What is the pathophysiology of HIV-associated lipodystrophy?

Updated: Sep 05, 2019
  • Author: David T Robles, MD, PhD, FAAD; Chief Editor: Dirk M Elston, MD  more...
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Answer

Although the precise mechanisms underlying HIV lipodystrophy are not well understood, several hypotheses based on in vitro and human studies may explain the pathogenesis of the lipid changes that take place. Most experts currently believe that HIV type 1 (HIV-1) protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine and zidovudine, are implicated. [5, 6, 7, 8, 9] Genetic factors in the patient may confer particular susceptibility. [10, 11] In addition, immunohistochemical components may play a role in the process of lipodystrophy in HIV patients. [12]

One mechanism in which PIs function is by down-regulating PPAR-gamma and C/EBP-alpha, which are key adipogenic transcription factors. Once these factors are down-regulated, there is an interruption with lipogenesis and adipocyte maturation. In addition, they create a large production of reactive oxygen species, which leads to the production of cytokines, macrophage recruitment, and inhibition of glucose transport 4 (GLUT-4), along with a deficiency in insulin signaling and the hormones leptin and adiponectin. [13, 14]  If adiponectin is replaced, studies have shown decreased PI toxicity. [16]  PIs have also been shown to activate endoplasmic reticulum stress pathways by depleting the calcium in adipocytes. In addition, they also interfere with the expression of regulator genes, CHOP, ATF4, and XBP, which further alters lipid metabolism and autophagy. [14]

PIs also have a high affinity for the catalytic site of HIV-1 protease, which shares a 60% sequence homology with 2 proteins involved in lipid metabolism, cytoplasmic retinoic acid–binding protein type 1 (CRABP-1), and low-density lipoprotein receptor–related protein (LDLR-RP).

Inhibition of CRABP-1 impairs the production of retinoic acid, leading to decreased fat storage and adipocyte apoptosis, with the subsequent release of lipids into the circulation. Inhibition of LDLR-RP results in hyperlipidemia secondary to the failure of hepatic and endothelial removal of chylomicrons and triglycerides from the circulation.

NRTIs inhibit mitochondrial DNA (mtDNA) polymerase gamma, leading to mtDNA depletion, respiratory chain dysfunction, and reduced energy production, which, in turn, causes insulin resistance and secondary dyslipidemia. [17, 18] Interestingly, mtDNA is depleted only at normal oxygen levels; hypoxic adipocytes do not take up triglycerides and are resistant to mtDNA-induced damage, except after treatment with NRTIs. [19]

Some PIs, particularly ritonavir, inhibit cytochrome P450 3A, a key enzyme in lipid metabolism. Ritonavir has also been shown to cause an extreme amount of apoptosis. On the other hand, atazanavir has been shown to cause apoptosis and autophagy. The PIs saquinavir, ritonavir, and nelfinavir directly inhibit the development of adipocytes from stem cells and increase the metabolic destruction of fat in existing adipocytes.

Taking genetics into account, a missense mutation in the resistin gene has been shown to have an association with hyperlipidemia, insulin resistance, and limb fat loss when combined with highly active antiretroviral therapy (HAART). [14] Other studies have shown that resistin can function as a useful biomarker for peripheral adipose tissue loss and may be the future of therapeutic strategies. [20] In addition, genetic variants exist in plasma levels, specifically an increased RBP4 and a decreased level of omenti, in patients with HIV-associated lipodystrophy. [21] Also associated is increased circulating fibroblast growth factor 23 (FGF23) levels. [22] Further studies are needed to examine how these updated associations can be incorporated in advancing treatments and early detection of lipodystrophy.

A 2016 study done on rats has shown that PIs reduce the activity of paraoxonase 1 (PON1), which is an HDL-bound esterase that inhibits the decomposing lipid peroxidation products, which further inhibits atherosclerosis. Therefore, there is a higher risk of atherosclerosis and a greater chance of experiencing lipodystrophy. [23]

In observation of immunohistochemical components, a 2014 cross-analytical study analyzed the cytokine expression from adipose tissue obtained in biopsies in 19 HIV patients experiencing lipodystrophy. As a result, tissue necrosis factor (TNF)–alpha and caspase-3 were more prominent in men than in women. In addition, the patients with lipodystrophy had less TNF-beta when being compared with the control group. Lastly, the group of individuals that experienced longer exposure to HIV and HAART had a positive association with levels of TNF-alpha. [12] As shown, sex differences lead toward different pathophysiologic outcomes, but more so, the elevation in cytokine production elevates the likelihood of developing lipodystrophy in HIV patients.

In another 2014 study focused on HIV patients with lipodystrophy, 21% of women and 37% of men were found to have growth hormone deficiencies (GHDs). Men who had GHD had higher amounts of visceral adipose tissue, subcutaneous adipose tissue, and trunk fat. Women who had GHD had significantly lower insulinlike growth factor-1 (IGF-1). Overall, adipose tissue distribution accounts for growth hormone sex differences; those with deficiencies have more problems with lipodystrophy. [24]

Evidence also suggests decreased insulin sensitivity and beta-cell dysfunction in patients with HIV-associated lipodystrophy. [25] Additionally, researchers have found that estrogen receptor expression is down-regulated in the subcutaneous adipose tissue of these patients. This is due to the effects of HAART regimens that include PIs. Stavudine has been particularly implicated in the apoptosis of adipocytes, affecting both dividing and differentiating cells. [26, 27]

In addition, HIV-1 may cause dyslipidemia and lipodystrophy in the absence of HAART, via impaired cholesterol efflux from macrophages and increased tumor necrosis factor–alpha, which modulates free fatty acid metabolism and lipid oxidation and attenuates insulin-mediated suppression of lipolysis. [17, 28]  Tumor necrosis factor‒like weak inducer of apoptosis (TWEAK) is a multifocal cytokine that is decreased in patients with HIV-associated lipodystrophy. [29]

A 2006 study in HIV-positive patients on HAART found that resting energy expenditure and lipid oxidation were significantly higher in those with lipodystrophy than in those without lipodystrophy. [30]  

More recent research has found an association with interleukins (ILs) and lipodystrophy, although this association not completely understood. Findings include lower levels of IL-18 and IL-18 mRNA receptors in skeletal muscle in patients with HIV-associated lipodystrophy. [31] In addition, lower levels of IL-4 and IL-10 are thought to influence the development of lipodystrophy in patients with HIV infection. [32]


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