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AIDS Reviews 2007;9:3-15
Patrick W.G. Mal on: Pathogenesis of HIV-Associated Lipodystrophy
Pathogenesis of Lipodystrophy and Lipid Abnormalities
in Patients Taking Antiretroviral Therapy
Patrick W.G. Mal on
National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
HIV-associated lipodystrophy, arising as a result of long-term therapy with antiretroviral medications,
is a complex syndrome characterized by changes in regional fat mass, dyslipidemia, and insulin
sensitivity that, once established, is difficult to reverse. The syndrome arises largely as a result of
effects of nucleoside reverse transcriptase inhibitors and protease inhibitors on lipid metabolism.
Many of these effects have their basis at a molecular level with nucleoside reverse transcriptase
inhibitors linked to inhibition of mitochondrial RNA transcription, depletion of mitochondrial DNA
and mitochondrial dysfunction and protease inhibitors linked with adipocyte toxicity through interfer-
ence with the function of essential cellular transcription factors such as sterol regulatory element
binding protein 1c. These molecular toxicities can affect non-adipose tissues, and together with
secondary effects on lipid and glucose metabolism of changes in body fat mass, help to contribute
to the dyslipidemia and insulin resistance characteristic of this syndrome. This review will summarize
what is known of the molecular mechanisms underlying HIV-associated lipodystrophy. A greater
understanding of these mechanisms is essential if effective therapeutic options are to be found.
(AIDS Reviews 2007;9:-15)
Corresponding author: Patrick W.G. Mal on, paddy.mal [email protected]
Key words
HIV. Mitochondria. Lipodystrophy. Antiretroviral.
Underlying this complex clinical picture is an equal- ly complex series of interconnected molecular distur-bances arising secondary to the effects of HIV infection HIV-associated lipodystrophy (HIV-LD) is a complex itself, direct drug-induced toxicities, and indirect ef- and variable syndrome, characterized by loss of subcu- fects of changes in body composition on other aspects taneous adipose tissue (lipoatrophy), most apparent from of lipid metabolism. the limbs, face, and but ocks, and accumulation of adi-
pose tissue in the intraabdominal space, the dorso-cervi- Lipoatrophy
cal regions (buf alo hump) and the breasts. Accompany-ing metabolic abnormalities include dyslipidemia, insulin HIV-LD is characterized by an initial gain fol owed resistance, diabetes mel itus, and lactic acidaemia1. by a selective, progressive No part of this publication may be loss of subcutaneous adipose tissue2. The potential for nucleoside reverse transcriptase inhibitors reproduced or photocopying (NRTI) to cause mitochon- drial toxicity and lipoatrophy has long been recog- Patrick W.G. Mal on nised3,4. Use of thymidine analog NRTI, such as National Centre in HIV Epidem iology and Clinical Research without the prior written permission zidovudine (AZT) and stavudine (d4T) are more University of New South WalesLevel 2, St Vincent's Medical Centre strongly associated with lipoatrophy than other NRTI5. of the publisher St. Vincent's Hospital, Sydney Several factors influence subcutaneous fat mass, in- Darlinghurst, NSW 2010 cluding the rate of differentiation of adipocytes from their precursor cel s, the size of adipocytes, and the E-mail: paddy.mal [email protected] rate of adipocyte death.
Permanyer Publications 2010 AIDS Reviews 2007;9
or d4T6,9. In addition to apoptosis, direct cytotoxicity of adipocytes also occurs in vitro with exposure to PI but In vitro, exposure to both NRTI and protease inhibi- not NRTI12.
tors (PI) has been shown to affect adipocyte differen-
tiation6-8. Among PI, exposure to nelfinavir (NFV) and Mitochondrial dysfunction
ritonavir (RTV) decreases expression of markers as-
sociated with adipocyte differentiation6,8. In contrast,
Mitochondria are essential for the normal physiolog- exposure to indinavir (IDV) at concentrations ≤ 20 µM ic function of most cel s, being primarily involved in the has been shown to decrease7, cause no change6 or generation of energy as adenosine triphosphate increase adipocyte differentiation or expression of ad- (ATP)16. Acetyl coenzyme A, produced from fatty acids ipogenic markers8, while exposure to saquinavir (SQV) in mitochondria through fatty acid oxidation, is used as has been shown to have no effect on adipocyte dif- a substrate for the citric acid cycle in the generation ferentiation6,8. With NRTI, although in vitro exposure of of ATP. The citric acid cycle produces nicotinamide adipocytes to AZT decreased expression of markers adenine dinucleotide phosphate, which undergoes of terminal differentiation8,9, this did not translate to an oxidative phosphorylation. This is control ed by the mi-overal adverse effect on adipocyte differentiation, re- tochondrial electron transport chain, which contains gardless of whether cel s were exposed to AZT alone four enzyme complexes (complexes I-IV) that transfer or in combination with other NRTI9.
protons from nicotinamide adenine dinucleotide phos-phate to a fifth complex cal ed ATP synthase (Fig. 1). The resulting electron gradient is used to drive the phosphorylation of adenosine diphosphate to ATP17.
Adipose-tissue biopsies from patients with HIV-LD Mitochondria contain their own DNA, which exists as show marked heterogeneity in the size of adipocytes10, a double-stranded loop of DNA encoding 13 proteins,
with smal er adipocytes compared to healthy controls11. 22 transfer RNA and two ribosomal RNA. Replication
Size of adipocytes is determined by the size of the of mitochondrial DNA (mtDNA) occurs independently
intracel ular lipid reservoir. In vitro, intracel ular lipid of cel division so mitochondrial number can increase
reservoirs are depleted in adipocytes exposed to both in response to changing cel ular energy requirements.
PI and NRTI6,7,9,12. With NRTI, this effect is most marked An important enzyme involved in replication of mtDNA
in cel s exposed to AZT and d4T9. In both adipocyte is the mtDNA polymerase-γ (DNA pol-γ)17.
cultures and adipose tissue exposed to NRTI, these
smal adipocytes accumulate clusters of smal lipid NRTI and mitochondrial DNA pol-γ
droplets9,13, a phenotype more characteristic of brown
rather then white adipocytes. With PI, effects on intracel-
In their active triphosphate form, NRTI are synthetic lular lipid vary considerably between PI, with NFV = SQV analogies of natural y occurring nucleotides (Table 1) > RTV > IDV = amprenavir in terms of ability to reduce capable of incorporation into growing strands of DNA intracel ular lipid accumulation6,12,14.
causing chain termination. In much the same way as Adipocyte size can also be reduced through lipoly- NRTI inhibit HIV reverse transcriptase, NRTI also have sis, which results in release of triglycerides from adi- the ability to inhibit DNA pol-γ within mitochondria18.
pocytes into the circulation. In vitro, exposure to NFV Inhibition of DNA pol-γ has been postulated to un- caused increased adipocyte lipolysis15, an effect seen derlie the toxicity of NRTI and the subsequent features in other studies with RTV and SQV at 10 µM concen- of mitochondrial dysfunction No part of this publication may be observed in several tis- trations14. Such an effect in vivo could contribute to sues, including adipose tissue4, which has a high both lipoatrophy and hypertriglyceridemia (discussed concentration of mitochondria. Resulting depletion of reproduced or photocopying mtDNA may reach a critical level or "threshold" at which the tissue is unable to meet its energy require- without the prior written permission ments. In adipose tissue, NRTI-induced mtDNA deple-tion to this threshold may result in decreased adipo- of the publisher Increased apoptosis – or programmed cel death cyte size, increased adipocyte death, and ultimately – has also been demonstrated in vivo in adipose- the development of lipoatrophy. This forms the basis tissue biopsies from individuals with HIV-LD10 and of the "DNA polymerase-γ" and "mitochondrial thresh-in adipocyte cultures exposed to several PI, AZT, old" hypotheses. Permanyer Publications 2010

Patrick W.G. Mal on: Pathogenesis of HIV-Associated Lipodystrophy
Figure 1. The mitochondrial electron transport chain. The mitochondrial electron transport chain regenerates NAD+ from NADH for use in
the citric acid cycle. The hydrogen ion (H+) is transferred across each complex, generating an electrochemical gradient across the inner
mitochondrial membrane which is used to drive formation of ATP from ADP. Complex I = NADH dehydrogenase. Complex II = succinate
dehydrogenase. Complex III = cytochrome C oxidoreductase. Complex IV = cytochrome oxidase. Complex V = ATP synthase. NAD: Nico-
tinamide adenine dinucleotide; NADH: nicotinamide adenine dinucleotide dehydrogenase; ADP: adenosine diphosphate; ATP: adenosine
triphosphate.
NRTI and mitochondria – in vitro studies
In hepatocytes (HepG2 cel s), NRTI both inhibit cell proliferation and cause mtDNA depletion. In contrast In vitro, inhibition of DNA pol-γ by NRTI has been to didanosine (ddI) and d4T, AZT inhibits growth and demonstrated in several different cel lines19,20 and in increases lactate production in HepG2 cel s without direct analysis of isolated DNA pol-γ enzyme18. The causing reductions in mtDNA20, suggesting that this NRTI differ in their potential for mitochondrial toxicity. NRTI may cause mitochondrial toxicity through mecha-The toxicity index introduced by Johnson, et al. clas- nisms other than inhibition of DNA pol-γ and mitochon-sifies NRTI toxicity by the affinity of NRTI for incorpora- drial depletion. For AZT in particular, its toxicity can-tion into DNA by the DNA pol-γ enzyme, and also their not be readily explained simply on the basis of resistance to removal by the exonuclease activity of inhibition of DNA pol-γ18. An alternative mechanism DNA pol-γ18. is inhibition of mitochondrial RNA (mtRNA) expres- What becomes apparent from in vitro studies of NRTI sion, observed in several cel lines exposed to NRTI23. In toxicity is that the order of ranking of toxicity differs HepG2 cel s, addition of uridine, a precursor of pyrimi-depending on the cel line used and the method for dine, protects cel s from some No part of this publication may be NRTI-induced mitochon- measuring mitochondrial dysfunction (Table 2)9,18-20. drial toxicity and partial y reverses mtDNA depletion24.
Both AZT and d4T are more toxic to adipocytes, while reproduced or photocopying zalcitabine (ddC) is more toxic to other cel types such NRTI and mitochondria – in vivo studies
as hepatocytes21 and peripheral blood mononuclear
without the prior written permission cel s (PBMC)22. However, the NRTI concentrations ex- Unlike in vitro studies, direct inhibition of DNA pol- amined in these studies varied considerably, with some γ in adipose tissue has not been conclusively shown of the publisher toxicities only observed at exposure to drug levels ei- in vivo. Instead, quantifying mitochondrial toxicity in ther rarely seen22 or not achievable19 in vivo, raising vivo has centered on demonstrating mtDNA deple-questions as to the clinical applicability of some of tion. Reflecting in vitro data, reductions in mtDNA these data.
with antiretroviral therapy (ART) have been observed Permanyer Publications 2010 AIDS Reviews 2007;9
Table 1. Classification of NRTI based on endogenous nucleotides
Zalcitabine (ddC) Tenofovir disoproxil Emtricitabine (FTC) Endogenous nucleotides are broadly classified into purine and pyrimidine, depending on their chemical structure. The NRTI have chemical structures similar to endogenous nucleotides except they lack a 3' hydroxyl group which results in chain termination of growing DNA.
in human tissues, including adipose tissue, liver, and observed low mtDNA levels in PBMC of HIV-infected PBMC25-27. ART-naive patients34,35, indicating that HIV infection Subcutaneous adipose-tissue biopsies from patients itself has an adverse effect on PBMC mtDNA. How- with HIV-LD show decreased mtDNA compared to both ever, some NRTI result in greater decreases in PBMC treated13 and untreated HIV-infected control groups25 mtDNA than others. Antiretroviral-naive patients treated and HIV-negative controls28. The available data support with AZT, either with or without ddI or ddC, experi-the in vitro data described above that suggest d4T and enced decreases in PBMC mtDNA, with greater de-AZT preferential y cause mitochondrial depletion in adi- creases seen in patients exposed to AZT/ddI or AZT/pose tissue. In a cross-sectional study, ART-naive pa- ddC versus AZT alone36. Another prospective study of tients had similar adipose-tissue mtDNA levels compared naive patients started on a variety of ART regimens to HIV-negative controls, whilst those treated with d4T found decreased PBMC mtDNA in those on AZT/ddC, and AZT had significantly lower levels28. In a similar but not those on AZT/3TC35. If fact, PBMC mtDNA study, patients treated with d4T or AZT had 87 and 66% levels in those on AZT/3TC increased over time. A lower adipose tissue mtDNA, respectively, compared to similar increase in PMBC mtDNA was also seen in ART-naive patients29. Reflecting clinical trials showing patients treated with ART for 48 weeks, some of whom incomplete restoration of limb fat with switching from were randomized to d4T37, with no differences in thymidine analog NRTI30, a study examining adipose tis- mtDNA whether or not patients received d4T. These sue mtDNA after stopping d4T showed partial recovery data suggest that it may be the ddC component of of mtDNA levels after 48 weeks, with levels remaining well ART (and possibly ddI) rather than AZT or d4T that below those of healthy controls31. In addition to changes mediates mtDNA depletion in PBMC. This would be in mtDNA, functional reduction in activity of mitochon- consistent with the in vitro results described above drial electron transport chain complexes, correlating with (Table 2)22.
mtDNA depletion, has also been observed32.
As for whether PBMC mtDNA reflects adipose tissue Although these studies support mtDNA depletion oc- mtDNA, only one study has shown correlations be- curring through inhibition of DNA pol-γ, a study in HIV- tween mtDNA levels in the two tissues38. However, negative healthy volunteers randomized to six weeks other prospective studies sho No part of this publication may be wed development of lipo- of AZT/3TC or d4T/3TC showed decreased mtRNA ex- dystrophy in those on thymidine analog NRTI-contain-pression, similar to that seen in vitro23, after only two ing ART accompanied by either no change37 or an reproduced or photocopying weeks exposure in the absence of mtDNA depletion33, increase35 in PBMC mtDNA. In addition, the MITOX providing an alternative mechanism behind mtDNA study, examining patients with established lipoatrophy without the prior written permission depletion rather than through inhibition of DNA pol-γ. randomized to have their thymidine analog NRTI re-placed with abacavir30, revealed no increases in PBMC, mitochondrial toxicity, and HIV-LD
PBMC mtDNA over 24 weeks in those who switched thymidine analog NRTI despite increases in limb fat PBMC mtDNA has been investigated as a potential mass, and no correlations between changes in limb surrogate for adipose tissue toxicity. Several studies fat mass and PBMC mtDNA39. Similarly, another switch Permanyer Publications 2010 Patrick W.G. Mal on: Pathogenesis of HIV-Associated Lipodystrophy
Table 2. Ranking of NRTI by mitochondrial dysfunction in vitro
Measure of toxicity
Most toxic
Least toxic
ddC > d4T > ddI > 3TC > PMPA > AZT > CBV ddC > ddI > d4T > AZT > 3TC = ABC = TDF ddC > ddI > d4T > AZT = 3TC ddC > ddI > AZT = 3TC = d4T d4T = AZT > ddC > ABC > ddI = 3TC = TDF HepG2 cel s are neoplastic cel s of hepatic origin. 3T3-L1 and 3T3–F442A cel s are pre-adipocyte cel lines. The toxicity index was estimated from the ability of NRTI to incorporate into mtDNA causing chain termination, and its resistance to excision from mtDNA by the exonuclease activity of DNA pol-γ. SkMC: human skeletal muscle cel s; PRTEC: proximal renal tubular epithelial cel s; mtDNA: mitochondrial DNA; PMPA: active form of tenofovir disoproxil fumarate (TDF); ddC: zalcitabine; d4T: stavudine; ddI: didanosine; 3TC: lamivudine; AZT: zidovudine: CBV: carbovir; ABC: abacavir.
study showed no correlation between changes in Stable inherited polymorphisms, present in the mito- mtDNA in adipose tissue and PBMC31.
chondrial genome, have evolved over thousands of Overal these results suggest that, although mea- years and have been used to identify historic human- surement of mtDNA in PBMC can detect toxicity within migratory patterns43. Although peripheral neuropathy
PBMC, it is a poor surrogate of NRTI-mediated toxicity with NRTI has been linked to certain mitochondrial
in adipose tissue. However, PBMC comprise several haplotypes44, the effect of different mitochondrial hap-
cel types, including lymphocytes and monocytes. lotypes on the development of HIV-LD is yet to be
Healthy volunteers exposed to AZT/3TC or d4T/3TC determined.
experienced decreased mtRNA expression in both
monocytes and adipose tissue33. Further research is Limitations to the DNA pol-γ hypothesis
required to determine if monocytes are a more suitable surrogate for adipose-tissue mitochondrial toxicity.
As a unifying explanation for NRTI-induced mito- chondrial dysfunction, the DNA pol-γ hypothesis runs Mitochondrial DNA deletions
into trouble as both in vitro and in vivo data suggest that mitochondrial dysfunction can occur without obvi- In theory, inhibition of DNA pol-γ resulting in chain ous depletion of mtDNA. Although ddI, one of the termination should lead to accumulation of short mtDNA strongest inhibitors of DNA pol-γ, causes mitochon- fragments or evidence of large mtDNA deletions. drial depletion, it has no effect on adipocyte differen-Although individual cases of mtDNA deletions with ART tiation, lipid accumulation, or expression of important have been described40,41 evidence supporting wide- adipogenic genes at both physiologic and supra-phys-spread mitochondrial deletions with ART has been iologic concentrations9. Alternative mechanisms, such lacking from both in vitro20 and in vivo studies13,26,31. Al- as inhibition of mtRNA transcr No part of this publication may be iption demonstrated both though one smal study did demonstrate increased mito- in vivo33 and in vitro23, could also give rise to mtDNA chondrial deletions in muscle of patients with HIV-LD42, a depletion and offer an additional mechanism for NRTI- reproduced or photocopying larger study showed no deletions or point mutations in induced mitochondrial toxicity independent to effects adipose tissue of those treated with NRTI compared to on DNA pol-γ.
without the prior written permission those not treated with NRTI13. In addition, no mitochon-
drial deletions were observed in 16 patients fol owed PI and lipid metabolism – sterol
of the publisher up for 48 weeks after discontinuing d4T31. This further regulatory element-binding proteins
brings into question the applicability of the DNA pol-γ
hypothesis as a unifying hypothesis to explain NRTI-
Protease inhibitors cause adipose tissue toxicity induced mitochondrial toxicity.
through effects on sterol regulatory element-binding Permanyer Publications 2010 AIDS Reviews 2007;9
Endoplasmic recticulum Figure 2. Intracel ular processing of SREBP-1.SREBP: sterol regulatory element-binding proteins; SCAP: SREBP cleavage-activating protein;
Chol: cholesterol; S1P: site-1 protease; S2P: site-2 protease; Reg: C-terminal regulatory domain that interacts with SCAP; PI: protease in-
hibitor; PPAR: peroxisome proliferator-activated receptors; EBP: enhancer-binding protein.
proteins (SREBP). These are sterol-sensing transcrip- responsive genes such as lipoprotein lipase (LPL)49, tion factors capable of changing intracel ular choles- an effect that was not easily reversible. In adipocytes, terol and fatty acid metabolism in response to intracel- exposure to the PI nelfinavir at 20 µM resulted in de-lular changes in sterol levels by affecting transcription creased rates of dif erentiation accompanied by decreased of a large number of genes45. The three principal iso- protein levels of the active portion of SREBP-1, while forms are SREBP-1a, SREBP-1c (both encoded by a levels of the inactive form were maintained6. When single gene by alternate splicing) and SREBP-2. In adipocytes were exposed to 10-50 µM IDV, SREBP-1 addition to roles in adipocyte differentiation, SREBP-1a accumulated outside the nucleus, suggesting that PI af-and -1c are also involved in regulation of genes impor- fect SREBP-1c maturation7. tant for fatty acid and glucose metabolism46, while In contrast, exposure to RTV in mice did not result in SREBP-2 regulates genes involved in cholesterol ho- changes in SREBP-1 mRNA levels in any tissues ex-meostasis45.
amined50. In fact, RTV exposure in mice resulted in In adipocytes, PI af ect the cel ular maturation of SRBEP- accumulation of mature SREBP-1 in the nuclei of liver 1c to its active form7. Immature isoforms of SREBP-1c re- cel s50. Similar accumulation of intracel ular SREBP-1 side in the endoplasmic reticulum (ER), complexed was seen in mouse adipocytes exposed to 10 µM RTV51. with SREBP cleavage activating protein. Upon sterol Interestingly, transgenic mic No part of this publication may be e engineered to overex- depletion, this complex migrates to the Golgi and is press SREBP-1 in adipose tissue developed a pheno-cleaved by site proteases (S1P and S2P), releasing an type characterized by decreased white fat depots, reproduced or photocopying active aminoterminal portion of the molecule that mi- decreased expression of markers of adipocyte differ-grates to the nucleus where it drives transcription of entiation, hypertrophy of lipid-laden brown fat, hepatic without the prior written permission responsive genes (Fig. 2)47. steatosis, hypertriglyceridemia, and insulin resis- Expression of SREBP-1c is significantly lower in the tance52, al of which bear striking similarities to HIV-LD. of the publisher adipose tissue of patients with HIV-LD compared to pa- These mouse data, although apparently conflicting with tients without HIV-LD11,48. In vitro, exposure of HepG2 the human data described above11, may be explained cel s to IDV inhibited SREPB-1c activity, measured by the by inhibition of the nuclear proteasome in cel s ex-transcriptional activity of promoter regions of SREBP-1c- posed to high doses of RTV, resulting in decreased Permanyer Publications 2010 Patrick W.G. Mal on: Pathogenesis of HIV-Associated Lipodystrophy
degradation of mature SREBP-1. This wil be discussed metabolism, and could explain how NRTI-induced mi-in more detail below.
tochondrial toxicity leads to lipoatrophy (Fig. 3).
PI and lipid metabolism – PPARγ
Peroxisome proliferator-activated receptors (PPAR) In HIV-LD, it seems a paradox that central fat in- are transcription factors that are important for normal creases while subcutaneous fat decreases. However, function of both differentiating and differentiated adi- accumulation of visceral adipose tissue and discreet pocytes53. PPARγ, expressed in several tissues includ- lipomatosis are both features of HIV-LD1. This paradox ing adipose tissue and liver, is decreased by exposure can be explained by the significant differences be-to PI. In adipocytes, exposure to NFV, SQV and RTV tween visceral and subcutaneous fat. Visceral fat, cen-at 10 µM concentrations resulted in decreased adipo- tered around the abdomen and trunk, is predominant-genesis and decreased expression of PPARγ-respon- ly comprised of brown adipocytes, which are involved sive mRNA14. Similar effects were observed in adipo- in thermoregulation and heat production. In contrast, cytes exposed to 10-50 µM IDV7. In lipoatrophic mice, subcutaneous fat is mostly made up of white adipo-ablation of PPARγ activity in liver resulted in hepatic cytes, involved in the storage of circulating lipids to steatosis, hypertriglyceridemia, and muscle insulin re- meet future energy requirements56. These two cell sistance54, al features seen in PI-treated patients with types have very different functional characteristics HIV-LD. Patients with HIV-LD have lower adipose tis- (Table 3), so it is not surprising that exposure to anti-sue expression of PPARγ than those without HIV-LD48, retrovirals may have very different effects on each tis-accompanied by decreases in expression of PPARγ- sue, with what seems like a preferential loss of white responsive downstream genes.
rather than brown adipocytes, giving rise to decreased subcutaneous adipose tissue, but maintained or even SREBP-1, PPARγ, and mitochondria
increased visceral adipose tissue.
Accumulation of fat over the dorso-cervical spine or The regulation of lipid metabolism by SREBP-1 and "buffalo hump" has been reported in 2-13% of HIV- PPARγ is linked to mitochondrial physiology through PPARγ infected patients, with a higher prevalence in cohorts coactivator-1. This PPARγ coactivator-1 not only inter- with HIV-LD57. Although not linked to hypercortisolism acts with PPARγ to affect transcription of lipid metabo- (such as that seen in Cushing's disease), patients with lism genes, but also regulates mitochondrial gene HIV-LD and buffalo hump are more insulin resistant transcription through nuclear respiratory factors (NRF1 with a higher prevalence of diabetes mel itus than pa-and NRF2), which regulate mitochondrial transcription tients with HIV-LD and no buffalo hump57. Similarly, in factor A. Through these mechanisms, PPARγ coactiva- patients with HIV-LD, abdominal fat accumulation is tor-1 can influence ATP production in cel s that use associated with increased intramyocel ular lipid, which lipid as an energy substrate55.
in turn is associated with insulin resistance58.
Although PI-induced effects in SREBP-1c and PPARγ are wel documented, until recently the mechanisms Dyslipidemia
whereby NRTI-induced mitochondrial toxicity affect
lipid metabolism, leading to lipoatrophy, were poorly
Both cholesterol and triglycerides are present in the understood. As previously mentioned, healthy volun- circulation as lipoproteins, molecules that comprise teers exposed to thymidine analog NRTI experience both lipids (in the form of es No part of this publication may be terified and nonesterified decreases in expression of functional y important mito- cholesterol and triglycerides) and apoprotein mole-chondrial genes33. In addition, decreases in PPARγ cules. The pattern of dyslipidemia seen in HIV-LD is reproduced or photocopying expression were also observed and closely correlated characterized by elevations in total and low density with changes in mtRNA expression, suggesting a link lipoprotein (LDL) cholesterol and triglyceride, together without the prior written permission between mitochondrial function and PPARγ expression. with decreases in high density lipoprotein (HDL) choles-However, it is unlikely that the downregulation in terol59,60. Elevated LDL and decreased HDL concentra- of the publisher mtDNA was mediated through PPARγ coactivator-1 as tions have both been independently associated with its expression actual y increased. Nevertheless, these atherosclerosis and cardiovascular disease61. Elevated changes would likely have a functional impact on both triglycerides, when present in smal very low density cel ular oxidative phosphorylation capacity and lipid lipoprotein (VLDL) particles rich in apolipoprotein B Permanyer Publications 2010 100 9
AIDS Reviews 2007;9
complex complex complex complex Figure . Mechanisms of PI and NRTI-induced mitochondrial dysfunction. Both PI and thymidine analog NRTI affect expression of PPARγ,
albeit through different mechanisms. The combination of decreased PPARγ expression and decreased fatty acid oxidation capacity resulting
from drug exposure could explain how these drugs cause adipocyte toxicity and lipoatrophy. PI: protease inhibitor; SREBP1: sterol regula-
tory element binding protein 1; FAO: fatty acid oxidation; PPAR: peroxisome proliferator activated receptor; –ve: negative; tNRTI: thymidine
analog nucleoside reverse transcriptase inhibitor; mtRNA: mitochondrial RNA; mtDNA: mitochondrial DNA; pol: polymerase.
(ApoB ), are also considered to be atherogenic, lipase (LPL) activity67, suggesting that hypertriglyceri- although it is not clear if this is the predominant form demia arises as a result of increased hepatic VLDL of VLDL seen in HIV-LD59,62,63. production rather than inhibition of its clearance from In HIV-LD, factors that are known to affect circulating the circulation by LPL. lipid levels include HIV infection itself, treatment with The interindividual variability in the prevalence and antiretrovirals (particularly PI) the effects of resulting severity of ART-associated dyslipidemia suggests an changes in body composition, and possible genetic important role for genetic factors in its pathogenesis. predispositions to dyslipidemia. With PI, the use of IDV One potential genetic target is ApoC-III, which forms a is associated with insulin resistance64,65, use of RTV major constituent of VLDL69. In HIV-infected males, and RTV-boosted lopinavir (LPVr) are associated more levels of ApoC-III correlate with plasma triglycerides70, with dyslipidemia66,67, while some recently introduced with ApoC-III levels in PI-treated males two to three PI are associated with neither significant dyslipidemia times higher than controls71.
No part of this publication may be or insulin resistance66.
Two ApoC-III polymorphisms (-455T > C and -482C Protease inhibitors induce hypertriglyceridemia in > T) have been associated with hypertriglyceridemia reproduced or photocopying part by increasing hepatic triglyceride production. In in HIV-infected patients on ART70,71. In studies of pre-vitro, exposure of HepG2 cel s to LPV, NFV, RTV, and dominantly Caucasian populations, cases of extreme without the prior written permission SQV at 10 µM concentrations stimulated triglyceride hypertriglyceridemia (> 7 mmol/l) were observed upon production, and exposure to RTV also increased choles- exposure to RTV in subjects expressing ApoC-III vari- of the publisher terol synthesis, an effect also seen in mice exposed to ants together with an ApoE variant, and higher triglyc-RTV68. This is supported by in vivo data where short- erides values were also observed in subjects with vari-term exposure to RTV in healthy volunteers resulted in ant ApoC-III72,73. However, when the effect of these elevated VLDL and ApoB, but with normal lipoprotein polymorphisms were examined across different eth- Permanyer Publications 2010 Patrick W.G. Mal on: Pathogenesis of HIV-Associated Lipodystrophy
Table . Comparison of white and brown adipocytes
Endocrine function Multi-locular inclusions Large lipid vacuole Mitochondrial content C/EBPα required for differentiation PPARγ expression C/EBP: CCAAT/enhancer binding protein; PPAR: peroxisome proliferators-activated receptor; UCP: uncoupling protein.
nicities, considerable variability in the effect of ApoC-III in vivo, PI may accumulate in certain cel s, such as polymorphisms on triglyceride metabolism were ob- hepatocytes, reaching levels capable of inhibiting pro-served, with some ethnic groups actual y protected teasome function, although experiments to confirm this against ART-induced rises in triglyceride if they carried are stil to be published. Such an effect could also the variant ApoC-III74. This shows the complexity of explain the accumulation of SREBP-1 previously de-genetic influences in drug-induced dyslipidemia in scribed. HIV-LD, and underscores the importance of race and In addition, variations in reliance by different tissues ethnicity in such studies.
on the proteasome may explain the apparent contra-dictory results in relation to SREBP-1 expression and Triglycerides, PI, SREBP-1, and the
nuclear localization in adipose tissue and liver. Based on these data, it has been hypothesized that PI may even have different effects on specific adipose tissue Exposure to RTV in mice results in increased produc- deposits, with decreased SREBP-1 expression in sub- tion and release of fatty acids by both liver and adipose cutaneous adipose tissue and increased SREBP-1 in
tissue, leading to elevated serum VLDL concentra- visceral adipose tissue, ultimately giving rise to both
tions50. Production of lipoproteins by the liver is regu- lipoatrophy and lipohypertrophy78. However, in vivo
lated by the proteasome, a complex of proteases re- data in humans to support this hypothesis is lacking.
sponsible for rapid degradation of many cel ular factors
including SREBP-1c75. Thus, increased triglyceride Insulin resistance
production observed in cel s exposed to PI may result
from a combination of excess available ApoB in hepa-
The insulin resistance observed in HIV-LD is thought tocytes, resulting from inhibition of the proteasome by to arise secondary to direct effects of antiretroviral PI, and hypersecretion of ApoB-containing VLDL fol- medications (particularly PI) on insulin-mediated whole-lowing stimulation from increased intracel ular levels of body glucose uptake79,80, and indirect effects of dys-fatty acids76. This combination of events could explain lipidemia, mitochondrial tox No part of this publication may be icity, inflammation, and the increased hepatic VLDL production in HIV-LD68.
changes in body composition on whole body insulin Controversy surrounds the role of the proteasome in sensitivity58,81. The path reproduced or photocopying ogenesis of insulin resistance PI toxicity. In vitro, RTV was capable of inhibiting the is complex, with circulating molecules synthesized activity of isolated proteasomes, but only at higher in one tissue capable of affecting insulin sensitivity in without the prior written permission concentrations than those seen in plasma with RTV other tissues. Examples of such molecules include therapy when corrected for protein binding77. Whether adipose tissue-derived factors such as leptin and adi- of the publisher intracel ular levels of PI within hepatocytes are suffi- ponectin.
cient to inhibit proteasome function, or if proteasomes Leptin is a hormone secreted predominantly by sub- are more susceptible to drug-induced inhibition in vivo cutaneous adipose tissue. Its predominant action is than in vitro, is yet to be determined. It is possible that that of an insulin sensitizer, although it may also have Permanyer Publications 2010 AIDS Reviews 2007;9
immunomodulatory actions82. In HIV-LD, leptin levels with HIV-LD. If inhibition of GLUT4 was the principal correlate with fat mass83, with high levels in those with mechanism underlying the insulin resistance seen in predominant fat accumulation and low levels in those HIV-LD, one would expect clinical y significant insulin with predominant lipoatrophy84. Current data suggests resistance to develop early into therapy. However, a that low leptin concentrations are more likely a conse- prospective study in ART-naive patients starting thera-quence rather than a cause of lipoatrophy. However, py showed insulin levels rising late into therapy, along-low leptin concentrations may contribute to the overall side increases in triglyceride levels2, and in those with increased insulin resistance observed in HIV-LD, and HIV-LD, insulin resistance was closely correlated with cen-leptin replacement, although having no effect on limb tral fat accumulation and buffalo hump57. This suggests fat mass, may have a beneficial effect on insulin resis- that secondary effects of changes in body composition tance85.
could be more important than acute direct effects of PI Adiponectin, also derived from adipose-tissue, is in- on GLUT4 in the overal development of insulin resis- volved in insulin resistance, lipid metabolism and in- tance and diabetes.
flammation86. Low adiponectin levels are seen in obe- Insulin resistance is also associated with accumula- sity and the metabolic syndrome. Adiponectin is tion of lipid within cel s such as muscle cel s and he-thought to lower insulin resistance by increasing fatty patocytes (termed lipotoxicity), as wel as with abdom-acid oxidation, thereby reducing intracel ular lipid levels inal obesity93. Lipotoxicity has been observed both in (lipotoxicity) and improving insulin sensitivity87. Reduced vitro and in vivo with exposure to NRTI and may be an adiponectin levels have been observed in HIV-LD88,89, important link between PI and NRTI toxicity in HIV-LD and were associated with increased insulin resistance. as it arises due to functional abnormalities of both In one study, adiponectin levels were higher in those lipid metabolism and mitochondrial function. Since nor-with more peripheral fat, but lower in those with more mal mitochondrial function is required for fatty acid trunk fat89, suggesting that loss of peripheral fat and oxidation, mitochondrial dysfunction leads to de-gain in central fat are associated with overal decreas- creased fatty acid oxidation and subsequently to a es in adiponectin. In HIV-infected subjects rosiglitazone build-up of intracel ular fatty acids17, which contributes and pioglitazone (both PPARγ agonists) improve insu- to insulin resistance. lin resistance, increase adiponectin levels, and reduce In HepG2 cel s, exposure to ddC results in both mito- liver fat content90,91. chondrial depletion and accumulation of intracel ular Protease inhibitors also affect the function of an intra- lipid24, while in vivo, intramyocel ular lipid accumulation has cel ular messenger cascade, resulting in the redistribu- been detected in skeletal muscle biopsies from patients
tion of an intracel ular glucose transporter (GLUT4). In with both congenital LD94 and patients with HIV-LD58
vitro, the PI indinavir selectively inhibits GLUT4 activity80 and correlate with increased insulin resistance.
and causes a rapid and reversible dose-dependent
decrease in insulin-stimulated glucose uptake by the Inflammation and HIV-LD
cel s92. Similar results were seen with exposure to RTV,
amprenavir, and NFV15,92. Co-treatment of adipocytes
When first described, some considered HIV-LD to be with both PI and thiazolidinedione protected the cel s part of an immune-mediated lipolytic process. Cross-from PI-induced lipolysis, but not from impairment of sectional data showing associations between develop-insulin-stimulated glucose uptake, suggesting that in- ment of HIV-LD and increases in CD4+ T-cel counts hibition of GLUT4 activity occurs by a mechanism in- supported a possible role for immune reconstitution in dependent to that of PI on PPARγ15. The PI-induced the development of HIV-LD95. H No part of this publication may be owever, several prospec- inhibition of GLUT4 occurring in vivo has been pro- tive studies have shown initial increases in limb fat during posed as a possible mechanism contributing to insulin the first six months of ART therapy when some of the reproduced or photocopying resistance seen in HIV-LD92, and human studies have greatest changes in CD4+ T-cel counts occur2,96. demonstrated acute decreases in insulin-mediated Adipose tissue macrophage accumulation has been without the prior written permission glucose disposal with IDV exposure79, supporting such observed in patients with HIV-LD, which are capable an effect in vivo. In addition, GLUT4 expression is of secreting proinflammatory cytokines. In addition, of the publisher significantly lower in adipose tissue of patients with cytokines such as tumor necrosis factor-α (TNFα) and HIV-LD compared to patients without HIV-LD48.
interleukin-6 (IL-6) are also released from adipose tis- It is difficult to determine how meaningful these data sue97 and are known to result in changes in body are to the overal insulin resistance seen in patients composition. TNFα impairs the action of the insulin Permanyer Publications 2010 Patrick W.G. Mal on: Pathogenesis of HIV-Associated Lipodystrophy
receptor, inhibits LPL and increases adipocyte lipoly- 3. Lewis W, Dalakas M. Mitochondrial toxicity of antiviral drugs. Nat sis, resulting in increased release of triglycerides into Med 1995;1:417-22.
4. Brinkman K, Smeitink J, Romijn J, Reiss P. Mitochondrial toxicity the circulation, which may then accumulate in muscle, induced by NRTI is a key factor in the pathogenesis of ART-related leading to increased insulin resistance98. Increased lipodystrophy. Lancet 1999;354:1112-5.
TNFα-mediated lipolysis of adipocytes could therefore 5. Bogner J, Vielhauer V, Beckmann R, et al. Stavudine versus zidovu- dine and the development of lipodystrophy. J Acquir Immune contribute to both lipoatrophy and insulin resis- Defic Syndr 2001;27:237-44.
6. Dowel P, Flexner C, Kwiterovich P, Lane M. Suppression of pre- adipocyte differentiation and promotion of adipocyte death by HIV The proinflammatory cytokine IL-6, most of which PI. J Biol Chem 2000;275:41325-32.
originates in visceral adipose tissue, is increased in 7. Caron M, Auclair M, Vigouroux C, Glorian M, Forest C, Capeau J. obesity and causes insulin resistance98. In the setting The HIV PI indinavir impairs SREBP-1 intranuclear localization, in-hibits preadipocyte differentiation, and induces insulin resistance. of HIV-LD, increased mRNA levels of IL-6 have been observed in adipose tissue of patients with HIV-LD 8. Roche R, Poizot-Martin I, Yazidi C, et al. Ef ects of antiretroviral drug compared to patients without HIV-LD48.
combinations on the dif erentiation of adipocytes. AIDS 2002;16:13-20.
9. Caron M, Auclair M, Lagathu C, et al. The HIV-1 NRTI stavudine and It is thought that PPARγ has anti-inflammatory prop- zidovudine alter adipocyte functions in vitro. AIDS 2004;18:2127-36.
erties, as increased PPARγ activity results in decreased 10. Domingo P, Matias-Guiu X, Pujol R, et al. Subcutaneous adipo- cyte apoptosis in HIV-1 PI-associated lipodystrophy. AIDS 1999; expression of both IL-6 and TNFα101. Such an anti-in- flammatory effect is supported by in vivo studies in 11. Bastard J, Caron M, Vidal H, et al. Association between altered which treatment with rosiglitazone resulted in de- expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differ- creased expression of IL-6 and increased expression entiation and insulin resistance. Lancet 2002;359:1026-31.
of adiponectin in HIV-LD patients, although no change 12. Janneh O, Hoggard P, Tjia J, et al. Intracel ular disposition and in levels of TNFα were detected102,103. metabolic effects of zidovudine, stavudine and four PI in cultured adipocytes. Antivir Ther 2003;8:417-26.
13. Walker U, Bickel M, Lutke Volksbeck S, et al. Evidence of NRTI-as- sociated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr 2002;29:117-21.
Lipoatrophy, once established, is largely irreversible 14. Lenhard J, Furfine E, Jain R, et al. HIV PI block adipogenesis and increase lipolysis in vitro. Antiviral Res 2000;47:121-9.
in the majority of patients, and despite the accumulat- 15. Rudich A, Vanounou S, Riesenberg K, et al. The HIV PI nelfinavir ing data in published literature, there is stil no effective induces insulin resistance and increases basal lipolysis in 3T3-L1 way to predict the onset of lipoatrophy in HIV-infected adipocytes. Diabetes 2001;50:1425-31.
16. Newmeyer D, Ferguson-Mil er S. Mitochondria: releasing power patients. Despite the early molecular changes in mtRNA for life and unleashing the machineries of death. Cel 2003;112: expression previously mentioned33, it is stil unclear if 17. Kakuda T. Pharmacology of nucleoside and nucleotide RTI-induced changes in any molecular parameter wil predict who mitochondrial toxicity. Clin Ther 2000;22:685-708.
develops lipoatrophy, or the severity of the lipoatrophy 18. Johnson A, Ray A, Hanes J, et al. Toxicity of antiviral nucleoside experienced. Studies measuring early changes in gene analogs and the human mtDNA polymerase. J Biol Chem 2001;276:40847-57.
expression in HIV-infected patients starting ART with 19. Birkus G, Hitchcock M, Cihlar T. Assessment of mitochondrial toxic-long-term fol ow-up of changes in body composition ity in human cel s treated with tenofovir: comparison with other are underway and wil help determine which, if any, NRTI. Antimicrob Agents Chemother 2002;46:716-23.
20. Walker U, Setzer B, Venhoff N. Increased long-term mitochondrial genetic marker predicts development of lipoatrophy.
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For effective screening of potential genetic predic- 21. Pan-Zhou X, Cui L, Zhou X, Sommadossi J, Darley-Usmar V. Dif- ferential effects of antiretroviral nucleoside analogs on mitochon- tors to be adopted into clinical practice, it would be drial function in HepG2 cel s. Antimicrob Agents Chemother preferable to find a peripheral blood surrogate that No part of this publication may be reflects changes in adipose tissue. As use of PBMC as 22. Setzer B, Schlesier M, Walker U. Effects of didanosine-related depletion of mtDNA in human T-lymphocytes. J Infect Dis 2005;191: a surrogate for adipose tissue toxicity is unlikely to be effective, further research into alternative surrogates, 23. Gal uzzi L, Pinti M, Troiano L, et al. Changes in mitochondrial RNA reproduced or photocopying such as peripheral blood monocytes, is needed. production in cel s treated with nucleoside analogs. Antivir Ther 2005;10:191-5.
24. Walker U, Venhoff N, Koch E, Olschewski M, Schneider J, Setzer without the prior written permission B. Uridine abrogates mitochondrial toxicity related to NRTI in HepG2 cel s. Antivir Ther 2003;8:463-70.
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