Differentially Altered Molecular Signature of Visceral Adipose Tissue in HIV-1–Associated Lipodystrophy

Abstract

Mitochondrial alterations are similar in VAT and SAT from patients, whereas adipogenic gene expression is decreased in SAT but unaltered in VAT, highlighting the relevance of adipogenic processes in the differential alterations of fat depots. Specific disturbances in inflammatory status in VAT relative to SAT are present. Milder induction of proinflammatory signaling in VAT could be involved in preventing fat wasting in this depot.

Fat Matters: Understanding the Role of Adipose Tissue in Health in HIV Infection

“…Growing evidence suggests depletion of mitochondrial DNA (mtDNA) in the adipose tissue of ART-treated and -untreated HIV-infected persons [47, 56, 57, 60-64]. Among ART-treated persons with lipodystrophy, mtDNA is depleted in both VAT and SAT, metabolism and adipogenesis markers are decreased in SAT, and less pro-inflammatory gene expression occurs in VAT, potentially protecting it from depletion [62]. Finally, SAT pro-inflammatory cytokines increase more with efavirenz (vs lopinavir-ritonavir) in combination with tenofovir and emtricitabine [59].…”

Adipose Tissue in HIV Infection

“…A small study of paired subcutaneous and visceral adipose tissue biopsies from HIV-infected persons found in vitro exposure to nelfinavir, lopinavir, or ritonavir (three older protease inhibitors) resulted in increased lipolysis and release of free fatty acids, decreased glyceroneogenesis, and increased IL-6 and TNF-α production in subcutaneous tissue, but few effects in visceral tissue (143). A small study of HIV-infected individuals on long-term NNRTI or protease inhibitor treatment with lipodystrophy found similar mtDNA content in subcutaneous and visceral adipose tissue biopsies (77). However, while mRNA expression of PPAR-γ, adiponectin, glucose transporter type 4 (GLUT4) and lipoprotein lipase were significantly lower in subcutaneous adipose tissue compared to HIV-negative controls, there was no difference in expression levels in visceral adipose tissue according to HIV status (77).…”

“…A small study of HIV-infected individuals on long-term NNRTI or protease inhibitor treatment with lipodystrophy found similar mtDNA content in subcutaneous and visceral adipose tissue biopsies (77). However, while mRNA expression of PPAR-γ, adiponectin, glucose transporter type 4 (GLUT4) and lipoprotein lipase were significantly lower in subcutaneous adipose tissue compared to HIV-negative controls, there was no difference in expression levels in visceral adipose tissue according to HIV status (77). In animals, exposure to zidovudine (a NRTI) reduced visceral adipocyte mtDNA content and mtDNA-encoded respiratory chain proteins, but these changes were comparatively greater in subcutaneous adipocytes (269).…”

Metabolic, mitochondrial, renal and hepatic safety of enfuvirtide and raltegravir antiretroviral administration: Randomized crossover clinical trial in healthy volunteers

“…A combination of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) has constituted the standard highly active antiretroviral treatment (HAART) for many years [1][2][3][4]. Despite harbouring validated therapeutic efficacy, some of these drugs as the virus itself have been associated with early metabolic, mitochondrial, renal and hepatic toxicity that may induce late organ-specific diseases including hyperlipidaemia, hyperlactatemia, insulin resistance and lipoatrophy [4][5][6][7][8][9][10][11].These alterations may result in an increased risk for cardiovascular disease, together with renal or hepatic disease [5,7,10,12]. Adverse clinical effects of PIs, NRTIs and NNRTIs have been associated with secondary interactions of these drugs with molecular pathways essential for cell function.…”