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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-2343
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 6 3575-3582
Copyright © 2005 by The Endocrine Society

In Vivo Evidence of Impaired Peripheral Fatty Acid Trapping in Patients with Human Immunodeficiency Virus-Associated Lipodystrophy

J. P. H. van Wijk, M. Castro Cabezas, E. J. P. de Koning, T. J. Rabelink, R. van der Geest and I. M. Hoepelman

Department of Internal Medicine and Infectious Disease, University Medical Center Utrecht (J.P.H.v.W., M.C.C., I.M.H.), 3508 GA Utrecht, The Netherlands; Department of Internal Medicine, St. Franciscus Gasthuis (M.C.C.), 3004 BA Rotterdam, The Netherlands; and Departments of Nephrology (E.J.P.d.K., T.J.R.) and Radiology (R.v.d.G.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Address all correspondence and requests for reprints to: Dr. Jeroen P. H. van Wijk, Departments of Internal Medicine and Infectious Disease, University Medical Center Utrecht, G02.402, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. E-mail: j.p.h.vanwijk{at}azu.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The use of antiretroviral combination therapy in HIV has been associated with lipodystrophy and several metabolic risk factors. We postulated that patients with HIV-lipodystrophy have impaired adipose tissue free fatty acid (FFA) trapping and, consequently, increased hepatic FFA delivery. We investigated FFA, hydroxybutyric acid (HBA; reflecting hepatic FFA oxidation), and triglyceride (TG) changes after a high fat meal in HIV-infected males with (LIPO; n = 26) and without (NONLIPO; n = 12) lipodystrophy and in healthy males (n = 35). Because defective peripheral FFA trapping has been associated with impaired action of complement component 3 (C3), we also determined postprandial C3 concentrations. The LIPO group had higher homeostasis model assessment scores compared with the other groups. Areas under the curve (AUCs) for FFA, HBA, and TG were higher in the LIPO group than in the NONLIPO group or the controls. No differences in TG-AUC, FFA-AUC, and HBA-AUC were observed between the NONLIPO group and controls. In HIV-infected patients, FFA-AUC and HBA-AUC were inversely related to sc adipose tissue area. Plasma C3 showed a postprandial increase in healthy controls, but not in the HIV-infected groups. C3 was not related to body fat distribution, postprandial FFA, or HBA. The present data suggest disturbed postprandial FFA metabolism in patients with HIV-lipodystrophy, most likely due to inadequate incorporation of FFA into TG in sc adipose tissue, but do not support a major role for C3 in these patients. The higher postprandial HBA levels reflect increased hepatic FFA delivery and may aggravate insulin resistance and dyslipidemia, leading to increased cardiovascular risk.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE USE OF highly active antiretroviral therapy (HAART) in HIV-infected patients has been associated with peripheral lipoatrophy, intraabdominal fat accumulation, and development of a buffalo hump (1, 2, 3). Approximately half of the HAART-treated HIV-infected patients will develop at least one of these symptoms after 12–18 months of therapy (3). Severe forms of HIV-lipodystrophy can be disfiguring and stigmatizing, and often lead to suboptimal adherence to HAART. Moreover, the associated insulin resistance and dyslipidemia increase the risk of cardiovascular disease (4).

Adipose tissue plays a crucial role in regulating free fatty acid (FFA) concentrations during the postprandial period by suppressing the release of FFA in the circulation and stimulating the uptake of FFA liberated from triglyceride (TG)-rich lipoproteins by lipoprotein lipase (LPL) (5). This pathway is also known as the pathway of adipocyte FFA trapping. In patients with HIV-lipodystrophy, this process may be impaired, because there is not sufficient sc adipose tissue to capture FFA. The results could be postprandial accumulation of FFA, which are exposed to extraadipose tissues, such as liver, skeletal muscle, and pancreas, aggravating insulin resistance and overproduction of very low density lipoprotein (VLDL) particles (5, 6).

Increased hepatic FFA delivery is a main determinant of VLDL secretion and postprandial lipemia in subjects with insulin resistance (6). Hydroxybutyric acid (HBA) is a marker of hepatic FFA oxidation. HBA is formed in liver mitochondria solely from FFA, and FFA availability is the major determinant of HBA production (7). Therefore, postprandial HBA appearance in plasma may serve as a marker of postprandial hepatic FFA delivery. The postprandial HBA increase is higher in patients with familial combined hyperlipidemia (FCHL) compared with controls, and this is paralleled by increased postprandial FFA levels (8). In an animal model of CD36-deficient mice, increased hepatic FFA delivery has been linked to increased hepatic ß-oxidation reflected in increased plasma levels of HBA (9).

It has been recognized that complement component 3 (C3) is involved in peripheral FFA trapping (10, 11). C3a-desArg [which is identical with acylating-stimulating protein (ASP)] is an immunologically inactive cleavage product of C3 and stimulates FFA and glucose uptake in adipocytes (10, 11). Chylomicrons are strong activators of adipocyte C3 production (12, 13), and it has been shown that after a high fat meal plasma C3 concentrations increase (13, 14, 15), especially when insulin effects are blunted (16). It is thought that effective postprandial C3-mediated diversion of FFA from the liver contributes to a healthy lipoprotein phenotype. Several groups have shown that adipocytes from patients with FCHL are resistant to the effects of C3 (17, 18, 19), leading to an exaggerated and prolonged postprandial C3 response (15), eventually resulting in abnormal diversion of FFA to the liver and VLDL overproduction (8, 15).

We postulated that patients with HIV-lipodystrophy have impaired peripheral FFA trapping, leading to postprandial FFA accumulation and increased hepatic FFA delivery. For this purpose, we investigated FFA, HBA, and TG changes after an acute oral fat challenge (10 h; 50 g/m2) in HAART-treated HIV-infected male patients with and without lipodystrophy and in healthy normolipidemic controls. Because impaired peripheral FFA trapping has been associated with impaired action of C3 in patients with FCHL, we also determined postprandial C3 concentrations.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Males between 18 and 65 yr of age with a documented HIV infection were recruited from the Department of Infectious Disease of University Medical Center Utrecht. Inclusion criteria were HIV-RNA less than 10.000 copies/ml and HAART for at least 18 months with no changes in the treatment regimen during 6 months before inclusion. Exclusion criteria were the presence of HIV-related symptoms, renal and/or liver disease, diabetes mellitus, use of lipid-lowering medication, and an alcohol intake greater than 3 U/d. The presence of HIV-lipodystrophy was defined as self-reported symptoms of loss of sc fat (face, arms, legs, and buttocks) with or without increased abdominal girth or development of a buffalo hump. These findings were confirmed by the investigator (J.P.H.v.W.) before enrolment. This definition may be considered a limitation, but we did not perform whole body, dual energy x-ray absorptiometry and were thus unable to use the objective case definition of lipodystrophy as published by Carr et al. (20). Healthy controls were recruited by advertisement and met the same inclusion as the HIV-infected patients. Participants visited our department after a 12-h fast for blood sampling and anthropometric measurements. Body fat mass was estimated using bioimpedance analysis (RJL Systems, Detroit, MI). The study protocol was approved by the local research ethics committee of University Medical Center Utrecht. All participants gave written informed consent.

Oral fat loading test and separation of lipoproteins

After placing a cannula for venous blood sampling, subjects rested for 30 min before administration of the fat load. Fresh cream [a 40% (wt/vol) fat emulsion representing a total energy content of 3700 kcal/liter] was ingested within 5 min at a dose of 50 g fat and 3.75 g glucose/m2 body surface (13, 14, 15, 16). Participants remained supine during the test and were only allowed to drink mineral water. Peripheral blood samples were obtained in sodium EDTA (2 mg/ml) and lithium-heparin tubes, kept on ice, and centrifuged immediately for 15 min at 800 x g at 4 C, then plasma was stored at –80 C. Lipoproteins were subfractionated by ultracentrifugation as described previously in detail (21). Consecutive runs were carried out to float a Svedberg flotation rate (Sf) greater than 400 (chylomicrons), a Sf of 60–400 (VLDL1), a Sf of 20–60 (VLDL2), a Sf of 12–20 (intermediate density lipoprotein), and a Sf of 2–12 [low density lipoprotein (LDL)]. Cholesterol was measured in each fraction. TG were measured only in the Sf greater than 400, Sf 60–400, and Sf 20–60.

Analytical methods

Total cholesterol and TG were measured in duplicate by colorimetric assay with the CHOD-PAP and GPO-PAP kits, respectively (Roche, Mannheim, Germany). FFA were measured by an enzymatic colorimetric method (Wako Chemicals, Neuss, Germany). For FFA measurements, a lipase inhibitor (Orlistat, Roche, Basel, Switzerland) was added to the plasma to block ex vivo lipolysis. Total serum C3 concentrations were measured by nephelometry (Nephelometry type II, Dade Behring, Deerfield, IL). Total plasma C3 measured in our study represented C3, C3b, and C3c production. Because C3a is the least immunogenic part of C3 and much smaller than the complete C3 molecule, the contribution of C3a or ASP to total C3 measured in our assay is negligible (15). HBA was measured spectrophotometrically by the principle of reduced nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide+ conversion after adding 3-hydroxybutyrate dehydrogenase. For this purpose, 0.5 ml blood from the lithium-heparin tubes was denutriated by adding 1 ml 0.7 M HClO4 immediately after collection. Apolipoprotein B (apoB) was measured by nephelometry using apoB monoclonal antibodies (OSAN 14/15, Dade Behring). Glucose was measured by standard enzymatical laboratory methods (Vitros 250, Johnson/Johnson, Rochester, NY). Insulin was measured by ELISA (Mercodia, Uppsala, Sweden). For estimation of insulin sensitivity, the homeostasis model assessment (HOMA) index (glucose x insulin/22.5) was calculated. CD4 cell counts were determined by flow cytometry, and HIV-RNA was determined by ultrasensitive assay

Cross-sectional computer tomography (CT)

A single-slice, cross-sectional CT scan at the L4–L5 level was performed, as described previously (22), to assess the distribution of sc and visceral abdominal fat (SAT and VAT, respectively). Briefly, a lateral scout image was obtained to identify the level of the L4 pedicle, which served as the landmark for the 1-cm single-slice image. The border of the intraabdominal cavity was outlined on the CT image, and total fat and VAT areas were quantified by selecting an attenuation range of –250 to –50 Hounsfield units. SAT was calculated as the difference between total fat area and VAT.

Statistical analysis

Data are expressed as the mean ± SD in the text, tables, and figures. Total integrated areas under the curve (AUCs) were calculated by the trapezoidal rule using PRISM version 4.0 (GraphPad, San Diego, CA). Incremental integrated AUCs (dAUCs) were also calculated after correction for the baseline value. Differences between two groups were analyzed by independent t test. Comparisons among the three groups were performed with repeated measures ANOVA with the least significance difference test as the post hoc analysis test and with Bonferroni correction to the P value. During serial measurements, time effects, when compared with T = 0 h, were tested using repeated measures ANOVA with Bonferroni correction for multiple comparisons. In HIV-infected patients, bivariate correlations were calculated using Pearson’s correlation coefficients. All significantly correlated variables were used as independent variables in stepwise multiple regression analysis with FFA-AUC and HBA-AUC as dependent variables. TG, insulin, and HOMA values were log-transformed before analysis due to nonparametric distribution. Calculations were performed using SPSS/PC+ 11.5 (SPSS, Inc., Chicago, IL). Statistical significance was taken at the 5% level.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
General characteristics and fasting lipoprotein profile

Thirty-eight HIV-infected patients were included in the study. Twenty-six of them were characterized as having clinical evident HIV-lipodystrophy according to both patient and investigator. All HIV-infected patients in both groups were currently receiving HAART with nucleoside reverse transcriptase inhibitors and a protease inhibitor and/or a nonnucleoside reverse transcriptase inhibitor (Table 1Go).


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  		TABLE 1. Baseline characteristics of HIV-infected patients with and without lipodystrophy and healthy controls

 
General characteristics and the fasting metabolic profile of HIV-infected patients with (LIPO group; n = 26) and without (NONLIPO; n = 12) lipodystrophy and healthy controls (n = 35) are shown in Table 1Go. The time since diagnosis of HIV infection, the time on HAART, and immunological parameters were similar between the LIPO and NONLIPO groups. Total body fat mass and SAT, which were measured only in the HIV-infected patients, were significantly lower in the LIPO group than in the NONLIPO group. The LIPO group had higher HOMA than the NONLIPO group and healthy controls. The fasting lipoprotein profile of the study group is listed in Table 2Go. Fasting plasma TG levels were increased in the LIPO group compared with the other groups due to higher TG levels in the Sf greater than 400, Sf 60–400, and Sf 20–60 fractions. ApoB and total cholesterol were similar in the LIPO and NONLIPO groups, but they were increased in both groups compared with levels in healthy controls. LDL cholesterol was lower in the LIPO group compared with the NONLIPO group.


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  		TABLE 2. Fasting lipoprotein profile of HIV-infected patients with and without lipodystrophy and healthy controls

 
Postprandial TG and FFA changes

In addition to higher fasting plasma TG, the postprandial TG increase (Fig. 1Go) was greater in the LIPO group than in the NONLIPO group and healthy controls, which resulted in higher TG-dAUC and total TG-AUC (Table 3Go). Although fasting FFA values were not significantly different among the groups, FFA levels increased postprandially more in the LIPO group than in the other groups. The incremental FFA response (FFA-dAUC) was higher in the LIPO group than in the NONLIPO group and healthy controls, leading to a higher absolute FFA response (FFA-AUC) in the former compared with the other groups. There were no differences in FFA-AUC and FFA-dAUC between the NONLIPO group and healthy controls.



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  		FIG. 1. Mean plasma TG (upper panel), FFA (middle panel), and HBA (lower panel) concentrations during the oral fat-loading test in HIV-infected patients with ({blacksquare}) and without ({square}) lipodystrophy and in healthy controls (•).

 

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  		TABLE 3. Fasting levels and total and incremental AUCs for TG, FFA, HBA, and C3 during an oral fat loading test

 
HBA changes in response to an oral fat-loading test

Fasting HBA values were higher in the LIPO group compared with healthy controls, with intermediate concentrations in the NONLIPO group. The postprandial HBA increase (HBA-dAUC) was 2 times higher in the LIPO group compared with the NONLIPO group and healthy controls (Fig. 1Go), which resulted in a significantly higher HBA-AUC. HBA-AUC and HBA-dAUC were similar in the NONLIPO group and healthy controls.

C3 changes in response to an oral fat-loading test

Fasting C3 was higher in the LIPO group compared with healthy controls, with intermediate concentrations in the NONLIPO group. C3 showed a significant increase in healthy controls (Fig. 2Go), reaching maximum concentrations 2 h postprandially. In contrast, in the LIPO and NONLIPO groups, there were no significant changes in C3 levels after the oral fat load. Hence, the incremental C3 response (C3-dAUC) was higher in healthy controls than in either the LIPO or NONLIPO group. However, the total C3-AUC was higher in the LIPO group compared with healthy controls due to the higher fasting levels.



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  		FIG. 2. Mean absolute (upper panel) and relative (lower panel) changes in C3 during the oral fat-loading test in HIV-infected patients with ({blacksquare}) and without ({square}) lipodystrophy and in healthy controls (•). *, P < 0.05 vs. baseline.

 
Correlations between postprandial lipemia and other parameters

HBA-AUC was positively associated with FFA-AUC and FFA-dAUC (r = 0.38 and r = 0.32, respectively; P < 0.05 for each) and was inversely related to body mass index (BMI) (r = –0.50; P < 0.01; Fig. 3Go), total body fat mass (r = –0.40; P < 0.05), hip circumference (r = –0.38; P < 0.05), and SAT (r = –0.42; P < 0.05), but not to waist circumference or VAT. Using stepwise multiple regression analysis, HBA-AUC was best predicted by fasting HBA (standardized ß = 0.35; P < 0.05) and BMI (standardized ß = –0.46; P < 0.005), explaining 35% of the variation. FFA-AUC was significantly related to total body fat mass (r = –0.37; P < 0.05), SAT (r = –0.35; P < 0.05) systolic and diastolic blood pressures (r = 0.39 for both; P < 0.05), HOMA (r = 0.40; P < 0.05), apoB (r = 0.48; P < 0.01), and TG-AUC (r = 0.71; P < 0.001). Fasting FFA (standardized ß = 0.34; P < 0.001), HBA-AUC (standardized ß = 0.27; P < 0.005), and TG-AUC (standardized ß = 0.62; P < 0.001) were the best predictors of FFA-AUC, explaining 77% of the variation. TG-AUC was related to fasting TG (r = 0.94; P < 0.05), cholesterol (r = 0.36; P < 0.05), apoB (r = 0.56; P < 0.05), high density lipoprotein cholesterol (r = –0.42; P < 0.05), systolic blood pressure (r = 0.37; P < 0.05), and HOMA (r = 0.68; P < 0.05), but not to body fat distribution. Fasting plasma C3 was related to fasting plasma glucose (r = 0.62; P < 0.01), HOMA (r = 0.54; P < 001), apoB (r = 0.61; P < 0.01), cholesterol (r = 0.48; P < 0.05), plasma TG (r = 0.71; P < 0.01), high density lipoprotein cholesterol (r = –0.37; P < 0.05), and systolic blood pressure (r = 0.42; P < 0.05), but not to body fat distribution or HBA-AUC.



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  		FIG. 3. Correlations between HBA-AUC and BMI (upper left panel), total body fat mass (upper right panel), hip circumference (lower left panel), and SAT area (lower right panel) in HIV-infected patients. For five subjects, the anthropometric data were incomplete. Hence, correlations are given for the remaining 33 subjects.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The data from the present study suggest impaired adipocyte FFA trapping that contributes to postprandial lipemia in patients with HIV-lipodystrophy. The negative relationships between postprandial concentrations of FFA and HBA and SAT area indicate that this fat compartment contributes most to the trapping defect. Our data do not support the concept that impaired FFA trapping in HIV involves malfunctioning of the C3 system, because there was no difference in the postprandial C3 response between the two HIV-infected groups.

Adipose tissue FFA trapping plays a crucial role in regulating FFA concentrations in the postprandial period (5). Despite similar fasting FFA levels, HIV-infected patients with lipodystrophy showed a much greater postprandial FFA increase than the patients without lipodystrophy and the controls. Postprandial FFA and HBA levels were both negatively associated with SAT, but not with VAT despite its direct portal drainage. These data are suggestive of an impaired ability to store FFA as TG in SAT in patients with HIV-lipodystrophy. In vivo evidence supporting this concept has been provided in a small study using oral labeled TG, which showed markedly diminished TG clearance and increased flux of labeled FFA in patients with HIV-lipodystrophy, indicating defective LPL function (23). In addition, defects in hormone-sensitive lipase-mediated inhibition of lipolysis have been described in the same population (24, 25, 26). Hypertriglyceridemia in HIV has been associated with increases in lipolysis, FFA oxidation, and hepatic reesterification (25, 26). Although increased FFA release from adipose tissue contributes to hypertriglyceridemia, insulin-induced suppression of lipolysis did not normalize the VLDL-TG secretion rate (25), suggesting additional defects in TG clearance (23).

The definition of lipodystrophy in patients with HIV infection is often arbitrary. Our subgroup allocation was based on self-reported symptoms and physician clinical judgment. The results of the CT scans showing a significantly lower SAT in the patients with lipodystrophy justifies this subgroup allocation approach.

If adipocyte FFA trapping is disturbed, then nonadipose tissues are exposed to excessive FFA concentrations, which may have several metabolic consequences. First, the elevated postprandial FFA may aggravate insulin resistance. Indeed, the patients with lipodystrophy had higher HOMA than patients without lipodystrophy. Also supportive is the close relationship between HOMA and FFA-AUC observed in the HIV-infected patients. Second, our data demonstrate marked increased postprandial HBA levels in patients with HIV-lipodystrophy. Because ketogenesis (HBA production) occurs predominantly in hepatocytes, and FFA availability is a major determinant of rates of ketone body production in man (7), postprandial ketone body appearance may reflect hepatic FFA delivery. Previously, the severity of insulin resistance in patients with HAART-associated lipodystrophy has been related to the extent of fat accumulation in the liver (27). Hepatic FFA accumulation may therefore play a causative role in the development of insulin resistance in these patients. Third, FFA reaching the liver may up-regulate the production of apoB-containing, TG-rich particles by the liver (25, 26). Although fasting apoB levels were similar in HIV-infected patients with and without lipodystrophy, TG levels were almost 2-fold increased in the patients with lipodystrophy. A possible explanation may be that protease inhibitor-containing regimens increased the secretion of VLDL particles in both groups, regardless of the presence of lipodystrophy, by inhibiting proteosomal degradation of apoB in the liver (28, 29). Hence, the 2-fold increased TG levels in HIV-infected patients with lipodystrophy caused relatively TG-enriched VLDL. Besides elevated hepatic production, defects in LPL-mediated TG clearance may contribute to hypertriglyceridemia in this population (23). In agreement, our data show an exaggerated and prolonged postprandial TG response in the patients with lipodystrophy. Finally, it should be noted that despite similar apoB, the patients with lipodystrophy had lower LDL cholesterol than the patients without lipodystrophy, suggesting the presence of atherogenic small dense LDL particles in the former. Taken together, disturbed postprandial FFA metabolism may induce a vicious circle of metabolic risk factors that increase cardiovascular risk in patients with HIV-lipodystrophy (4).

Insulin and ASP are principal determinants of FFA trapping by adipose tissue. The ability of insulin to suppress FFA release and to up-regulate LPL-mediated TG clearance is impaired in subjects with insulin resistance (30, 31, 32). Our data suggest similar impairments in patients with HIV-lipodystrophy. The pathway of FFA trapping is also regulated by the C3 system. However, our data do not support the concept that impaired FFA trapping in HIV involves malfunctioning of the C3 system, because there was no difference in the postprandial C3 response between the two HIV-infected groups. Moreover, C3 was not associated with body fat distribution or with FFA and HBA levels. In a previous study, the absolute production of ASP as well as the percent conversion of C3 to ASP were significantly lower in HIV-infected subjects with lipodystrophy than in subjects without lipodystrophy or control subjects (33). We observed a strong relationship between C3 and several parameters of the insulin resistance syndrome, in agreement with the literature (13, 14, 15, 16, 17, 34, 35).

Several studies have investigated FFA metabolism in relation to body composition and insulin resistance in patients with HIV-lipodystrophy (24, 25, 26, 36, 37, 38, 39). However, most of these studies have been performed in the fasting state or under hyperinsulinemic conditions. Basal lipolytic rates are generally increased in patients with HIV-lipodystrophy (24, 25, 26), suggesting impaired action of hormone-sensitive lipase. In addition, several studies have reported elevated FFA levels after glucose or insulin challenge (37, 38, 39), suggesting resistance to the action of insulin to the suppression of lipolysis. High FFA levels have been related to markers of insulin resistance and body composition in HIV-infected patients (24, 37). For example, FFA levels after a standard glucose challenge were positively associated with VAT (24). In contrast, fasting FFA levels were inversely associated with SAT in the same study. Our study using a high fat meal (under low insulin conditions) showed that increased postprandial FFA levels were related to markers of insulin resistance (HOMA) and lipoatrophy (low SAT) in HIV-infected patients.

In conclusion, the results of the present study suggest disturbed postprandial FFA metabolism in patients with HIV-lipodystrophy, most likely due to inadequate incorporation of FFA into TG in sc adipose tissue. The higher postprandial HBA levels reflect increased hepatic FFA delivery and may aggravate several metabolic risk factors, ultimately leading to an increased risk for cardiovascular disease in these patients.


   Footnotes
 
This work was supported by The Netherlands Organization for Scientific Research (J.P.H.v.W.).

First Published Online March 22, 2005

Abbreviations: apoB, Apolipoprotein B; ASP, acylating-stimulating protein; AUC, area under the curve; BMI, body mass index; C3, complement component 3; CT, computer tomography; dAUC, incremental integrated area under the curve; FCHL, familial combined hyperlipidemia; FFA, free fatty acid; HAART, highly active antiretroviral therapy; HBA, hydroxybutyric acid; HOMA, homeostasis model assessment; LDL, low-density lipoprotein; LIPO, with lipodystrophy; LPL, lipoprotein lipase; NONLIPO, without lipodystrophy; SAT, sc abdominal fat; Sf, Svedberg flotation rate; TG, triglyceride; VAT, visceral abdominal fat; VLDL, very low-density lipoprotein.

Received December 1, 2004.

Accepted March 10, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Carr A 2003 HIV lipodystrophy: risk factors, pathogenesis, diagnosis and management. AIDS 17(Suppl 1):S141–S148
  2. Shevitz A, Wanke CA, Falutz J, Kotler DP 2001 Clinical perspectives on HIV-associated lipodystrophy syndrome: an update. AIDS 15:1917–1930[CrossRef][Medline]
  3. Carr A, Cooper DA 2000 Adverse effects of antiretroviral therapy. Lancet 356:1423–1430[CrossRef][Medline]
  4. Friis-Moller N, Sabin CA, Weber R, d’Arminio Monforte A, El-Sadr WM, Reiss P, Thiebaut R, Morfeldt L, De Wit S, Pradier C, Calvo G, Law MG, Kirk O, Phillips AN, Lundgren JD, Data Collection on Adverse Events of Anti-HIV Drugs Study Group 2003 Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 349:1993–2003[Abstract/Free Full Text]
  5. Frayn KN 2002 Adipose tissue as a buffer for daily lipid flux. Diabetologia 45:1201–1210[CrossRef][Medline]
  6. Taskinen MR 2003 Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 46:733–749[CrossRef][Medline]
  7. Miles JM, Haymond MW, Nissen SL, Gerich JE 1983 Effects of free fatty acid availability, glucagon excess, and insulin deficiency on ketone body production in postabsorptive man. J Clin Invest 71:1554–1561
  8. Meijssen S, Castro Cabezas M, Twickler TB, Jansen H, Erkelens DW 2000 In vivo evidence of defective postprandial and postabsorptive free fatty acid metabolism in familial combined hyperlipidemia. J Lipid Res 41:1096–1102[Abstract/Free Full Text]
  9. Goudriaan JR, Dahlmans VE, Teusink B, Ouwens DM, Febbraio M, Maassen JA, Romijn JA, Havekes LM, Voshol PJ 2003 CD36 deficiency increases insulin sensitivity in muscle, but induces insulin resistance in the liver in mice. J Lipid Res 44:2270–2277[Abstract/Free Full Text]
  10. Cianflone K, Maslowska M, Sniderman AD 1999 Acylation stimulating protein (ASP), an adipocyte autocrine: new directions. Semin Cell Dev Biol 10:31–41[CrossRef][Medline]
  11. Sniderman AD, Cianflone K, Arner P, Summers LK, Frayn KN 1998 The adipocyte, fatty acid trapping, and atherogenesis. Arterioscler Thromb Vasc Biol 18:147–151[Free Full Text]
  12. Scantlebury T, Maslowska M, Cianflone K 1998 Chylomicron-specific enhancement of acylation stimulating protein and precursor protein C3 production in differentiated human adipocytes. J Biol Chem 273:20903–20909[Abstract/Free Full Text]
  13. Verseyden C, Meijssen S, van Dijk H, Jansen H, Castro Cabezas M 2003 Effects of atorvastatin on fasting and postprandial complement component 3 response in familial combined hyperlipidemia. J Lipid Res 44:2100–2108[Abstract/Free Full Text]
  14. Halkes CJ, van Dijk H, de Jaegere PP, Plokker HW, van der Helm Y, Erkelens DW, Castro Cabezas M 2001 Postprandial increase of complement component 3 in normolipidemic patients with coronary artery disease: effects of expanded-dose simvastatin. Arterioscler Thromb Vasc Biol 21:1526–1530[Abstract/Free Full Text]
  15. Meijssen S, van Dijk H, Verseyden C, Erkelens DW, Castro Cabezas M 2002 Delayed and exaggerated postprandial complement component 3 response in familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol 22:811–816[Abstract/Free Full Text]
  16. van Oostrom AJ, van Dijk H, Verseyden C, Sniderman A, Cianflone K, Rabelink TJ, Castro Cabezas M 2004 Addition of glucose to an oral fat load reduces postprandial free fatty acids and prevents the postprandial rise of complement component 3. Am J Clin Nutr 79:510–515[Abstract/Free Full Text]
  17. Ylitalo K, Porkka KV, Meri S, Nuotio I, Suurinkeroinen L, Vakkilainen J, Pajukanta P, Viikari JS, Peltonen L, Ehnholm C, Taskinen MR 1997 Serum complement and familial combined hyperlipidemia. Atherosclerosis 129:271–277[CrossRef][Medline]
  18. Kwiterovich Jr P, Motevalli M, Miller M 1990 Acylation-stimulatory activity in hyperapobetalipoproteinemic fibroblasts: enhanced cholesterol esterification with another serum basic protein, BP II. Proc Natl Acad Sci USA 87:8980–8984[Abstract/Free Full Text]
  19. Cianflone KM, Maslowska MH, Sniderman AD 1990 Impaired response of fibroblasts from patients with hyperapobetalipoproteinemia to acylation-stimulating protein. J Clin Invest 85:722–730
  20. Carr A, Emery S, Law M, Puls R, Lundgren JD, Powderly WG, HIV Lipodystrophy Case Definition Study Group 2003 An objective case definition of lipodystrophy in HIV-infected adults: a case-control study. Lancet 361:726–735[CrossRef][Medline]
  21. Verseyden C, Meijssen S, Castro Cabezas M 2002 Postprandial changes of apoB-100 and apoB-48 in TG rich lipoproteins in familial combined hyperlipidemia. J Lipid Res 43:274–280[Abstract/Free Full Text]
  22. Borkan GA, Gerzof SG, Robbins AH, Hults DE, Silbert CK, Silbert JE 1982 Assessment of abdominal fat content by computed tomography. Am J Clin Nutr 36:172–177[Abstract/Free Full Text]
  23. Sekhar RV, Iyer D, Gaubatz J, Rehman K, Maldonado M, Pownall HJ, Visnegerwala F, Jahoor F, Balasubramanyam A 2003 Marked impairment of dietary triglyceride disposal contributes to hypertriglyceridemia in HIV lipodystrophy syndrome. Antiviral Ther 8:L46
  24. Hadigan C, Borgonha S, Rabe J, Young V, Grinspoon S 2002 Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy. Metabolism 51:1143–1147[CrossRef][Medline]
  25. Reeds DN, Mittendorfer B, Patterson BW, Powderly WG, Yarasheski KE, Klein S 2003 Alterations in lipid kinetics in men with HIV-dyslipidemia. Am J Physiol 285:E490–E497
  26. Sekhar RV, Jahoor F, White AC, Pownall HJ, Visnegarwala F, Rodriguez-Barradas MC, Sharma M, Reeds PJ, Balasubramanyam A 2002 Metabolic basis of HIV-lipodystrophy syndrome. Am J Physiol 283:E332–E327
  27. Sutinen J, Hakkinen AM, Westerbacka J, Seppala-Lindroos A, Vehkavaara S, Halavaara J, Jarvinen A, Ristola M, Yki-Jarvinen H 2002 Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy. AIDS 16:2183–2193[CrossRef][Medline]
  28. Mooser V, Carr A 2001 Antiretroviral therapy-associated hyperlipidaemia in HIV disease. Curr Opin Lipidol 12:313–319[CrossRef][Medline]
  29. Liang JS, Distler O, Cooper DA, Jamil H, Deckelbaum RJ, Ginsberg HN, Sturley SL 2001 HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. Nat Med 7:1327–1331[CrossRef][Medline]
  30. Coppack SW, Evans RD, Fisher RM, Frayn KN, Gibbons GF, Humphreys SM, Kirk ML, Potts JL, Hockaday TD 1992 Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal. Metabolism 41:264–272[CrossRef][Medline]
  31. Skowronski R, Hollenbeck CB, Varasteh BB, Chen Y-DI, Reaven GM 1991 Regulation of non-esterified fatty acid and glycerol concentration by insulin in normal individuals and patients with type 2 diabetes. Diabet Med 8:330–333[Medline]
  32. Ong JM, Kern PA 1989 Effect of feeding and obesity on lipoprotein lipase activity, immunoreactive protein, and messenger RNA levels in human adipose tissue. J Clin Invest 84:305–311
  33. Kotler DP, Ionescu G, Johnson JA, Inada Y, He Q, Engelson ES, Albu JB 2003 Studies of adipose tissue metabolism in human immunodeficiency virus-associated lipodystrophy. Clin Infect Dis 37(Suppl 2):S47–S51
  34. Weyer C, Tataranni PA, Pratley RE 2000 Insulin action and insulinemia are closely related to the fasting complement C3, but not acylation stimulating protein concentration. Diabetes Care 23:779–785[Abstract/Free Full Text]
  35. Muscari A, Massarelli G, Bastagli L, Poggiopollini G, Tomassetti V, Drago G, Martignani C, Pacilli P, Boni P, Puddu P 2000 Relationship of serum C3 to fasting insulin, risk factors and previous ischaemic events in middle-aged men. Eur Heart J 21:1081–1090[Abstract/Free Full Text]
  36. Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC 2000 Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquired Immune Defic Syndr 25:312–321
  37. Meininger G, Hadigan C, Laposata M, Brown J, Rabe J, Louca J, Aliabadi N, Grinspoon S 2002 Elevated concentrations of free fatty acids are associated with increased insulin response to standard glucose challenge in human immunodeficiency virus-infected subjects with fat redistribution. Metabolism 51:260–266[CrossRef][Medline]
  38. van der Valk M, Bisschop PH, Romijn JA, Ackermans MT, Lange JM, Endert E, Reiss P, Sauerwein HP 2001 Lipodystrophy in HIV-1-positive patients is associated with insulin resistance in multiple metabolic pathways. AIDS 15:2093–2100[CrossRef][Medline]
  39. Woerle HJ, Mariuz PR, Meyer C, Reichman RC, Popa EM, Dostou JM, Welle SL, Gerich JE 2003 Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens. Diabetes 52:918–925[Abstract/Free Full Text]



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