Visceral adiposity, C-peptide levels, and low lipase activities predict HIV-dyslipidemia

Kevin E. Yarasheski, Pablo Tebas, Sherry Claxton, Donna Marin, Trey Coleman, William G. Powderly, and Clay F. Semenkovich

Division of Endocrinology, Metabolism and Lipid Research, Division of Infectious Diseases, Departments of Internal Medicine, Cell Biology and Physiology, Washington University Medical School, St. Louis, Missouri 63110

Submitted 24 January 2003 ; accepted in final form 24 June 2003


    ABSTRACT
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
Protease inhibitor-based highly active antiretroviral therapy (PI-HAART) has been implicated in dyslipidemia, peripheral insulin resistance, and abnormal adipose tissue deposition in human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome, or AIDS. In vitro evidence indicates that some PIs reduce adipocyte lipoprotein (LPL) and hepatic lipase (HL) expression and activities. We examined whether LPL and HL activities are reduced in HIV-infected patients with dyslipidemia. Fasting serum lipids, glucoregulatory hormones, and postheparin LPL and HL activities, as well as whole body and regional adiposity, were measured in 19 HIV-seronegative controls, 9 HIV+ patients naive to all anti-HIV medications, 9 HIV+ patients naive to PIs, 9 HIV+ patients with prior PI experience but not currently receiving PIs, and 47 HIV+ patients receiving PI-HAART. The PI-HAART group had low LPL and HL activities. However, multiple linear regression analysis indicated that low postheparin LPL activity contributed only partially to HIV-dyslipidemia. Central adiposity and high C-peptide levels (an indicator of high insulin secretion) were stronger predictors of HIV-dyslipidemia. Low LPL and HL activities, by themselves, were insufficient to explain HIV-dyslipidemia because the PI-naive group had low LPL and HL activities but had normal adiposity, C-peptide levels, and serum lipid and lipoprotein levels. HDL-cholesterol was lower in PI-HAART and PI-naive groups than seronegative controls and was directly associated with LPL activity. These findings suggest that HIV-dyslipidemia is mediated primarily by factors that influence triglyceride and lipoprotein synthesis (e.g., central adiposity and hyperinsulinemia) and mediated only partially by factors that influence triglyceride clearance (e.g., lipase activity).

acquired immunodeficiency syndrome; human immunodeficiency virus; metabolic complications; insulin resistance; central obesity; aspartyl protease inhibitors; lipoprotein lipase; magnetic resonance imaging


HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) has dramatically reduced the morbidity and mortality rates associated with human immunodeficiency virus-1 infection [HIV (4)]. However, HAART has been associated with several metabolic anomalies (28). HAART typically consists of two nucleoside analog reverse transcriptase inhibitors (NRTI), combined with one or two inhibitors of the HIV-aspartyl protease inhibitor (PI), or a nonnucleoside analog reverse transcriptase inhibitor (NNRTI). Before the availability of PIs, NRTI and/or NNRTI therapies were associated with a mild hypertriglyceridemia that was attributed to an increased rate of hepatic lipogenesis (10, 12, 13, 15). Although very effective against HIV, the addition of PI to this regimen (PI-HAART) has been associated with severe hypertriglyceridemia (>400 mg/dl, >4.5 mM) (16). An increased rate of hepatic lipogenesis may still contribute to hypertriglyceridemia in the PI-HAART era, but reduced triglyceride clearance and conversion need to be examined.

Lipoprotein lipase (LPL) is the enzyme primarily responsible for triglyceride clearance from the circulation (7). LPL is synthesized and secreted from parenchymal tissues and transported to the capillary endothelium in skeletal muscle, adipose tissue, and heart, where it hydrolyzes lipoprotein triglycerides (chylomicrons, VLDL) to provide fatty acids to these tissues. Heparin administration releases LPL from the capillary endothelium, and postheparin LPL activity is absent in type I hyperlipoproteinemia, a rare disorder associated with severe chylomicronemia and low to absent HDL-cholesterol (3). Hepatic lipase (HL) is an enzyme with considerable homology to LPL that is also capable of hydrolyzing triglycerides of plasma lipoproteins. HL is bound to the hepatocyte surface and, like LPL, can be released into the circulation by heparin. Unlike LPL, the consequences of HL deficiency are poorly defined. In LPL deficiency, HDL levels are decreased, whereas HL deficiency tends to be associated with increased HDL (6).

In vitro evidence from C3H10T1/2 murine mesenchymal stem cells (19), human and 3T3-L1 preadipocytes (32, 33), and 3T3-F442A adipocytes (26) indicates that incubation with varying amounts of several HIV-PIs inhibits adipocyte differentiation, LPL mRNA expression, and LPL activity. In human embryonic kidney and hepatoma cell lines transfected with an LPL promoter construct that contained three putative sterol-regulatory elements, indinavir (a PI) reduced sterol-regulatory element-binding protein-1c-dependent LPL reporter gene activity. Notwithstanding the technical difficulties inherent in in vitro treatment of cells with HIV-PIs (18), these studies would predict that HIV-infected patients receiving PI-HAART would have low LPL activity, and this might contribute to HIV-associated dyslipidemia. One preliminary report found lower-than-normal postheparin LPL and HL activities in 12 HIV-infected patients with severe hypertriglyceridemia (1). To test the hypothesis that impaired postheparin LPL activity contributes to the dyslipidemia associated with PI-HAART, we measured postheparin LPL and HL enzyme activities and lipid profiles in a cross section of people living with HIV and treated with different antiviral regimens.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
Experimental subjects. Seventy-four HIV-infected subjects and 19 seronegative controls were enrolled in this cross-sectional study. (HIV)-infected subjects were consecutively enrolled from the acquired immunodeficiency syndrome AIDS Clinical Trials Unit, the Infectious Disease Clinic at Washington University Medical School, and several community practices. Most subjects seen were included unless they 1) were not fasting, 2) would/could not provide informed consent for the research procedures, 3) were habitual illegal drug users or known alcoholics, 4) were taking other medications that might affect glucose/lipid metabolism (angiotensin I-converting enzyme inhibitors, cyclosporine, furosemide, hydrochlorothiazides, lithium, prednisone, {beta}-blockers, terbutaline, megesterol acetate, anabolic steroids, or lipid- or cholesterol-lowering agents), or 5) had a contraindication for heparin administration (history of pancreatitis or a blood clotting disorder). HIV-infected subjects were questioned about their antiviral medication history. For the majority of subjects, medical and pharmacy records were reviewed to document start and stop dates for all medications. We tabulated the number of weeks each patient received each medication and calculated the average weeks of exposure to each medication (Fig. 1).



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Fig. 1. Medication exposure (wk) was not different among the 3 HIV-infected groups receiving treatment. PI-HAART, protease inhibitor (PI)-based highly active antiretroviral therapy. When the duration of medication exposure was normalized to the duration of HIV infection, there were no differences among the groups. AZT, zidovudine; 3TC, lamivudine; d4T, stavudine; ddI, didanosine; ddC, zalcitabine; EFV, efavirenz; NVP, nevirapine, DLV, delavirdine; IDV, indinavir; RTV, ritonavir; SQV, saquinavir; NFV, nelfinavir; APV, amprenavir.

 

Patients were assigned to a group on the basis of their current (at least the previous 6 mo) medications. Groups were as follows: HIV+ taking PI-based HAART (n = 47; Table 1), HIV+ with PI experience but no PI use within the previous 6 mo (n = 9), HIV+ but naive to PIs (n = 9), HIV+ with no exposure to anti-HIV medications (n = 9), and seronegative controls (n = 19). Subjects were queried about personal and family history (parents and siblings) of diabetes, cardiovascular disease (hypertension, myocardial infarct, bypass surgery, stroke), and hypercholesterolemia (>5.2 mM), as well as exercise habits (>3or <3 days/wk) and personal use of tobacco and alcohol (>3 drinks/day; Table 2). The Human Studies Committee at Washington University Medical School approved all procedures, and informed consent was obtained from each volunteer before enrollment.


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Table 1. Subject characteristics

 

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Table 2. Risk factors/family history

 

Body composition. All subjects had height and weight measured while they wore minimal clothing or a hospital gown. Adipose and lean tissue mass in the trunk and appendicular regions was determined using a Hologic QDR 2000 dual-energy X-ray absorptiometer (DEXA) in 90% of the subjects. A Hologic-certified radiology technician identified the regions of interest (arms, legs, trunk) and used Hologic Enhanced Array Whole Body software (v. 5.71A) to quantify bone mineral density and adipose and lean tissue mass in each region. Trunk-to-appendicular adipose tissue ratio (T/A) was calculated as trunk fat/(right and left arm and leg fat), as previously described (14).

Adipose tissue cross-sectional area in the abdomen was measured using 1H magnetic resonance imaging (MRI) in a subset of patients (77% of all subjects). A series of three to five axial MRI images of the abdomen (8 mm thick) was obtained at the level of lumbar 4–5 intervertebral space. Subcutaneous (SAT) and intra-abdominal (VAT) adipose tissue cross-sectional areas were measured in each axial image by use of NIH Image software (v. 1.61b7). The areas from serial images of the abdomen were averaged. The total abdominal adipose area was calculated (SAT + VAT = TAT), and intra-abdominal adiposity was expressed as VAT/TAT (21).

Serum lipids and lipoproteins. Blood was collected from an antecubital vein after an overnight (10- to 15-h) fast. Serum triglycerides, total cholesterol, and HDL-cholesterol were measured in the Core Laboratory for Clinical Studies at Washington University Medical Center. Serum total cholesterol and glycerol-blanked triglyceride concentrations were measured using enzymatic kits from Bayer and Diagnostics on a Hitachi 917 analyzer. HDL-cholesterol concentration was measured as above after precipitation of apolipoprotein B-containing lipoproteins from serum by means of dextran sulfate (31). In samples with triglycerides <=4.5 mM (<400 mg/dl), LDL-cholesterol concentration was estimated using the Friedewald equation (8). In samples with triglycerides >4.5 mM, LDL-cholesterol concentration was not measured. The accuracy of these methods is verified and standardized by participation in the Centers for Disease Control (CDC) Lipid Standardization Program, the CDC Cholesterol Reference Method Laboratory Network, and the College of American Pathologists external proficiency program (23). Fasting insulin concentration was determined by a commercial laboratory (Linco Research Laboratories, St. Charles, MO) using a double-antibody radioimmunoassay (RIA). Fasting C-peptide and glucagon concentrations were determined by RIA.

Heparin-releasable LPL and HL activities. In all subjects, 60 U heparin/kg were administered intravenously after the baseline blood collection. A blood sample was collected 10 min after heparin administration. Postheparin plasma was incubated with high- and low-salt extraction buffers. LPL, but not HL activity, is inhibited by high salt concentrations. The low-salt extract contains both LPL and HL activities, and the high-salt fraction contains only HL activity. The difference between the lipase activities in low- and high-salt fractions is equivalent to the LPL activity. LPL and HL activities were quantified ex vivo by measuring the rate at which postheparin plasma converted [14C]triolein to 14C-labeled free fatty acids under standardized conditions (60-min incubation at 37°C). 14C-free fatty acids were extracted from the incubation and quantitated using a liquid scintillation counter (30). In separate experiments involving serial dilutions of postheparin plasma, we determined that extremely high serum triglyceride levels did not artifactually reduce LPL activity in this ex vivo assay.

Statistics. Data are reported as means ± SE. Differences among the groups were identified using ANOVA and the least significant difference post hoc test where indicated. Pearson correlation analysis was used to identify linear associations between two variables. Multiple linear regression analysis was used to identify the best predictor(s) of hypertriglyceridemia after controlling for each of the variables that were related to triglyceride levels in this cohort. Predictors included in the multiple regression were C-peptide levels as an indicator of insulin secretion, DEXA-derived T/A ratio as an indicator of visceral adiposity, VAT/TAT, medication exposure, demographics, and lipase activities. The assumptions underlying the multiple linear regression model were examined. The predictors selected were linearly related to triglyceride levels. The residuals for each predictor were distributed normally, and any individual outliers that excessively biased the model were removed. Predictors that contributed a high degree of multicolinearity were removed from the model (e.g., insulin, VAT/TAT). {chi}2 Analysis was used to determine whether a history of diabetes, cardiovascular disease, hypercholesterolemia, exercise, or tobacco or alcohol use was independent of the group assignment. P values of <0.05 were considered statistically significant.


    RESULTS
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
All groups were similar with respect to age, gender, and ethnic distribution (Table 1). On the basis of self-report, the patients who were naive to all antiviral medications had been infected with HIV for a shorter time (P < 0.03). The group naive to all HIV medications also had the highest viral load, but their CD4 count was similar to that of all HIV-infected groups. A personal or family history of diabetes and cardiovascular disease and a personal history of ethanol use and regular exercise were independent of the group into which subjects were classified (Table 2). However, the proportion of subjects who reported a family history of cardiovascular disease or a personal history of hypercholesterolemia or tobacco use was not equivalent among the five groups (Table 2).

Average exposure to all anti-HIV medications was not different among PI-HAART, prior-PI-experience, and PI-naive groups (Fig. 1). In the groups with PI experience, PI use was predominantly distributed among indinavir, nelfinavir, ritonavir, and saquinavir, whereas amprenavir use was very low (Fig. 1). When medication exposure was normalized to the duration of HIV infection, there was no difference in exposure among the groups.

On average, all groups had similar body weight, body mass index, lean body mass, and percentage of body weight that was adipose tissue (Table 1). Despite this, T/A was greater in the PI-HAART group than in seronegative controls, subjects naive to all medications, and subjects with prior PI experience (P < 0.003; Table 1). The PI-naive group had a higher T/A than the seronegative controls and the group that was naive to all anti-HIV medications (P < 0.041). On the basis of the limited analysis of abdominal adipose tissue cross-sectional areas, the VAT/TAT ratio was greater in the PI-HAART group than in seronegative controls, subjects naive to all medications, and subjects with prior PI experience (P < 0.05). Only the PI-HAART group had an average VAT/TAT >0.40, a threshold value used to identify abnormally high intra-abdominal adiposity (21). Fat distribution in the PI-HAART group was "mixed": ~16% of the PI-HAART subjects had a normal body fat distribution and/or appearance (i.e., no unusual phenotype), ~30% had severe peripheral fat atrophy without excessive central adiposity, and ~54% had modest to severe peripheral fat atrophy and central adipose tissue accumulation as their predominant phenotype. DEXA-derived T/A ratio correlated with VAT/TAT (r = 0.62, P <= 0.0001) in the 70 subjects on whom both measures were available. As a result, T/A values were used to represent visceral adiposity in subsequent multiple regression analyses.

There were no differences in fasting insulin and glucagon concentrations among the five groups (Table 1). C-peptide levels were higher in PI-HAART than in control and naive-to-all-medication groups (Table 1). The PI-HAART and PI-naive groups had lower HDL concentrations than the seronegative group (P < 0.04). Fasting triglycerides (7.4 ± 1.8 mM) were higher in the PI-HAART group than in the seronegative controls. Total-cholesterol levels (7.1 ± 0.7 mM) were higher in the PI-HAART group than in the control and PI-naive groups (Table 1). The triglyceride and total- and HDL-cholesterol levels in the PI-HAART group and the triglyceride and HDL-cholesterol levels in the PI-naive group represent a high risk for cardiovascular disease by National Cholesterol Education Program guidelines (23). Calculated LDL-cholesterol levels were not higher in the PI-HAART group, but the LDL level could not be calculated in 18 of the PI-HAART subjects because their triglyceride levels were >4.5 mM.

Heparin-releasable LPL activity was lower in the PI-HAART group than in control, PI-naive, and prior-PI-experience groups (P < 0.03; Table 1). LPL activity was lower in the naive-to-all-HIV-medications group than in the prior-PI-experience group, but triglyceride and lipoprotein levels were normal in these two groups. HL activity was lower in PI-HAART than in PI-naive, prior-PI-experience, and seronegative groups (P < 0.04).

Heparin-releasable LPL and HL activities were inversely related to fasting serum triglycerides (r = –0.305, P = 0.003 for LPL; r = –0.215, P = 0.04, n = 93 for HL; Fig. 2). When the seven subjects with the highest triglycerides were removed from the regression analysis, heparin-releasable LPL and HL activities remained inversely related to fasting serum triglycerides (r = –0.258, P = 0.02 for LPL; r = –0.261, P = 0.02 for HL, n = 86; Fig. 2, insets). When only the PI-HAART subjects were considered, LPL activity (r = –0.404, P = 0.005, n = 47) but not HL activity (r = –0.258, P = 0.080, n = 47) was inversely related to serum triglycerides. LPL activity was directly associated with fasting HDL-cholesterol concentrations (r = 0.55, P<= 0.0001, n = 93).



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Fig. 2. Fasting serum triglyceride concentrations were inversely related to heparin-releasable lipoprotein lipase (LPL) activity (r = –0.305, P = 0.003, n = 93) and hepatic lipase (HL) activity (r = –0.215, P = 0.04, n = 93). FFA, free fatty acids. Insets: plots show the same associations after the 7 subjects with the highest triglycerides (>11 mM) were removed. Heparin-releasable LPL and HL activities remained inversely related to fasting triglycerides (r = –0.258, P = 0.02 for LPL, r = –0.261, P = 0.02 for HL; n = 86).

 

When all subjects were included in a multiple linear regression analysis where triglyceride level was the dependent variable, T/A (P = 0.015), C-peptide levels (P = 0.002), and LPL activity (P = 0.030) were significantly correlated (partially) with triglyceride levels; the model explained 40% of the variance (P < 0.0001). The predictive strength of this model was good; i.e., the standard error of the estimate (±244) was less than the standard deviation of the mean for triglyceride levels (±315). On the basis of the standardized {beta}-coefficients, the relative importance of the three variables that significantly contributed to the model-predicted triglyceride level, after independent control for each variable, was highest for C-peptide levels (0.36), intermediate for T/A (0.27), and lowest for LPL activity (–0.21).


    DISCUSSION
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
These findings suggest that low postheparin LPL and HL activities contributed only partially to HIV-associated dyslipidemia. The presence of central adiposity and the presence of high C-peptide levels (an indication of high insulin secretion) were stronger predictors of HIV-dyslipidemia than low LPL and HL activities. Low LPL and HL activities, by themselves, were insufficient to explain HIV-dyslipidemia, because we identified a group of HIV-infected subjects who were naive to all antiviral medications and had normal adiposity, C-peptide levels, and serum lipid and lipoprotein levels but low LPL and HL activities. As suggested previously (1113, 15), perhaps a higher plasma HIV viremia reduced LPL and HL activities in these subjects. In conjunction with previous evidence, these findings suggest that several factors, including central adiposity, high insulin secretion, HIV-induced elevations in proinflammatory cytokines (12), accelerated rates of hepatic lipogenesis (15) and lipoprotein synthesis (20, 27), and reduced rates of lipoprotein clearance (29), contribute to HIV-associated dyslipidemia. On the basis of the present findings, we suggest that elevated rates of triglyceride and lipoprotein synthesis, perhaps induced by central adiposity and high insulin levels, contribute more to HIV-dyslipidemia than low rates of lipase-mediated triglyceride clearance.

Our findings are limited by the fact that we cannot determine the temporal relationships among the strongest predictors of HIV-dyslipidemia. For example, it is possible that PI-HAART directly reduced insulin sensitivity (17) and indirectly increased visceral adiposity (9) and that both directly inhibited LPL activity. Recent publications support the notion that trunk adiposity, hyperinsulinemia, and hypertriglyceridemia can be dissociated in people living with HIV and receiving PI-HAART (22, 24). Collectively, these findings support the hypothesis that HIV-related metabolic complications represent a combination of different syndromes with different etiologies.

Other evidence from the present study supports the notion that the pathogenesis of HIV-dyslipidemia is multifactorial. The subjects naive to all anti-HIV medications had low LPL and HL activities but normal serum triglyceride and cholesterol levels. Although this group had a higher viral load than the other groups studied, they did not have an AIDS diagnosis. Perhaps having a slightly higher plasma viral load (1 log) reduced their lipase activities, but the level of plasma HIV viremia was not sufficient to increase the rate of triglyceride synthesis (or triglyceride-rich lipoproteins), so their serum lipid levels were normal. The PI-naive group had normal LPL and HL activities but reduced HDL-cholesterol and a tendency toward elevated serum triglyceride levels. Their visceral adiposity (T/A = 1.33) probably contributed to their moderate dyslipidemia, perhaps through an accelerated rate of triglyceride synthesis. The PI-HAART group had visceral adiposity, high insulin and C-peptide levels, and low LPL and HL activities, but we cannot eliminate their history of tobacco use or genetic factors as contributors to HIV-dyslipidemia.

In support of the findings of Purnell et al. (25), postheparin HL activity was lower in the PI-HAART group. Purnell et al. administered RTV to nonobese, seronegative, normolipidemic subjects for 2 wk and found modest elevations in plasma triglycerides, no effect on postheparin LPL activity, and a reduction in HL activity, but HDL levels were not increased. The PI-HAART group in the present study had greater visceral adiposity and low HL activity. Decreased HL activity has been associated with fewer small, dense LDL particles, and higher HDL-cholesterol levels, both reflecting a more favorable lipid profile. We observed low HDL-cholesterol levels in the setting of low HL activity. LDL and HDL particle size/density were not measured in this study, so we cannot confirm the physiological action of the low HL activity. However, PI-HAART subjects had significantly lower levels of HDL-cholesterol. LPL activity was directly related to HDL-cholesterol levels, and HL activity did not contribute significantly to the multiple regression model that predicted triglyceride levels. This suggests that, in this wide spectrum of HIV-infected subjects (from medication naive to PI-HAART), low HL activity is not a primary mediator of HIV-dyslipidemia. LPL is known to be required for the generation of HDL-cholesterol (5), and physiologically induced changes in LPL activity directly affect HDL-cholesterol levels (30).

Purnell et al. (25) did not find reduced postheparin LPL activity in HIV-seronegative controls given RTV for 2 wk, whereas we found that LPL activity was lower in PI-HAART recipients. Potential reasons for these different observations include the following. PI-HAART-treated patients received antecedent treatment with NRTI or NNRTI medications followed by the addition of PIs; HIV-infected subjects may experience multidrug interactions that result in higher circulating drug concentrations (especially with PIs); and our HIV-infected cohort may have had greater whole body or visceral adipose deposition or greater baseline triglyceride or insulin levels. Purnell et al. did not report adiposity or fasting insulin levels in their seronegative subjects.

These in vivo findings only modestly support previous in vitro studies (19, 26, 32, 33) finding that some PIs or NRTIs have direct inhibitory effects on lipase expression, processing, secretion, or activity and might therefore contribute to PI-HAART-associated dyslipidemia. On the basis of the present findings, it seems unlikely that HIV PIs have a potent inhibitory effect on proteases (known or unknown) that are involved in LPL and HL processing.

Another limitation to this cross-sectional study is that we do not know the body fat distribution of the subjects before HIV infection or before initiation of antiviral therapy. The exceptionally high serum triglycerides observed in some PI-HAART subjects (>11.3 mM, >1000 mg/dl) may imply that these subjects have a different metabolic syndrome than subjects with lower triglycerides. Perhaps a certain genotype (e.g., LPL polymorphism), lifestyle, or behavioral factor made them more susceptible to dyslipidemia. As a result, antecedent adiposity, regional fat distribution, or insulin resistance may have contributed to dyslipidemia or reduced lipase activities.

One potential confounder is the use of the T/A ratio in subjects receiving PI-HAART. As noted by Safrin and Grunfeld (28), this ratio may be artifactually elevated in subjects with two different syndromes (i.e., large trunk adipose depot vs. peripheral lipoatrophy). Both anthropomorphic alterations have been reported in PI-HAART, probably with different etiologies. In the present study, T/A measured using DEXA and VAT/TAT measured using MRI were correlated. This suggests that only minor errors are introduced when the DEXA-derived T/A ratio is used to identify HIV-infected subjects with visceral adipose tissue deposition.

In summary, LPL activity was low in HIV-infected people treated with PIs, but visceral adiposity and high insulin secretion were more robust predictors of HIV-hypertriglyceridemia. An additional lipid abnormality was low HDL-cholesterol, a powerful determinant of cardiovascular risk (2), which implies that PI-based regimens, although reducing morbidity and mortality, may predispose to cardiovascular disease. Given the risk associated with low HDL-cholesterol, it will be important to examine tissue-specific as well as fat depot-specific LPL expression and genetic polymorphisms for lipases to better define the mechanisms responsible for the metabolic complications of current therapies for people living with HIV.


    DISCLOSURES
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
This work was supported by the National Institutes of Health Grants DK-49393, DK-54163, DK-59531, DK-56341, AI-25903, AG-14658, HL-58427, and RR-00036, and by The Campbell Foundation.


    ACKNOWLEDGMENTS
 
We thank Drs. David Parks and David Prelutsky for referring patients. Dr. Curtis Parvin provided biostatistical advice.


    FOOTNOTES
 

Address for reprint requests and other correspondence: K. E. Yarasheski, Washington Univ. Medical School, Division of Endocrinology, Metabolism and Lipid Research, 660 South Euclid Ave., Box 8127, St. Louis, MO 63110 (E-mail: key{at}im.wustl.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


    REFERENCES
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 MATERIALS AND METHODS
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 DISCUSSION
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 REFERENCES
 

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