Differential Effects of Efavirenz and Lopinavir/Ritonavir on Human Adipocyte Differentiation, Gene Expression and Release of Adipokines and Pro-Inflammatory Cytokines.

Abstract

In the present study, a comparative assessment of the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r; 4:1) on human adipocytes in culture has been performed. Human pre-adipocytes were treated with EFV or LPV/r during or after adipogenic differentiation. Acquisition of adipocyte morphology, expression of gene markers of mitochondrial toxicity, adipogenesis and inflammation, and release of adipokines and cytokines to the medium were measured. Results indicated that EFV and LPV/r impaired adipocyte differentiation in association with a reduction in transcript levels for adipogenic differentiation genes (adiponectin, lipoprotein lipase, leptin) and master regulators of adipogenesis (PPAR, C/EBP). The effects were greater with EFV than LPV/r. Both LPV/r and EFV induced increases in monocytechemoattactant protein-1 (MCP-1) mRNA levels, but the effect was greater with EFV. Similarly, the release of proinflammatory cytokines and other inflammation-related molecules (interleukins 6 and 8, MCP-1, PAI-1) was enhanced to a much higher degree by EFV than by LPV/r. Adiponectin and leptin release by adipocytes was reduced by both drugs, although to a higher extent by EFV. Neither drug affected mitochondrial DNA levels, transcripts encoding mitochondrial proteins or lactate release by adipocytes. In previously differentiated adipocytes, EFV caused a significant reduction in PPARγ and adiponectin expression, whereas LPV/r did not. We conclude that both EFV and LPV/r impair human adipogenesis, reduce adipokine release and increase the expression and release of inflammation-related cytokines, but the overall effects are greater with EFV. These findings may have implications for the pathogenesis of HIV-1-associated lipodystrophy and the development of HIV-1 therapies.

Differential Subcutaneous Adipose Tissue Gene Expression Patterns in a Randomized Clinical Trial of Efavirenz or Lopinavir-Ritonavir in Antiretroviral-Naive Patients

“…mRNAs of genes involved in adipogenesis, glucose and lipid metabolism, mitochondrial metabolism, and inflammation were assessed in the study. These mRNAs have previously been assessed, in vitro and in vivo, in ART-associated body fat studies (15,18). Selected genes and a brief functional description of each one are shown in Table 1.…”

“…Moreover, gene expression studies of subcutaneous adipose tissue may help us to better understand the mechanisms behind body fat changes in HIV-infected patients who initiate ART. Antiretroviral-drug-induced gene expression changes have been detected in adipocytes, in vitro (15,16) and in vivo, in healthy volunteers (17) and in HIV-infected patients (18)(19)(20)(21). In this study, we aimed to compare the effects of efavirenz (EFV) and those of ritonavir-boosted lopinavir (LPV/r), combined with emtricitabine and tenofovir, on body fat changes to evaluate the in vivo influence of each regimen on human subcutaneous adipose tissue gene expression and, additionally, to assess whether these transcript changes may be correlated with fat changes.…”

Immunosenescence and hurdles in the clinical management of older HIV-patients

“…22,23 GallegoEscuredo et al compared adipocyte differentiation after efavirenz and lopinavir/ritonavir treatment, finding that both efavirenz and lopinavir/ritonavir impaired human adipogenesis and increased the expression and secretion of inflammation-related cytokines, but the overall effects were greater with efavirenz. 24 Contrarily maraviroc, a chemokine receptor CCR5 antagonist, does not alter adipocyte differentiation and seems to have anti-inflammatory properties exerted by inhibition of the expression and release of pro-inflammatory cytokines. 25 Coinfections and pro-inflammatory pattern HIV itself, especially before the start of HAART, herpesviridae, in particular cytomegalovirus (CMV), and hepatitis viruses cause a prolonged stimulus to the immune system, reducing in particular the capability of proliferation of the T cells and depleting T-cells receptor (TCR) repertoire.…”

Dysregulation of Endoplasmic Reticulum Stress and Autophagic Responses by the Antiretroviral Drug Efavirenz

“…Protease inhibitors used in HIV treatment have been associated with the development of dyslipidemia (Overton et al, 2012) and inhibition of normal proteasome function (Piccinini et al, 2005). Several studies have linked the use of ARVds, in particular, efavirenz, to hepatotoxicity via multiple mechanisms, including alterations of calcium homeostasis, mitochondrial damage, enhanced proinflammatory cytokine levels, and interference with the cannabinoid receptor CB1 (Blas-Garcia et al, 2010;Gallego-Escuredo et al, 2010;Apostolova et al, 2011Apostolova et al, , 2013Hecht et al, 2013); however, the toxicity and impact of those drugs have not been extensively studied in the context of the BBB.…”