HIV-associated lipodystrophy (LD) is a disorder characterized by a selective damage of the adipose tissue
resulting in part from antiretroviral drugs [ 1, 2]. The LD syndrome includes progressive
subcutaneous fat loss and/or central fat accumulation along with dyslipidemia,
glucose alterations, and insulin resistance, altogether generating
cardiovascular dysfunctions [ 3, 4]. Recent studies have hypothesized that HIV
itself could play a role in the LD phenotype (see Giralt et al. [ 5]). However, the risk of developing fat tissue redistribution
has been related in priority to the antiretroviral treatment (ART) and mainly to the use of two classes of
drugs, protease inhibitors (PIs) and nucleoside reverse transcriptase
inhibitors (NRTIs) [ 6– 8]. Lipoatrophy in the face and extremities has been
linked repeatedly to the use of stavudine (and to a lesser extend zidovudine)
among NRTIs [ 7, 9, 10] and increases with long-term exposure [ 11]. PIs have been mainly associated with central fat
accumulation along with insulin resistance. However, nelfinavir or indinavir
can independently decrease limb fat level in patients cotreated with NRTIs [ 7, 12]. Peripheral fat loss and
central fat accumulation can occur simultaneously, though lipoatrophy may
emerge as the more dominant feature on prolonged treatments [ 12, 13]. Recently, a role for the
nonnucleoside analog efavirenz in lipoatrophy has been reported but needs to be
confirmed [ 14]. The pathogenesis
of adipose cell dysfunction includes the mitochondrial toxicity of NRTIs [ 15– 19] and the adverse effects of
PIs and NRTIs on the adipocyte differentiation status [ 17, 20– 26], insulin sensitivity [ 27, 28], survival [ 17, 18, 23, 29], ability to secrete a variety
of adipokines [ 30– 33], and longevity [ 19, 34]. The oxidative stress induced
by both PIs and NRTIs at the fat cell level [ 19, 28, 33– 35] probably plays a major role
in the setup of lipodystrophy. Severe adipose
tissue alterations have been reported in HIV-infected patients with ART-related
lipodystrophy. Lipoatrophic adipose tissue biopsies present major histological
alterations with decreased and heterogeneous size of adipocytes, increased
fibrosis, altered mitochondria, and macrophage infiltration [ 1, 2, 36– 38], consistent with a profound
remodeling of subcutaneous fat tissue. The presence of isolated fat droplets,
macrophages, and apoptotic cells in the enlarged vascular stroma argues for a
progressive destruction of subcutaneous adipocytes [ 1, 2, 29, 37, 39, 40]. PPAR γ is expressed in priority in
adipocytes. It is also expressed in different other cell types including macrophages and
regulates genes associated with growth, differentiation, insulin sensitivity,
inflammation, and immunity [ 41– 46] (see [ 5]). PPAR γ plays an essential role in the development and
normal function of white adipocytes, where it mediates part of the regulatory
effect of dietary fatty acids on gene expression [ 43, 47], regulates the differentiation program [ 48] and insulin sensitivity [ 45]. PPAR γ also controls the production and secretion of
adipokines such as leptin and adiponectin, which are important mediators of
insulin action in peripheral tissues [ 42]. In brown adipocytes, PPAR γ also controls the adipogenic program and the
switch from white to brown adipocytes [ 49]. In macrophages, PPAR γ controls alternative activation and improves
insulin resistance [ 50]. It plays an important role in macrophage
inflammation and cholesterol homeostasis and inhibits the production of
proinflammatory cytokines through inhibition of the NF κB
and AP-1 pathways [ 48, 51– 54]. Loss-of-function or
dominant-negative mutations in the PPARG gene in humans (see [ 5]), and genetically-induced PPAR γ
deficiency in mice [ 55, 56] are responsible for lipodystrophic syndromes
with insulin resistance, showing the primarily involvement of PPAR γ
defects in adipose tissue development and metabolic roles. Alternatively, other
causes of adipocyte differentiation defects lead to a secondary decreased PPAR γ
expression and/or function, that further contribute to adipose tissue
dysfunction, as shown in vivo in murine models [ 57] or in vitro [ 58– 60]. In that setting, the implication of
PPARγ in the ART effect has been demonstrated both
in vitro, in cultured adipocytes and macrophages, and ex vivo, in adipose
tissue samples from patients, and has been confirmed by the beneficial effects,
at least partial, of the PPARγ
agonists, thiazolidinediones. PPARγ
defects, although probably secondary to the multiple deleterious consequences
of ART on adipose tissue, play a central role in ART-related lipodystrophy and
metabolic alterations. |
2. Effects of ART on PPAR γ Expression and Signaling in Cultured Adipocytes PPARγ contributes to the setup of the
differentiation program and to insulin sensitivity. PIs and NRTIs, the two
major classes of antiretrovirals associated with lipodystrophy in HIV-infected patients,
may interfere at several steps of PPARγ signaling in adipose cells, such as
differentiation, insulin action, oxidative stress, inflammation, and
mitochondrial function. A number of studies have clearly
shown that the first generation PIs, indinavir, nelfinavir, and ritonavir, used
at concentrations comparable to their Cmax in patients' serum or at
suprapharmacological concentrations, impaired adipocyte differentiation [ 20, 21, 23, 25, 26, 32, 61– 67]. They were also shown to induce insulin
resistance [ 21, 23, 27, 33, 62, 67– 70] in murine and human cultured adipocytes. This
was associated with a reduced protein and mRNA expression of PPAR γ in both murine [ 20, 21, 25, 26, 64] and human adipocytes [ 24, 66, 71, 72]. Interestingly, decreased PPAR γ expression was also observed in mature
adipocytes chronically incubated with PIs, consistent with PI-induced adipose
cell dedifferentiation. Most PIs (nelfinavir, indinavir,
saquinavir, ritonavir, and amprenavir) were shown to acutely inhibit insulin
activation of glucose uptake in cultured adipocytes, via a direct inhibition of
the glucose transporter Glut4 [ 73]. Indinavir and nelfinavir also altered the
activation of proximal steps in insulin signaling as revealed by decreased
phosphorylation of extracellular-regulated kinase (ERK) 1/2 and Akt/protein
kinase B. Accordingly, distal events in insulin signaling pathways, glucose
transport, and lipogenesis were also affected [ 21, 30, 74]. Regarding PPAR γ, cell imaging studies revealed that indinavir
and nelfinavir but not amprenavir severely decreased nuclear expression of PPAR γ [ 21], indicating for the first time that the
transcriptional activity of PPAR γ may be defective in PI-treated cells. The
beneficial effect of rosiglitazone [ 21, 23, 32] confirmed the implication of PPAR γ in PI action, and indicated that PIs act
upstream of PPAR γ in its signaling cascade to alter adipocyte
differentiation and insulin sensitivity. Recent data of our laboratory further
support the implication of PPAR γ in PI action by showing that two angiotensin
II-receptor blockers (telmisartan and irbesartan), that display partial PPAR γ agonist activity [ 75], prevented the PI effects on lipid
accumulation and insulin response in murine and human adipocytes (Boccara F. et al., unpublished results). The effect of ritonavir on insulin
signaling has been particularly studied since this commonly prescribed PI is
associated with dyslipidemia and metabolic disorders in HIV-infected patients [ 67, 76, 77]. Ritonavir induced insulin resistance in
cultured adipocytes [ 24, 32, 64]. Another study reported that ritonavir reduced
differentiation and insulin sensitivity in human preadipocytes and adipocytes
but surprisingly without decreasing PPAR γ2 gene expression [ 68]. However, the protein expression and the
activation of PPAR γ have not been evaluated in this study. The mechanism whereby PIs alter
adipose cell differentiation and insulin sensitivity is obviously complex and
multifactorial. Impaired SREBP-1 nuclear penetration [ 21, 22] may inhibit the activation of PPAR γ or related adipogenic transcription factors
thus leading to defective adipogenesis and insulin resistance. When going
further into the mechanism of PI action, we and others demonstrated that some
PIs prevented the maturation of lamin A/C [ 22, 34, 78], a nuclear membrane protein essential for
normal nuclear membrane folding and for nuclear penetration of SREBP-1 [ 59, 79, 80]. Defective SREBP-1c signaling may explain the decreased differentiation
and insulin resistance of PI-treated cells and the ability of PPAR γ agonists to overcome the PI effects on fat
cell differentiation and insulin response [ 21]. NRTI therapy is also associated
with fat tissue disease in HIV-infected patients. In murine adipose cell lines
and primary cultured human adipocytes, stavudine and zidovudine, but not other
NRTIs (tenofovir, abacavir, didanosine, and lamivudine), alter lipid storage [ 23, 31, 33, 81]. They also decrease the expression and
secretion of adiponectin in cultured human and murine adipocytes [ 23, 32, 33, 82] and induce oxidative stress, suggesting that
they could secondarily participate to the insulin resistance setup [ 33]. The negative effect of NRTIs on PPAR γ expression and signaling has been reported
only in a few studies. Stavudine or zidovudine have a modest, or no effect, on
adipose cell differentiation assessed by the gene expression profile of
differentiating adipocytes [ 25] and by protein and mRNA expression of
adipogenic transcription factors, among them PPAR γ [ 20, 25, 31, 32, 82]. Altered adipocyte lipid phenotype and insulin
sensitivity resulting from NRTI treatment are suspected to result from their
mitochondrial toxicity [ 15– 18]. We recently reported that stavudine or
zidovudine, but not other NRTIs, triggers mitochondrial oxidative stress and
premature senescence in cultured fibroblasts and adipocytes [ 19]. Stavudine also altered in human preadipocytes
[ 72] the expression of the PPAR γ coreceptor 1-alpha (PGC1- α) a transcriptional coactivator upregulated by
thiazolidinediones which controls mitochondrial function and biogenesis, and
metabolic pathways and integrates insulin signaling and mitochondrial function [ 83, 84]. Stavudine
increased its expression together with mitochondria number [ 72]. Thus, conversely to PIs, in vitro, thymidine analogs
have no or mild detrimental effect on PPAR γ function. The non-NRTI class
of antiretrovirals has not yet, as a class, been associated with long-term
toxicity [ 7] even if efavirenz was shown in one study to be
associated with lipoatrophy [ 14]. Very few studies report
experimental in vitro findings
on the effects of the non-NRTIs efavirenz or nevirapine on white adipose cell
functions. Efavirenz but not nevirapine induced a delayed and moderate
reduction in lipid accumulation in both murine and human cultured adipocytes,
and decreased SREBP-1c and PPAR γ expression [ 85]. |
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