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Department of Medicine, The University of Hong Kong, Hong Kong, China
Address all correspondence and requests for reprints to: Aimin Xu, Department of Medicine, The University of Hong Kong, L8-33A, New Laboratory Block, 21 Sassoon Road, Hong Kong, China. E-mail: amxu{at}hkucc.hku.hk.
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Abstract |
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Introduction |
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Pharmacological studies have shown that adiponectin replacement therapy in mice can alleviate many metabolic abnormalities in obese mice as well as mice with lipoatrophy (2, 4). Acute injection of a truncated globular domain of adiponectin into mice decreases postprandial plasma glucose, free fatty acids (FFAs), and triglycerides (TGs), and chronic administration of this protein causes sustained weight loss without reducing food intake (3). Both in vivo and in vitro studies have found that full-length adiponectin generated from mammalian cells can enhance the sensitivity of insulin to inhibit hepatic glucose production by suppressing expression of several key enzymes involved in gluconeogenesis, such as phosphoenolpyruvate carboxylase and glucose-6-phosphatase (2, 11). We have recently reported that adiponectin replacement therapy can ameliorate fatty liver diseases and lipid abnormalities associated with alcoholic consumption and obesity by enhancing fatty acid oxidation and inhibiting the production of proinflammatory cytokine TNF-
in the liver tissue (12).
Highly active antiretroviral therapy (HAART), a combination of nonnucleoside inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors (PIs), is widely used to control HIV infection and the development of AIDS. However, this antiretroviral therapy is often associated with severe metabolic disorders, such as subcutaneous fat wasting (lipoatrophy), visceral adiposity, insulin resistance, and hyperlipidemia (13). Furthermore, long-term HAART also contributes to a high incidence of vascular disorders, coronary artery disease, and myocardial infarction in HIV-infected patients (14).
Metabolic complications arising from HAART are multifactorial and complex, including the drug-drug interactions, exacerbation of preexisting conditions, and reconstruction of immune system functions (15). Although HIV infection itself and nucleoside reverse transcriptase inhibitors have been associated with metabolic abnormalities, there are increasing clinical and epidemiological data that suggest a central role for HIV PIs in the causation of metabolic complications (16).
There are currently five United States Food and Drug Administration-approved HIV PIs available for AIDS therapy, including amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir. Elevation in serum TG and cholesterol levels is among the most prevalent features of the PI therapy-associated metabolic syndrome in patients as well as in animal models (17). Several recent studies have specifically implicated ritonavir, indinavir, or nelfinavir therapy as having the greatest effects on lipid metabolism (18, 19, 20). The causative role of HIV PIs in metabolic disorders was confirmed by two recent independent findings that administration of ritonavir or indinavir alone into noninfected healthy volunteers is sufficient to induce hyperlipidemia in these subjects (21, 22). Furthermore, two recent clinical studies on HIV-infected children demonstrates that hypertriglyceridemia and hypercholesterolemia are found only in those individuals receiving PI-containing anti-HIV therapy (23, 24).
The mechanisms that underlie HIV PI-mediated dyslipidemia remain incompletely understood. It has been suggested that different PIs might induce lipid abnormalities through distinct mechanisms (25). Many studies have provided evidence that some of HIV PIs block adipocyte differentiation, possibly by inhibiting the expression of adipogenic transcription factors CAAT box enhancer binding protein- (C/EBP-) and peroxisome proliferator-activated receptor-
(PPAR-) (26, 27, 28) or by impairing sterol regulatory element-binding protein-1 (SREBP-1) intranuclear localization (29). The inhibition of adipocyte differentiation has been proposed to be a primary etiology of PI-associated periphery lipoatrophy. In addition, some of the HIV PIs, such as indinavir and nelfinavir, have been shown to directly impede insulin signal transduction pathways and decrease glucose uptake in adipocytes (30). PI-induced lipid abnormalities have previously been thought to be a consequence of lipoatrophy or insulin resistance. However, hyperlipidemia, especially hypertriglyceridemia, has been observed in animal models and patients who do not have any observable peripheral lipoatrophy, visceral lipohypertrophy, or insulin resistance (31, 32).
In this study, we investigated the potential role of adiponectin in the pathogenesis of HIV PI-induced metabolic disorders. Our results demonstrate that several HIV PIs, such as ritonavir, nelfinavir, and indinavir, inhibit adiponectin production from adipocytes, with ritonavir having the greatest effect. Adiponectin deficiency aggravates dyslipidemia associated with ritonavir treatment, and adiponectin supplement attenuates this disorder, partly through inhibiting de novo lipid synthesis and enhancing fatty acid combustion in the liver tissue.
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Materials and Methods |
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Maintenance and differentiation of 3T3-L1 cells
The 3T3-L1 cells were maintained as subconfluent cultures in DMEM supplemented with 10% fetal bovine serum. For differentiation, postconfluent cells were induced by incubation with 0.25 µM dexamethasone, 0.5 mM 3-isobutyl-methylxanthione, and 10 µg/ml insulin for 2 d. This is followed by incubation with 10 µg/ml insulin for 2 d. The cells were then maintained in DMEM with 10% fetal bovine serum for another 4 d. Staining with Oil red O revealed that more than 90% of cells exhibited typical morphology of adipocytes.
Northern blot and Western blot analysis for adiponectin expression
Ten micrograms of total RNA purified from 3T3-L1 adipocytes were separated on a 1.2% formaldehyde-denaturing agarose gel and transferred to nylon membranes (Amersham Pharmacia, Arlington Heights, IL). Hybridization was performed as described previously (33). The membranes were visualized using a phosphorimager and quantified using MacBAS software (Fujifilm). For Western blot, approximately 5 µg of proteins collected from culture media of 3T3-L1 adipocytes were separated by 12% SDS-PAGE, transferred to nitrocellulose membrane, and probed with rabbit antimouse adiponectin antibody (11). The proteins reactive to the primary antibodies were visualized by enhanced chemiluminescence detection, and quantified using Image Master software (Amersham Pharmacia).
Measurement of adiponectin levels using ELISA
The production of rabbit polyclonal antibodies against full-length mouse adiponectin and its globular domain was described previously (11, 12); the antibodies were purified using a protein G-coupled Sepharose 4B column. A 100-µl volume of diluted mouse sera or culture media from 3T3-L1 adipocytes or standard samples of adiponectin were applied to 96-well microtiter plates coated with the polyclonal antibody against the globular domain of adiponectin. After incubation at room temperature for 120 min, the wells were washed and incubated for another 60 min with the polyclonal antibody against mouse full-length adiponectin labeled with biotin. The wells were washed again and incubated with streptavidin-conjugated horseradish peroxidase for 60 min and subsequently reacted with tetramethylbenzidine reagent for 15 min. Then, 100 µl of 2 M H2SO4 were added to each well to stop the reaction, and the absorbance at 450 nm was measured. Intra- and interassay coefficients of variance were 5.3–7.6% and 4.1–6.4%, respectively. Lower limits of detection for this assay are 0.5–2 ng of adiponectin protein.
Analysis of hepatic palmitate oxidation
Postnuclear supernatant was prepared from fresh liver by homogenization in 10 vol of an ice-cold buffer (0.25 M sucrose, 2 mM Na2-EDTA, and 10 mM Tris-HCl at pH 7.4) and centrifugation at 3000 x g for 1 min. The rates of fatty acid oxidation of liver homogenates were analyzed using [1-14C]palmitate (Amersham Biosciences, Uppsala, Sweden), as we described previously (12).
Isolation of primary hepatocytes and measurement of synthesis rates for TGs, fatty acids, and cholesterol
Primary hepatocytes were isolated from mice treated with vehicle, ritonavir, or ritonavir plus adiponectin using a method we described previously (11). After isolation and washing, cells were suspended in DMEM containing 10 mM HEPES at pH 7.4, 5% fetal bovine serum, and 0.1 mg/ml gentamicin, plated onto six-well dishes coated with collagen, and incubated in a 37 C incubator for 6 h. Lipid radiolabeling was initiated by adding 5 µCi/well [14C]acetic acid (Amersham Biosciences) and incubating with the cells for an additional 24 h in the absence or presence of 20 µM ritonavir or 20 µM ritonavir plus 10 µg/ml adiponectin. Culture media and cells were harvested, and lipids from these samples were extracted in chloroform-methanol (2:1). The pellets were suspended in 1 ml of 2-propanol, sonicated at 4 C with five bursts of 10 sec each, and centrifuged for 15 min at 5000 x g. The supernatant was aspirated, and the pellet was reextracted as above. The extracts were dried under a stream of N2 and dissolved in chloroform. Radiolabeled fatty acids, TGs, and cholesterol were separated using silica gel 60 thin layer chromatographic plates (Merck, Darmstadt, Germany) as described previously (34). Briefly, 10 µl of lipid extracts from each sample was applied to the thin layer chromatographic plates and then developed in a mobile phase of hexane/diethyl ether/acetic (70:30:1). After separation, the plates were exposed to x-ray film, and each lipid fraction was localized by comparison with standard TGs, fatty acids, and cholesterol (Sigma-Aldrich, St. Louis, MO). Each radiolabeled lipid species was then scraped from the plates, and their relative synthesis rates were determined by liquid scintillation counting.
Measurement of glucose, insulin, TGs, FFAs, cholesterol, and alanine aminotransferase levels
Blood glucose from tail vein was measured using a Glucometer Elite (Bayer, Leverkusen, Germany). The levels of plasma FFAs and TGs were determined using a Roche FFA kit and TG glycerol phosphate oxidase reagent (Pointe Scientific, Inc., Lincoln Park, MI), respectively. Circulating levels of mouse insulin were quantified using commercial ELISA kits from Mercodia AB (Uppsala, Sweden).
Expression and purification of recombinant adiponectin from HEK293 cells
Mouse adiponectin was expressed in HEK293 cells transiently transfected with a vector that encodes FLAG epitope-tagged adiponectin, as described previously (11, 12). The protein was purified using anti-FLAG M2 affinity gel (Sigma-Aldrich) and eluted with 150 µg/ml FLAG peptide. The eluted protein was concentrated using a concentrator with molecular mass cutoff of 10,000 Da (Vivascience, Hannover, Germany). FLAG peptides were removed by extensive wash with excessive volumes of saline.
Statistical analysis
Experiments were reproduced in at least two independent experiments. The results were presented as the mean of at least triplicate determinations ± SD. Significance was determined by Student’s t test or one-way ANOVA. In all statistical comparisons, a P < 0.05 was considered statistically significant.
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Results |
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). Quantitative analysis using both Western blot and ELISA revealed that the secretion of adiponectin into the culture medium was also markedly inhibited after treatment with 20 µM of these three HIV PIs, with ritonavir having the most pronounced effects (Fig. 1, B and C). Ritonavir inhibited adiponectin production in a dose-dependent manner, and this effect could be observed at a concentration as low as 5 µM (Fig. 1D).
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). Ritonavir treatment also induced a drastic elevation of plasma TGs (Fig. 2B). There was a close inverse relationship between circulating concentrations of adiponectin and of TGs. Furthermore, decreases in adiponectin concentrations slightly preceded the development of hypertriglyceridemia, indicating that adiponectin deficiency might be a causative factor for ritonavir-induced lipid abnormality in mice.
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). The elevated concentrations of plasma adiponectin remained constant throughout the course of treatment. Remarkably, replenishment of recombinant adiponectin markedly decreased ritonavir-induced elevations of plasma TGs and FFAs (Fig. 3, B and C).
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). Ritonavir or adiponectin had no obvious effects on food consumption, body weight gains, adiposity, and plasma levels of insulin and glucose within the period of treatment.
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, A and B). However, adiponectin had little effect on ritonavir-induced elevations of hepatic cholesterol synthesis (Fig. 4C). Ritonavir caused a slight but not significant decrease in hepatic fatty acid oxidation (Fig. 5). In contrast, adiponectin significantly increased the rates of fatty acid oxidation in hepatocytes. These results suggest that adiponectin ameliorates ritonavir-induced liver abnormalities and dyslipidemia by inhibiting hepatic TG and fatty acid synthesis and enhancing fatty acid oxidation.
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Discussion |
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In the present study, we demonstrated for the first time that some of HIV PIs (indinavir, nelfinavir, and ritonavir) could directly decrease mRNA expression of the adiponectin gene and inhibit adiponectin secretion from adipocytes, with ritonavir having the greatest effect (Fig. 1
). This result is consistent with the clinical findings that PI-associated hyperlipidemia was most severe with ritonavir, followed by nelfinavir and indinavir therapy in HIV-infected patients (19).
The cellular mechanism that underlies this PI-mediated inhibition of adiponectin gene expression remains to be elucidated. The two key adipogenic transcription factors PPAR- and C/EBP- have recently been implicated in the expression induction of the adiponectin gene (40, 41). PPAR- agonists can increase adiponectin expression and secretion in 3T3-L1 adipocytes in animal models as well as human subjects (2, 4). However, we have recently found that treatment of 3T3-L1 adipocytes with the aforementioned three HIV PIs had no obvious effect on expression of either the PPAR- or C/EBP- gene (data not shown), suggesting that HIV PI-mediated inhibition of adiponectin production is not due to their direct effect on transcriptional suppression of these two transcription factors. It is still possible that these PIs can inhibit the activities of PPAR- or C/EBP- at a posttranscriptional level. Alternatively, HIV PI attenuates adiponectin gene expression via a mechanism independent of these two transcription factors.
Previous studies on both animal models and human subjects have demonstrated that ritonavir therapy alone causes dyslipidemia in the absence of obvious lipodystrophy and insulin resistance (19, 22, 35). In line with these results, we found that intragastric administration of ritonavir induces hypoadiponectinemia as well as hypertriglyceridemia in a time-dependent manner. The inverse relationship between plasma levels of adiponectin and of TGs suggests that adiponectin deficiency is one of the important factors that contribute to ritonavir-induced lipid abnormalities. The direct causative role of hypoadiponectinemia is further confirmed by the finding that adiponectin replacement therapy markedly attenuated ritonavir-induced elevations of TGs and FFAs. However, the fact that adiponectin treatment had little effect on ritonavir-induced hypercholesterolemia and hepatic cholesterol synthesis implicates that hypoadiponectinemia cannot fully explain the metabolic abnormalities induced by HIV PIs. Indeed, it has recently been demonstrated that ritonavir can directly elevate hepatic apolipoprotein B production and increase very low-density lipoprotein secretion (42).
It is increasingly recognized that some of the HIV PIs can directly act on hepatocytes and interfere with many lipid metabolic pathways (42, 43). Both in vitro and in vivo studies indicate that selective HIV PIs (ABT-378, ritonavir, nelfinavir, and saquinavir) stimulate de novo synthesis of TGs, fatty acids, and cholesterol in the liver cells, which consequently causes hepatomegaly and steatosis (35, 44). In this study, we found that adiponectin treatment decreases ritonavir- induced synthesis of TG and fatty acids. In addition, adiponectin enhances hepatic fatty acid combustion, although ritonavir has little effect on this process. The mechanisms that underlie the effects of adiponectin on hepatic lipid metabolism are currently unknown. A recent study has shown that full-length adiponectin can activate 5'-AMP-activated protein kinase in primary hepatocytes, which consequently phosphorylate acetyl-CoA carboxylase and attenuate the activity of this enzyme (45). Inhibition of acetyl-CoA carboxylase activity will directly reduce the rate of fatty acid synthesis and indirectly enhance fatty acid oxidation by reducing the production of malonyl-CoA (an inhibitor of carnitine palmitoyltransferase I). Activation of 5'-AMP- activated protein kinase can also phosphorylate and inhibit glycerol phosphate acyl transferase, a key enzyme involved in triacylglycerol synthesis (46, 47). In addition, adiponectin has recently been shown to activate PPAR- activity in hepatocytes, which may also contribute to its lipid-lowering effect (48). The detailed receptor and postreceptor events that underlie the hepatic actions of adiponectin are currently under investigation in our laboratory.
In addition to its direct effects on hepatic lipid metabolism, it is important to note that the muscular actions of adiponectin might also play a role in the alleviation of ritonavir-induced dyslipidemia. In this regard, a truncated COOH-terminal globular domain of adiponectin has been shown to increase fatty acid oxidation and energy expenditure in the muscle tissue, by up-regulating the expression of several genes involved in this process, such as acyl-CoA oxidase and uncoupling protein 2 (3, 4). Increases of muscular fatty acid combustion will consequently improve dyslipidemia by enhancing lipid clearance from the circulation.
The widespread application of PI-based HAART has dramatically reduced the morbidity and mortality of AIDS in HIV-infected patients. However, the detrimental side effects of the PI-based therapies, especially hyperlipidemia and insulin resistance, are now becoming a significant public health issue. Dyslipidemia and insulin resistance could certainly contribute to the accelerated atherosclerosis and coronary heart disease in HIV-infected patients. Furthermore, a recent study indicates that some of the HIV PIs can directly promote atherosclerotic lesion formation by increasing CD36-dependent cholesteryl ester accumulation in macrophages (49). There is currently no effective strategy available for the prevention or treatment of these disorders associated with PI-based therapy.
A major novel finding of our present study is that adiponectin replacement therapy can improve dyslipidemia induced by ritonavir. Notably, in addition to its beneficial effect on lipid metabolism, adiponectin has recently been shown to have direct antiatherogenic functions. This protein accumulates in injured vessel walls and dose-dependently inhibits TNF--induced cell adhesion in human aortic endothelial cells (50). It can also block lipid accumulation in monocyte-derived macrophages through suppressing the expression of macrophage scavenger receptor A (51). In addition, adiponectin can suppress the proliferation and migration of smooth muscle cells stimulated by various growth factors (52). The direct antiatherogenic role of adiponectin was further confirmed by two recent in vivo studies, which demonstrate that atherosclerosis in apolipoprotein E-deficient mice is markedly alleviated by either injection of adenovirus that expresses adiponectin or by crossing the globular domain of adiponectin transgenic mice with apolipoprotein E-deficient mice (48, 53). Thus, the results from the present study and others collectively implicate that adiponectin or its agonists might be useful for the prevention and/or treatment of metabolic and vascular disorders associated with selective HIV PI-based therapy in HIV-infected patients.
It was previously shown that certain types of HIV PIs could induce insulin resistance in vitro as well as in vivo (21, 30). On the other hand, a longitudinal study on HIV-infected men demonstrated that HIV PIs induce only an increase of TG level without modification of fasting glycemia and insulin sensitivity (31). In our present study, we found that treatment of C57 mice with ritonavir for a period of 2 wk has no obvious effects on blood glucose and insulin levels. Intraperitoneal glucose tolerance and insulin tolerance tests also showed that ritonavir did not affect insulin sensitivity and glucose tolerance (data not shown). In line with our findings, studies from two other independent groups have also found that ritonavir treatment for a period of 1–2 wk did not cause hyperglycemia and insulin resistance (18, 35). These results further suggest that different HIV PIs may have distinct metabolic effects. It is also possible that the relatively short duration of the ritonavir treatment period in our study is not sufficient to induce insulin resistance and diabetes. These possibilities are currently under investigation in our laboratory.
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Footnotes |
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Abbreviations: C/EBP, CAAT box enhancer binding protein; FFAs, free fatty acids; HAART, highly active antiretroviral therapy; PIs, protease inhibitors; PPAR, peroxisome proliferator-activated receptor; TGs, triglycerides.
Received September 2, 2003.
Accepted for publication October 21, 2003.
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