Sections of 1 Endocrinology, 2 Infectious Diseases, and 3 Atherosclerosis, Department of Medicine, and 4 Department of Pediatrics, Children's Nutrition Research Center and US Department of Agriculture/Agricultural Research Service, Baylor College of Medicine, Houston 77030; and 5 Ben Taub General Hospital, Houston, Texas 77030
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Human
immunodeficiency virus (HIV)-lipodystrophy syndrome (HLS) is
characterized by hypertriglyceridemia, low high-density lipoprotein-cholesterol, lipoatrophy, and central adiposity. We investigated fasting lipid metabolism in six men with HLS and six
non-HIV-infected controls. Compared with controls, HLS patients had
lower fat mass (15.9 ± 1.3 vs. 22.3 ± 1.7 kg,
P < 0.05) but higher plasma glycerol rate of
appearance (Ra), an index of total lipolysis (964.71 ± 103.33 vs. 611.08 ± 63.38 µmol · kg
fat1 · h
1, P < 0.05), Ra palmitate, an index of net lipolysis (731.49 ± 72.36 vs. 419.72 ± 33.78 µmol · kg
fat
1 · h
1, P < 0.01), Ra free fatty acids (2,094.74 ± 182.18 vs.
1,470.87 ± 202.80 µmol · kg
fat
1 · h
1, P < 0.05), and rates of intra-adipocyte (799.40 ± 157.69 vs. 362.36 ± 74.87 µmol · kg
fat
1 · h
1, P < 0.01) and intrahepatic fatty acid reesterification (1,352.08 ± 123.90 vs. 955.56 ± 124.09 µmol · kg
fat
1 · h
1, P < 0.05). Resting energy expenditure was increased in HLS patients (30.51 ± 2.53 vs. 25.34 ± 1.04 kcal · kg lean body
mass
1 · day
1, P < 0.05), associated with increased non-plasma-derived fatty acid
oxidation (139.04 ± 24.17 vs. 47.87 ± 18.81 µmol · kg lean body
mass
1 · min
1, P < 0.02). The lipoatrophy observed in HIV lipodystrophy is associated with
accelerated lipolysis. Increased hepatic reesterification promotes the
hypertriglyceridemia observed in this syndrome.
lipolysis; hypertriglyceridemia; very low density lipoprotein; high-density lipoprotein-cholesterol
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
HUMAN IMMUNODEFICIENCY VIRUS (HIV)-lipodystrophy syndrome (HLS), a novel metabolic illness characterized by body fat redistribution, dyslipidemia, and insulin resistance, has become common since the widespread use of highly active antiretroviral therapy (HAART) (3, 4, 24, 26, 39). Although various HAART agents (3, 4, 24, 26, 39), HIV infection per se (12, 18), and inflammatory cytokines (7, 23) have been imputed as etiologic agents, the mechanistic basis of HLS is unknown. Current therapies do not effectively reverse the metabolic abnormalities (10, 40), particularly the lipid disorders that increase the risk of cardiovascular disease (16, 21). In addition, the syndrome interferes with effective HIV therapy, because patients are sometimes switched to less efficacious drug combinations due to the concern that various potent HAART agents may be responsible for the metabolic abnormalities. Therefore, it is important to identify the fundamental lipid kinetic defects in this unique form of lipodystrophy to direct therapy toward the specific pathogenic mechanisms.
We hypothesized that HLS patients would have an accelerated rate of whole body lipolysis to facilitate fat redistribution. If unaccompanied by an equivalent increase in fatty acid oxidation, the increased release of free fatty acids (FFA) would result in increased hepatic fatty acid reesterification to triglycerides (TG). Alternatively, decreased disposal of TG, alone or in combination with increased hepatic fatty acid reesterification, could lead to hypertriglyceridemia. To test these hypotheses, we used stable isotope tracer techniques with mass spectrometry to measure lipid kinetics and body composition in the fasted state in men with HLS compared with non-HIV-infected men.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Subjects.
The study was approved by the Baylor Institutional Review Board for
human subject research. Six male patients with HLS were recruited. In
the absence of a standard case definition, HLS was defined by three
criteria: 1) change in body habitus, consisting of fat loss
in the extremities and increased abdominal girth, as observed by the
patient and confirmed by his primary physician (5);
2) Lipodystrophy Score, based on morphological abnormalities in each of five body regions, as assessed by a single investigator [A,
abdominal obesity; B, "buffalo hump" (posterior cervical fat pad);
C, supraclavicular fat pad; E, extremity fat loss; F, facial fat
loss]; a 4-point intensity scale was used (0, no change; 1, mild
change; 2, moderate change; 3, severe change), and a score of 2 in at
least two regions was required; 3) fasting plasma TG
concentration
300 mg/dl (3.39 mmol/l). All HLS subjects had the
"mixed" phenotype of HIV lipodystrophy (peripheral fat atrophy and
central adiposity) as described by Saint-Marc et al. (33). All HLS subjects were free of diabetes mellitus, thyroid disorders, hypercortisolemia, liver or renal impairment, and hypogonadism and had
had no HIV-associated opportunistic infections or illnesses for
5 yr.
Six healthy, age- and body mass index (BMI)-matched non-HIV-infected
men were recruited as controls. All subjects had sedentary lifestyles
(exercising <2 times/wk), and none consumed unusual diets or dietary supplements.
|
Study design and isotope infusion protocol.
The study consisted of an intravenous infusion of stable isotopes to
measure lipid kinetics in the fasted state in six HLS subjects and six
controls. Lipid-lowering medications were discontinued 2 wk before each
study. For 2 days preceding each study, subjects consumed a standard
diet that provided 30 kcal and 1 g protein · kg body
wt1 · day
1. All subjects were
fasted for 10 h before each study.
Sample analyses. Plasma glucose concentrations were measured using a glucose analyzer (YSI, Yellow Springs, OH). Plasma insulin concentrations were measured by radioimmunoassay for human insulin (Linco Research, St. Charles, MO). Plasma FFA concentrations were measured by a spectrophotometric assay utilizing reactions catalyzed by acyl-CoA synthase and acyl-CoA oxidase (Wako Chemicals, Neusse, Germany).
Plasma palmitate and glycerol concentrations were determined by in vitro isotope dilution (11) with the use of [2,2-2H2]palmitate (98% 2H) and [2-13C]glycerol (99% 13C, Cambridge Isotope Laboratories, Andover, MA) as internal standards. The tracer-to-tracee ratios of plasma free palmitate were determined by negative chemical ionization gas chromatography-mass spectrometry (NCI-GC-MS) using a Hewlett-Packard 5989B GC-MS system (Hewlett Packard, Fullerton, CA) (14). The pentafluorobenzyl derivative was prepared and analyzed by selectively monitoring ions from mass-to-charge ratios (m/z) 255 to 256. The plasma glycerol tracer/tracee ratio was measured by NCI-GC-MS on its heptafluorobutyric acid derivative, with selective monitoring of ions from m/z 680 to 685 (11). Breath 13CO2 content was determined by gas isotope ratio mass spectrometry on a Europa Tracermass Stable Isotope Analyzer (Europa Scientific, Crewe, UK).Calculations.
The following calculations were used. For Ra palmitate and
Ra glycerol
![]() |
![]() |
![]() |
![]() |
Statistical analysis. Group data were compared using a paired t-test. Differences were considered significant at P < 0.05. The correlation coefficient r was determined using the formula of Pearson and Lee (see Ref. 38). Data are expressed as means ± SE.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All HLS subjects were on a HAART regimen that included the
protease inhibitor indinavir, and five subjects were also taking the
nucleoside analog stavudine (Table 1). The RNA viral load was
suppressed to <400 copies/ml in all subjects except one. The CD4 count
was below the normal range (500/mm3) in four patients.
Lipodystrophy Score assessment revealed that all patients had
peripheral and facial fat loss together with abdominal obesity, and
five had an abnormality in every region.
Compared with controls, the HLS group had a significantly lower
(P < 0.02) fat mass but no difference in body weight,
BMI, TBW, or lean body mass (Table 2).
HLS patients had significantly higher fasting concentrations of plasma
glucose (P < 0.01), insulin (P < 0.001), total cholesterol (P < 0.001), and TG
(P < 0.01) and significantly lower (P < 0.05) fasting concentrations of plasma high-density lipoprotein
(HDL)-cholesterol (Table 2). The plasma concentrations of low-density
lipoprotein-cholesterol, Hb A1c, thyroid-stimulating
hormone, free thyroxine, 8 AM cortisol, testosterone, and hemoglobin
and indexes of renal and liver functions were within the normal range
in both groups.
|
Compared with controls, the HLS group had significantly higher
(P < 0.05) resting energy expenditure (Table
3). Whole body carbohydrate oxidation was
similar in the groups, but whole body fatty acid oxidation was
significantly higher (P < 0.02) in the HLS patients.
Plasma-derived FFA oxidation was similar in the groups; hence, the
increase in whole body fatty acid oxidation in the HLS group was due to
a significantly higher (P < 0.02) rate of oxidation of
fatty acids derived from sources other than the plasma FFA pool (Table
3).
|
Ra glycerol, an index of the rate of total lipolysis, was
significantly faster (P < 0.05) in the HLS subjects,
as was Ra palmitate (P < 0.01), an index
of the rate of net lipolysis (Table 4). Ra FFA, calculated from Ra palmitate, was also
faster in the HLS group (P < 0.05). The faster rates
of entry of glycerol, palmitate, and FFA into the circulation were
associated with significantly higher (P < 0.01) plasma
concentrations of glycerol (+80%), palmitate (+100%), and total FFA
(+42%) in the HLS group. The increase in the rate of net lipolysis in
the HLS subjects occurred despite a concomitant, and significant
(P < 0.05) increase in the rate of fatty acid
reesterification within the adipocyte. Because plasma-derived FFA
oxidation was similar in both groups, a significantly greater (P < 0.05) amount of the FFA released into the plasma
compartment as a result of the increased net lipolysis was available
for hepatic reesterification in the HLS patients (Table 4).
|
There was a positive correlation between the rate of hepatic
reesterification and fasting plasma TG concentration in control subjects (r = 0.88) but not in HLS patients
(r = 0.17).
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The clinical, anthropomorphic, and biochemical features of our HLS subjects are consistent with a well described phenotype that includes peripheral and facial lipoatrophy, central adiposity, elevated plasma TG, total cholesterol, glucose, and insulin concentrations, and a low plasma HDL-cholesterol concentration (16). Our results indicate a defect in the regulation of intra-adipocyte lipolysis in the HLS subjects that could lead to both the characteristic dyslipidemia and lipoatrophy. The rates of both total and net lipolysis were elevated in the HLS patients in the fasted state despite their reduced total fat mass. This could be due to either increased tissue-specific lipolysis via hormone-sensitive lipase or increased lipoprotein lipase or hepatic lipase activity against TG-rich lipoproteins. However, we have recently found that the HLS patients also had severely compromised disposal of CM- and very low density lipoprotein (VLDL)-TG in the postprandial state (R. Sekhar, F. Jahoor, and A. Balasubramanyam, unpublished observations), suggesting impairment in hepatic and lipoprotein lipase activities. Hence, the elevated plasma FFA levels in the HLS patients likely resulted from hyperlipolytic activity in adipocytes.
Hyperlipolytic activity and the attendant increased release of FFAs would drive processes for which fatty acids are substrates. The principal fates of plasma FFAs are oxidation and esterification. In the HLS patients, there was no compensatory increase in the oxidation of plasma-derived FFA in response to the increased rate of fatty acid release; hence, a greater amount of plasma FFA was available for hepatic extraction and conversion to glycerolipids. TG comprise the largest fraction of hepatic glycerolipids and are assembled into VLDL and secreted into the plasma compartment. Hepatic VLDL-TG production is known to increase linearly with plasma FFA concentration (34). Our data indicate that this mechanism could contribute significantly to hypertriglyceridemia in HLS. Elevated plasma FFAs would also exacerbate hypertriglyceridemia by inhibiting lipoprotein lipase activity (36).
Elevated plasma FFAs resulting from the hyperlipolytic state could also stimulate the activity of cholesteryl ester transfer protein (CETP) (1, 22) and thus provide a mechanism for the low HDL-cholesterol levels in HLS patients. An expanded pool of TG-rich lipoproteins in HLS patients is available to accept a greater amount of cholesteryl esters from HDL, thereby depleting HDL of its cholesterol content and lowering the measured plasma HDL-cholesterol level. Previous studies have shown that CETP-mediated transfer of HDL-cholesteryl esters to TG-rich lipoproteins increases with plasma TG levels (30).
With respect to the anthropomorphic changes, lipoatrophy and diminution of whole body fat mass would be facilitated by the high rate of net lipolysis, impaired TG storage, and increased energy expenditure that are largely met by increased oxidation of non-plasma-derived fatty acids. However, these mechanisms do not directly explain the occurrence of central visceral fat accumulation in patients with HLS. Increased central adiposity would require an additional defect, namely, either decreased lipolysis or increased fatty acid deposition outstripping the rate of lipolysis in visceral fat depots.
The present study was not designed to define the cause of HIV lipodystrophy but primarily to define the abnormal lipid kinetics that underlie it. However, previous studies of lipid metabolism in HIV-infected patients suggest etiologies that may underlie these defects. Hypertriglyceridemia and low plasma HDL-cholesterol levels were observed in HIV-infected patients before the advent of HAART (12, 13). Hence, factors intrinsic to HIV-1 infection per se could contribute to the dysregulation of lipolysis, hepatic TG synthesis, and TG disposal, as they do to other defects associated with dyslipidemia in HIV-infected patients, such as accelerated de novo hepatic lipogenesis (18) and decreased hepatic synthesis of HDL-apolipoprotein AI (19). In the context of HLS, which occurs mainly in patients treated with HAART, protease inhibitors may play an etiologic role (28, 31). Purnell et al. (31) showed in healthy, non-HIV-infected subjects that ritonavir increases plasma TG, mainly in the VLDL fraction, while decreasing hepatic lipase activity by 20% and leaving lipoprotein lipase activity unchanged. They suggested that protease inhibitors cause hypertriglyceridemia by increasing hepatic VLDL synthesis, a mechanism that is consistent with our kinetic data.
There is a strong positive correlation between the hepatic reesterification rate and the fasting plasma TG concentration in the control group but not in the HLS group. The absence of a correlation suggests a profound degree of dysregulation of the kinetics of reesterification in patients with HIV lipodystrophy, whereas the greater discrepancy between the two groups in the fasting TG levels compared with the rates of hepatic reesterification implies the existence of another source of plasma TG in the HLS patients. We speculate that this additional pool is derived from dietary TG that is cleared poorly and therefore persists in the plasma despite the fact the HLS subjects have been fasting for 12 h. This is consistent with our preliminary results from an ongoing study of dietary TG clearance in HLS patients.
Our HLS patients were taking HAART regimens that included indinavir in all and stavudine in all but one. These drugs, alone or together, have been implicated in the pathophysiology of HIV lipodystrophy. Nucleoside analogs such as stavudine impair mitochondrial DNA replication in liver, muscle, and white adipose tissue, and this could result in lipoatrophy by depleting cellular energy stores (9, 33). In HIV-infected men, stavudine is associated directly with an increased rate of total lipolysis and inversely with subcutaneous fat area (15). Protease inhibitors inhibit differentiation of transformed preadipocytes in vitro (6, 44). HAART-associated HIV lipodystrophy has also been associated with insulin resistance, and this was manifested in our HLS subjects who had elevated fasting insulin levels, central obesity, hypertriglyceridemia and low HDL-cholesterol levels. In addition to the HAART agents themselves, several factors could have contributed to the insulin resistance, including genetic background, degree of physical activity, smoking, and stress. We tried to control for these factors to the extent possible. Our subjects, both HLS patients and controls, were similar in relation to family history of diabetes (none having first degree relatives with diabetes) and physical activity (all sedentary). However, it is likely that the key contributor to insulin resistance in these patients was the elevated plasma entry rate of FFAs resulting from the elevated rates of intra-adipocyte lipolysis without a concomitant increase in plasma fatty acid oxidation. The resultant deposition of fatty acids and TG in myocytes and hepatocytes would result in significant reductions in glucose uptake and oxidation (25) and in other manifestations of insulin resistance (e.g., hypertriglyceridemia from increased hepatic reesterification and VLDL-TG synthesis in the liver).
Many features of HLS resemble those of hypercortisolemic states. Healthy persons undergoing hypercortisolemic "clamps" exhibit increased whole body lipolysis but decreased intra-abdominal lipolysis (35). In vitro studies of adipocytes taken from patients with Cushing's syndrome show that abdominal adipocytes have diminished hormone-sensitive lipase activity and increased lipoprotein lipase activity, whereas peripheral subcutaneous adipocytes have greater sensitivity to catecholamine-mediated lipolysis (32). These biochemical characteristics are consistent with the whole body lipid kinetics of our HLS patients and could underlie the phenotype of peripheral lipoatrophy and visceral adiposity. Although hypercortisolism is not a feature of HLS (27, 43), it is possible that the glucocorticoid receptor is activated by alternative mechanisms in HLS patients (20).
Because of the association of HLS with various HAART agents, patients are frequently switched to alternative therapeutic combinations of reduced antiretroviral efficacy. This may increase their risk of acquiring HIV-associated infections. In view of this risk, as well as the abnormal cardiovascular and metabolic profile, there has been an understandable urgency to treat HLS despite a lack of clear understanding of the underlying metabolic defects. To date, conventional antilipid agents (e.g, statins, fibric acid derivatives) (11) have proven relatively ineffective in reversing the abnormalities. Our results suggest that rational therapy of HLS might be directed at inhibiting lipolysis (17) and enhancing triglyceride disposal (29, 42).
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Margaret Frazer and Melanie Del Rosario for expert technical assistance in mass spectrometry, Dr. Mario Maldonado and Barbara Sepcie for help in recruiting HLS subjects, Holly Paskell, Lynne Scott, and the nursing, pharmacy, and dietary staffs of the Baylor General Clinical Research Center (GCRC) for excellent care of subjects and meticulous attention to protocol, and John Gaubatz for help in measuring lipoprotein subfraction concentrations.
![]() |
FOOTNOTES |
---|
Much of this work was performed in the Baylor Children's Nutrition Research Center, which is supported by the US Department of Agriculture/Agricultural Research Service (USDA/ARS) under Cooperative Agreement No. 5862-5-01003. The contents of this manuscript do not necessarily reflect the views or policies of the USDA. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government.
This work was also supported by a Developmental Award of the Baylor Center for AIDS Research Core Support Grant AI-36211 (National Institute of Allergy and Infectious Diseases), a Chao Scholar award, an award from the Siegler Foundation, and the Baylor GCRC (National Institutes of Health Grant RR-0188).
Address for reprint requests and other correspondence: A. Balasubramanyam, Division of Endocrinology, Dept. of Medicine, Rm. 537E, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030-2600 (E-mail: ashokb{at}bcm.tmc.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.
April 23, 2002;10.1152/ajpendo.00058.2002
Received 11 February 2002; accepted in final form 18 April 2002.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Barter, PJ,
Chang LB,
and
Rajaram OV.
Sodium oleate dissociates the heteroexchange of cholesteryl esters and triacylglycerol between HDL and triacylglycerol-rich lipoproteins.
Biochim Biophys Acta
1047:
294-297,
1990[ISI][Medline].
2.
Blaak, EE,
van Aggel-Leijssen DP,
Wagenmakers AJ,
Saris WH,
and
van Baak MA.
Impaired oxidation of plasma-derived fatty acids in type 2 diabetic subjects during moderate-intensity exercise.
Diabetes
49:
2102-2107,
2000[Abstract].
3.
Buss, N,
and
Duff F.
Protease inhibitors in HIV infection. Lipodystrophy may be a consequence of prolonged survival.
Br Med J
318:
122,
1999
4.
Carr, A,
Samaras K,
Burton S,
Law M,
Freund J,
Chisholm DJ,
and
Cooper DA.
A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.
AIDS
12:
F51-F58,
1998[ISI][Medline].
5.
Carr, A,
Samaras K,
Thorisdottir A,
Kaufmann GR,
Chisholm DJ,
and
Cooper DA.
Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study.
Lancet
353:
2093-2099,
1999[ISI][Medline].
6.
Dowell, P,
Flexner C,
Kwiterovich PO,
and
Lane MD.
Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors.
J Biol Chem
275:
41325-41332,
2000
7.
Fernandez-Miranda, C,
Pulido F,
Carrillo JL,
Larumbe S,
Gomez Izquierdo T,
Ortuno B,
Rubio R,
and
del Palacio A.
Lipoprotein alterations in patients with HIV infection: relation with cellular and humoral immune markers.
Clin Chim Acta
274:
63-70,
1998[ISI][Medline].
8.
Frayn, KN.
Calculation of substrate oxidation rates in vivo from gaseous exchange.
J Appl Physiol
55:
628-634,
1983
9.
Gaou, I,
Malliti M,
Guimont MC,
Letteron P,
Demeilliers C,
Peytavin G,
Degott C,
Pessayre D,
and
Fromenty B.
Effect of stavudine on mitochondrial genome and fatty acid oxidation in lean and obese mice.
J Pharmacol Exp Ther
297:
516-523,
2001
10.
Geletko, SM,
and
ZuWallack AR.
Treatment of hyperlipidemia in HIV-infected patients.
Am J Health Syst Pharm
58:
607-614,
2001[ISI][Medline].
11.
Gilker, CD,
Pesola GR,
and
Matthews DE.
A mass spectrometric method for measuring glycerol levels and enrichments in plasma using 13C and 2H stable isotopic tracers.
Anal Biochem
205:
172-178,
1992[ISI][Medline].
12.
Grunfeld, C,
Kotler DP,
Hamadeh R,
Tierney A,
Wang J,
and
Pierson RN.
Hypertriglyceridemia in the acquired immunodeficiency syndrome.
Am J Med
86:
27-31,
1989[ISI][Medline].
13.
Grunfeld, C,
Pang M,
Doerrler W,
Shigenaga JK,
Jensen P,
and
Feingold KR.
Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.
J Clin Endocrinol Metab
74:
1045-1052,
1992[Abstract].
14.
Hachey, DL,
Patterson BW,
Reeds PJ,
and
Elsas LJ.
Isotopic determination of organic keto acid pentafluorobenzyl esters in biological fluids by negative chemical ionization gas chromatography/mass spectrometry.
Anal Chem
63:
919-923,
1991[ISI][Medline].
15.
Hadigan, C,
Borgonha S,
Rabe J,
Young V,
and
Grinspoon S.
Increased rates of lipolysis among HIV-infected men with and without fat redistribution (Abstract 7).
In: 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. Athens, Greece: International Medical, 2001.
16.
Hadigan, C,
Meigs JB,
Corcoran C,
Rietschel P,
Piecuch S,
Basgoz N,
Davis B,
Sax P,
Stanley T,
Wilson PW,
D'Agostino RB,
and
Grinspoon S.
Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy.
Clin Infect Dis
32:
130-139,
2001[ISI][Medline].
17.
Hadigan, C,
Rabe J,
Aliabadi N,
Breu J,
and
Grinspoon S.
Acute inhibition of lipolysis improves insulin sensitivity in patients with HIV lipodystrophy and insulin resistance (Abstract OR20-1).
In: 83rd Annual Meeting of the Endocrine Society. Bethesda, MD: Endocr Soc, 2001.
18.
Hellerstein, MK,
Grunfeld C,
Wu K,
Christiansen M,
Kaempfer S,
Kletke C,
and
Shackleton CH.
Increased de novo hepatic lipogenesis in human immunodeficiency virus infection.
J Clin Endocrinol Metab
76:
559-565,
1993[Abstract].
19.
Jahoor, F,
Gazzard B,
Phillips G,
Sharpstone D,
Delrosario M,
Frazer ME,
Heird W,
Smith R,
and
Jackson A.
The acute-phase protein response to human immunodeficiency virus infection in human subjects.
Am J Physiol Endocrinol Metab
276:
E1092-E1098,
1999
20.
Kino, T,
Gragerov A,
Kopp JB,
Stauber RH,
Pavlakis GN,
and
Chrousos GP.
The HIV-1 virion-associated protein Vpr is a coactivator of the human glucocorticoid receptor.
J Exp Med
189:
51-62,
1999
21.
Krishnaswamy, G,
Chi DS,
Kelley JL,
Sarubbi F,
Smith JK,
and
Peiris A.
The cardiovascular and metabolic complications of HIV infection.
Cardiol Rev
8:
260-268,
2000[Medline].
22.
Lagrost, L,
Florentin E,
Guyard-Dangremont V,
Athias A,
Gandjini H,
Lallemant C,
and
Gambert P.
Evidence for nonesterified fatty acids as modulators of neutral lipid transfers in normolipidemic human plasma.
Arterioscler Thromb Vasc Biol
15:
1388-1396,
1995
23.
Ledru, E,
Christeff N,
Patey O,
de Truchis P,
Melchior JC,
and
Gougeon ML.
Alteration of tumor necrosis factor-alpha T-cell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome.
Blood
95:
3191-3198,
2000
24.
Lo, JC,
Mulligan K,
Tai VW,
Algren H,
and
Schambelan M.
Body shape changes in HIV-infected patients.
J Acquir Immune Defic Syndr Hum Retrovirol
19:
307-308,
1998[ISI][Medline].
25.
McGarry, JD.
Banting lecture 2001. Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.
Diabetes
51:
7-18,
2002
26.
Miller, KD,
Jones E,
Yanovski JA,
Shankar R,
Feuerstein I,
and
Falloon J.
Visceral abdominal-fat accumulation associated with use of indinavir.
Lancet
351:
871-875,
1998[ISI][Medline].
27.
Miller, KK,
Daly PA,
Sentochnik D,
Doweiko J,
Samore M,
Basgoz NO,
and
Grinspoon SK.
Pseudo-Cushing's syndrome in human immunodeficiency virus-infected patients.
Clin Infect Dis
27:
68-72,
1998[ISI][Medline].
28.
Noor, MA,
Lo JC,
Mulligan K,
Schwarz JM,
Halvorsen RA,
Schambelan M,
and
Grunfeld C.
Metabolic effects of indinavir in healthy HIV-seronegative men.
AIDS
15:
F11-F18,
2001[ISI][Medline].
29.
Pownall, HJ.
Dietary ethanol is associated with reduced lipolysis of intestinally derived lipoproteins.
J Lipid Res
35:
2105-2113,
1994[Abstract].
30.
Pownall, HJ,
Brauchi D,
Kilinc C,
Osmundsen K,
Pao Q,
Payton-Ross C,
Gotto AM, Jr,
and
Ballantyne CM.
Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins.
Atherosclerosis
143:
285-297,
1999[ISI][Medline].
31.
Purnell, JQ,
Zambon A,
Knopp RH,
Pizzuti DJ,
Achari R,
Leonard JM,
Locke C,
and
Brunzell JD.
Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects.
AIDS
14:
51-57,
2000[ISI][Medline].
32.
Rebuffe-Scrive, M,
Krotkiewski M,
Elfverson J,
and
Bjorntorp P.
Muscle and adipose tissue morphology and metabolism in Cushing's syndrome.
J Clin Endocrinol Metab
67:
1122-1128,
1988[Abstract].
33.
Saint-Marc, T,
Partisani M,
Poizot-Martin I,
Rouviere O,
Bruno F,
Avellaneda R,
Lang JM,
Gastaut JA,
and
Touraine JL.
Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study.
AIDS
14:
37-49,
2000[ISI][Medline].
34.
Salam, WH,
Wilcox HG,
and
Heimberg M.
Effects of oleic acid on the biosynthesis of lipoprotein apoproteins and distribution into the very-low-density lipoprotein by the isolated perfused rat liver.
Biochem J
251:
809-816,
1988[ISI][Medline].
35.
Samra, JS,
Clark ML,
Humphreys SM,
MacDonald IA,
Bannister PA,
and
Frayn KN.
Effects of physiological hypercortisolemia on the regulation of lipolysis in subcutaneous adipose tissue.
J Clin Endocrinol Metab
83:
626-631,
1998
36.
Saxena, U,
Witte LD,
and
Goldberg IJ.
Release of endothelial cell lipoprotein lipase by plasma lipoproteins and free fatty acids.
J Biol Chem
264:
4349-4355,
1989
37.
Sidossis, LS,
Coggan AR,
Gastaldelli A,
and
Wolfe RR.
A new correction factor for use in tracer estimations of plasma fatty acid oxidation.
Am J Physiol Endocrinol Metab
269:
E649-E656,
1995
38.
Snedecor, GW.
Statistical Methods. Ames, IA: Iowa State University, 1980.
39.
Viraben, R,
and
Aquilina C.
Indinavir-associated lipodystrophy.
AIDS
12:
F37-39,
1998[ISI][Medline].
40.
Visnegarwala, F,
Maldonado M,
Sajja P,
Vanek N,
Balasubramanyam A,
and
White AC.
Inconsistent effects of lipid-lowering drugs in the management of HIV-associated hyperlipidemias (Abstract 489).
In: 1st IAS Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina: Int AIDS Soc, 2001.
41.
Wang, Z,
Deurenberg P,
Wang W,
Pietrobelli A,
Baumgartner RN,
and
Heymsfield SB.
Hydration of fat-free body mass: new physiological modeling approach.
Am J Physiol Endocrinol Metab
276:
E995-E1003,
1999
42.
Weintraub, MS,
Zechner R,
Brown A,
Eisenberg S,
and
Breslow JL.
Dietary polyunsaturated fats of the -6 and
-3 series reduce postprandial lipoprotein levels. Chronic and acute effects of fat saturation on postprandial lipoprotein metabolism.
J Clin Invest
82:
1884-1893,
1988[ISI][Medline].
43.
Yanovski, JA,
Miller KD,
Kino T,
Friedman TC,
Chrousos GP,
Tsigos C,
and
Falloon J.
Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy.
J Clin Endocrinol Metab
84:
1925-1931,
1999
44.
Zhang, B,
MacNaul K,
Szalkowski D,
Li Z,
Berger J,
and
Moller DE.
Inhibition of adipocyte differentiation by HIV protease inhibitors.
J Clin Endocrinol Metab
84:
4274-4277,
1999