role in the regulation of energy balance (2). Three proteins are required for the generation of ASP: third component of complement (C3), factor B, and adipsin (complement factor D) (3, 4). The product, C3a, is a nonglycosylated 77-amino acid, N-terminal fragment of the {alpha}-chain of C3. The terminal arginine is then rapidly removed by carboxypeptidase N to produce C3adesArg, also termed ASP (1). ASP increases the rate of fatty acid uptake by adipocytes, thereby stimulating TG synthesis. This effect appears to involve the specific actions of ASP to increase glucose transport into adipocytes (5, 6) and to increase the activity of diacylglycerol acyltransferase, which is the final enzyme involved in the synthesis of a TG molecule (7). It has been shown that ASP also influences fatty acid release from adipocytes (8). Therefore, ASP plays a role in regulating fatty acid balance in the adipocyte. Several studies reported elevated fasting plasma ASP concentrations in individuals with obesity (9, 10) and coronary artery disease (11). However, two recent reports have demonstrated that both obese Pima Indians (12) and patients with familial combined hyperlipidemia (13) have normal plasma ASP concentrations. In vivo studies in humans have demonstrated that the production and release of ASP by adipocytes markedly increases in the second half of the postprandial period (14). Furthermore, the increase in ASP production during this period correlates with maximal TG clearance and fatty acid uptake by adipocytes. Moreover, obese subjects have elevated plasma ASP levels compared with normal subjects (9, 10), but their plasma ASP decreases with prolonged fasting and weight loss (15). Thus, plasma ASP levels correlate with the expansion and contraction of adipose tissue mass, similar to leptin levels.

Leptin, the product of the obese gene, is mainly produced by adipocytes, and its circulating levels reflect the amount of energy stored in adipose tissue (16, 17). Leptin also reflects recent energy intake and dietary macronutrient composition, independently of any change in adipose tissue mass. Therefore, low leptin levels in fasting are an important signal of reduced energy intake before there is any appreciable loss of body fat stores (18). This protein is produced predominantly by adipocytes and exerts its effects on brain, endocrine pancreas, and other organs by activating transmembrane receptors. Although body weight accounts for approximately 50–60% of leptin’s variability, other factors, such as gender, age, and hormone (mainly insulin) and cytokine levels also contribute to the regulation of leptin (19). In addition to its role as a hormonal regulator of body weight and energy expenditure, leptin is now implicated as a regulatory molecule in lipid metabolism, hemopoiesis, insulin action, ovarian function, reproduction, immune function, and angiogenesis (20). Recent data from our group provide further insight into multiple system effects of leptin, as human congenital leptin deficiency is associated with multiple hormonal defects (21). Circulating leptin, which is partly cleared by the kidney, has been reported to increase in chronic renal failure (22), but is not changed in the nephrotic syndrome (23). However, the role of hyperleptinemia in uremic patients is not clear, and it is not known whether elevated leptin levels contribute to uremic anorexia, weight loss, and changes in body composition (24).

Although hyperlipidemia is one of the most striking manifestations of the nephrotic syndrome, underlying pathophysiological mechanisms have not yet been fully elucidated. Increased hepatic synthesis and decreased catabolism of lipoproteins and their delayed removal from plasma have been documented in both animal and human nephrotic syndromes (25, 26, 27, 28). Also, it has been shown that hepatic synthesis of albumin, fibrinogen, {alpha}2-macroglobulin, apolipoprotein B-100 (apoB-100), and lipoprotein(a) [Lp(a)] are increased in human nephrotic syndrome (29, 30, 31, 32). Catabolic defects have also been ascribed in part to the urinary losses of enzymes and/or apoproteins in lipoprotein metabolism (33, 34). In addition to increased blood lipid levels, the composition of each of the lipoprotein classes is abnormal (35). The characteristic disorder in blood lipoprotein composition in nephrotic patients is an increase in the low density lipoprotein (LDL), very low density lipoprotein (VLDL) (36), but no change (36) or a decrease in high density lipoprotein (HDL) (35), resulting in an increase in the LDL/HDL cholesterol ratio. Lp(a) (37) and apoB (36) are increased in the serum of nephrotic patients, but the concentrations of apoAI remain unchanged. Prolonged hyperlipidemia in patients with the nephrotic syndrome may cause accelerated atherosclerosis and be associated with an increased risk of coronary heart disease (38). However, it is not clear whether ASP and leptin may play a role in dyslipidemia in the nephrotic syndrome. As hyperlipidemia is one of the most striking manifestations of the nephrotic syndrome, we have investigated the alterations in fasting plasma ASP and leptin levels and their relation to circulating lipids in individuals affected with this disorder.

Subjects and Methods

Twenty-five untreated patients with the nephrotic syndrome (15–42 yr of age; mean age, 24.3 ± 6.4 yr) and 25 age-, sex-, and body mass index (BMI)-matched healthy subjects (16–40 yr; mean age, 24.2 ± 6.0 yr) were enrolled in the study.

Percutaneous renal biopsies were performed in all patients with nephrotic syndrome. The underlying renal diseases of nephrotic syndrome were amyloidosis in nine patients, membranous glomerulonephritis in eight patients, focal segmental glomerulosclerosis in five patients, mesangial proliferative glomerulonephritis in one patient, membranoproliferative glomerulonephritis in one patient, and minimal change glomerulopathy in one patient. Patients were excluded from the study if they had a family history or known previous history of primary hyperlipidemia, hypothyroidism, autoimmune disease, acute infection, or chronic liver disease. All patients presented with severe proteinuria (>3.5 g/d), hypoalbuminemia (<3 g/dl), hypercholesterolemia (total cholesterol, >250 mg/dl), and normal serum creatinine (<1.3 mg/dl). All subjects gave informed consent for participating in the study. The study protocol was approved by the local ethics committee of Gulhane School of Medicine.

Blood samples were drawn for determination of plasma ASP concentrations using prechilled syringes and prechilled glass tubes containing EDTA. All blood samples were drawn after an overnight fast and were immediately centrifuged at 4 C and stored at -80 C until assayed.

Plasma total cholesterol, TG, LDL, VLDL, HDL, Lp(a), apoAI, apoB, urinary protein (Upro), serum albumin, ASP, and leptin were determined in all patients and controls.

Upro was detected by turbidimetric method in 24-h urine specimens. Total plasma cholesterol, TG, and HDL cholesterol were measured by enzymatic colorimetric method with Olympus Corp. AU 600 autoanalyzer using reagents from Olympus Corp. (Hamburg, Germany). VLDL was isolated by ultracentrifugation, and VLDL cholesterol was determined enzymatically. LDL cholesterol was calculated by Friedewald’s formula. As Lp(a) values were high, LDL cholesterol was adjusted to reflect the contribution of Lp(a) cholesterol: LDL cholesterol = LDLcalculated - (Lp(a)/3) (39). Plasma apoA-I, apoB, and Lp(a) were measured by nephelometry with reagents from Beckman (Galway, Ireland). Plasma leptin levels were measured by immunoradiometric assay (human leptin IRMA, DSL-23100, Diagnostics Systems Laboratories, Inc., Webster, TX). The assay sensitivity was 0.10 ng/ml. The intraassay coefficient of variation at 2.0 ng/ml was 12% (n = 15). Plasma ASP concentrations were measured by RIA (Biotrak, Amersham Pharmacia Biotech, Little Chalfont, UK), which used a rabbit anti-C3adesArg (ASP) and avoided interference with the precursor (C3) by a selective precipitation step (normal range, 20–500 ng/ml; sensitivity, <40 ng/ml; coefficient of variation, 3–9%). C3 levels were measured by nephelometry with reagents from Beckman Coulter, Inc. (Immage, In Vitro Diagnostic, Beckman Coulter, Inc., Fullerton, CA).

Statistical analysis

All values are presented as the mean ± SD. Comparisons between the groups were made using Mann-Whitney U test according to distribution characteristics of the dataset. Correlations between the variables were investigated using Spearman’s {rho} test. {alpha} was set at 0.05 in each test.

Results

Plasma lipid profiles, fasting ASP and leptin concentrations, and other parameters in patient and control groups are given in Table 1Go. Plasma lipid concentrations such as TG, total cholesterol, Lp(a), apoB, LDL cholesterol, VLDL, and Upro in nephrotic patients were significantly higher than those in controls, whereas plasma albumin, HDL, and apoAI levels were significantly lower than the control subjects.


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  		Table 1. Clinical and laboratory features of nephrotic patients and controls

 
Fasting plasma ASP concentrations were significantly elevated in the patient group (133.72 ± 65.14 nmol/liter) compared with the controls (29.93 ± 12.68 nmol/liter; P < 0.001), whereas leptin concentrations (2.69 ± 2.06 vs. 3.99 ± 2.99 ng/ml) were not significantly different between patients and controls. Plasma C3 levels were also not significantly different between the two groups (1.01 ± 0.25 vs. 1.06 ± 0.23 g/liter; P = 0.662).

Neither ASP nor leptin correlated with any lipid parameter, Upro, or plasma albumin levels in both groups (Table 2Go). BMIs correlated in a positive manner with plasma leptin levels in both nephrotic syndrome patients (rs = 0.86; P < 0.001) and controls (rs = 0.98; P < 0.001), whereas ASP did not correlate with BMI. Neither nephrotic syndrome patients (rs = -0.12; P = 0.58) nor controls (rs = 0.22; P = 0.28) had a significant correlation between plasma leptin and ASP levels. However, ASP levels showed a positive correlation with C3 levels in both patient groups (rs = 0.92; P < 0.001; Fig. 1Go) and in the control group (rs = 0. 68; P < 0.001; Table 2Go).


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  		Table 2. Correlations of fasting plasma leptin and ASP with other parameters in nephrotic patients and controls

 


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  		Figure 1. Correlation between ASP and C3 levels in patients with the nephrotic syndrome.

 
Discussion

Plasma fasting ASP concentrations in patients with the nephrotic syndrome were not investigated previously, and our results indicate that fasting plasma ASP, but not leptin, were significantly elevated compared with control values. Moreover, fasting plasma ASP concentrations were not related to BMI, proteinuria, or plasma albumin, leptin, or lipid levels, but were related to C3 levels.

We did not find any relation between fasting ASP and other lipids such as apoAI, apoB, Lp(a), LDL, VLDL, and total cholesterol in patient and control groups. Similarly, Maslowska et al. (9) found no correlation between fasting ASP and TG or apoB levels in obese patients. Recently, Ylitalo et al. (13) found a weak correlation between ASP and lipid variables in Finnish patients with familial combined hyperlipidemia. In contrast, Cianflone et al. (11) found significant positive correlations between fasting ASP and TG, VLDL, or apoB in patients with coronary artery disease. Thus, the study population or sample size may explain this discrepancy. It is still possible that there exists no systematic relationship between fasting ASP and apoB or plasma lipids because only two extremes are represented and not continuity values. However, increased ASP levels are associated with elevated TG, apoB, and LDL cholesterol levels; in the latter three these elevations result from increased fatty acid flux to the liver, one possible cause of ASP resistance. Although our finding suggests that circulating ASP levels are not associated with plasma lipids, it does not exclude a role for ASP in the regulation of fatty acid uptake by adipocytes, as the action of ASP is not only dependent on the existing ASP concentration, but also on the sensitivity of target tissues to ASP, as indicated by Sniderman et al. (40). The increased ASP levels in the setting of dyslipidemia raise the possibility of an ASP receptor defect in adipocytes in the nephrotic syndrome (41). Thus, ASP can be elevated because adipocyte fatty acid trapping is impaired due to receptor defects. It has been shown that total ASP production correlates positively with fatty acid incorporation into adipose tissue (14). With regard to data from both mice and humans, elevated plasma ASP levels might be due to either impaired or enhanced adipocyte fatty acid trapping, and there is no direct way to clarify which prevails (41). As suggested by Sniderman et al. (41), plasma apoB levels may help distinguish between those two mechanisms. ApoB levels are elevated in the presence of impaired trapping, leading to increased fatty acid flux to the liver. However, apoB levels are normal in the latter setting, as fatty acid flux is expected to be normal. As apoB levels are elevated, it is likely that impaired fatty acid trapping is the reason for increased ASP levels in the nephrotic syndrome. Thus, ASP resistance does exist and is reminiscent of insulin resistance, and our findings are consistent with that concept (41), favoring the presumption that resistance to ASP may play a pivotal role in dyslipidemia of the nephrotic syndrome.

It is also possible to consider that the main source of elevated circulating ASP levels is the liver and not adipose tissue in the nephrotic syndrome. Due to the hypoproteinemia of nephrotic syndrome, hepatic protein synthesis is nonspecifically increased, and this is a major contributor to the well known hyperlipoproteinemia (25, 26, 30, 31, 32). The liver makes C3 and factor B, two of the three components required for the synthesis of ASP, and the production of both of these can be increased by certain cytokines such as IL-6 (42). Although it is not generally known, human hepatocytes produce significant amounts of factor D/adipsin (43). Therefore, all three factors needed for ASP production are present in the liver. As ASP acts on adipocytes mainly as a paracrine factor to increase TG synthesis and storage, the elevated ASP levels would not be sufficiently high to increase adipocyte glucose transport and diacylglycerol acyltransferase activity if the ASP was being produced outside of adipose tissue. Thus, it is also possible that ASP activity is maximal, but cannot keep up with increased rates of lipid production by the liver. Thus, further studies are needed to evaluate the role or contribution of hepatocytes in elevated ASP levels in nephrotic syndrome

In agreement with the report of Weyer et al. (44) in nondiabetic obese Pima Indians, we also found no significant correlation between fasting ASP and BMI in both nephrotic subjects and controls. In contrast to our finding, Sniderman et al. (10) reported a positive correlation between fasting ASP and BMI in obese women. However, Maslowska et al. (9) recently demonstrated no correlation between fasting ASP and BMI in a large population of obese subjects. Similarly, Cianflone et al. (11) found no relation between fasting ASP and BMI in patients with coronary artery disease. Taking together, our data suggest that, contrary to plasma leptin, BMI is not a critical determinant of fasting ASP concentrations in the nephrotic syndrome.

Our data also show a large interindividual variability in ASP levels in both nephrotic subjects and healthy adults, as observed in previous studies (9). These finding suggest that the control of ASP is not tight or that many factors may contribute to ASP production or its metabolism (3).

The clinical phenotype that results from the dysfunction of the ASP pathway will be determined in part by the response to insulin (40, 41). However, Weyer et al. (44) recently demonstrated that insulinemia or insulin action is not related to fasting ASP. Moreover, we have not determined any relation between fasting ASP and insulin in type 2 diabetic subjects (45). Similarly, Koistinen et al. (46) did not find any relation between fasting ASP and insulin sensitivity in type 2 diabetic subjects. Thus, we consider that the lack of measurement of insulin sensitivity in this study does not invalidate our results.

Animal studies suggest a relation between ASP and leptin. Markedly reduced adipsin expression has been previously shown in ob/ob and db/db mice (47). Thus, defects in leptin signaling may influence ASP production. On the other hand, mice lacking ASP have marked alterations in plasma leptin levels (2). The lack of association between these two hormones may be due to their inherently different regulatory pathways. Moreover, we found no significant difference in leptin levels between patients and controls, in contrast to increased ASP concentration in nephrotic patients. Similarly, Chabova et al. (23) also found no significant difference in leptin levels in the nephrotic syndrome compared with controls. These findings suggest that leptin has no influence on ASP concentrations at least in the nephrotic syndrome.

The major physiological role of leptin may be as a signal of inadequate triglyceride reserve in adipose tissue (48). Leptin also reflects recent energy intake and dietary macronutrient composition independently of any change in adipose tissue mass. Therefore, low leptin levels in fasting are an important signal of reduced energy intake, before there is any appreciable loss of body fat stores (18). A recent study in rats reported a TG-lowering effect of leptin (49), and a study in mice reported an attenuating effect of leptin on the lipogenic effect of insulin in skeletal muscle (50). We have not established a relation between leptin and plasma TG or other lipid parameters in nephrotic subjects. Thus, our data suggest that plasma leptin levels are normal in the nephrotic syndrome and do not play a role in the dyslipidemia observed in this syndrome. Studies in humans of the relationship between TG concentrations and leptin have to date reported controversial observations. Similar to our finding, one study in humans also found no association between TG and leptin (51). However, two other studies (52, 53) found an association of TG with leptin. This controversy might partly be explained by the selection of specific study populations or by small sample sizes.

Our findings showed that plasma ASP levels were significantly elevated, whereas leptin levels were normal in the nephrotic syndrome. Increased ASP levels in the setting of dyslipidemia in the nephrotic syndrome raise the possibility of an ASP receptor defect in adipocytes, which may also suggest the existence of a so-called ASP resistance. Moreover, it is also possible that ASP activity is maximal, but cannot keep up with increased rates of lipid production by the liver. Thus, further studies are needed to elucidate the mechanism or source (adipocytes, the liver, or both) of elevated ASP concentrations in the nephrotic syndrome.

Acknowledgments

We are grateful to Dr. Alp Ikizler (Vanderbilt University, Nashville, TN) and Dr. Gokhan Ozisik (Northwestern University, Chicago, IL) for critical review of the manuscript.

Footnotes

This work was supported in part by the Research Center of Gulhane School of Medicine.

Abbreviations: apoB-100, Apolipoprotein B-100; ASP, acylation-stimulating protein; BMI, body mass index; C3, third component of complement; HDL, high density lipoprotein; LDL, low density lipoprotein; Lp(a), lipoprotein(a); TG, triglyceride; Upro, urinary protein; VLDL, very low density lipoprotein.

Received April 13, 2001.

Accepted July 31, 2001.

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P. J. Havel
Update on Adipocyte Hormones: Regulation of Energy Balance and Carbohydrate/Lipid Metabolism
Diabetes, February 1, 2004; 53(90001): S143 - 151.
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