Abstract
A serious metabolic syndrome combining insulin-resistance, dyslipidemia, central adiposity, and peripheral lipoatrophy has arisen in HIV-infected patients receiving highly active antiretroviral therapy. The aim of this work was to examine the effects of the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz on adipocyte differentiation and metabolism. When induced to differentiate in the presence of efavirenz (5-50 microm), 3T3-F442A preadipocytes failed to accumulate cytoplasmic triacylglycerol droplets. This phenomenon was rapidly reversible and was also readily detectable in the 3T3-L1 preadipose cell line and in primary cultures of human preadipocytes. When applied to mature 3T3-F442A adipocytes, efavirenz induced a delayed and moderate reduction in cell triglyceride content. Measurement of [(3)H]deoxyglucose uptake, basal and agonist-stimulated lipolysis, and cell viability indicated that these pathways are not involved in efavirenz effects on triacylglycerol accumulation. By contrast, we found that the NNRTI induced a dramatic dose- and time-dependent decrease in gene and protein expression of the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c). Adipose conversion was only altered at the highest efavirenz concentrations, as suggested by the mild reduction in peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding protein-alpha. CCAAT/enhancer-binding protein-beta remained unchanged. The inhibition of SREBP-1c expression was accompanied by a sharp reduction in the expression of SREBP-1c target genes and in the adipocyte lipogenic activity in efavirenz-treated cells. Finally, the inhibitory effect of efavirenz on cell triglyceride accumulation was prevented by directly providing free fatty acids to the cells and was reversed by overexpression of a dominant positive form of SREBP-1c, reinforcing the implication of this transcription factor in the antilipogenic effect of the drug. When considered together, these results demonstrate for the first time that the NNRTI efavirenz induces a strong inhibition of the SREBP-1c-dependent lipogenic pathway that might contribute to adipose tissue atrophy.
Highlights
The widespread use of highly active antiretroviral therapy (HAART)1 has radically transformed the prognosis of HIVinfected patients in the developed countries [1, 2]
Glycemic and lipidic disturbances are observed in genetic syndromes of generalized or partial lipodystrophy [17] and in transgenic models of lipoatrophy resulting from manipulation of major adipogenic transcription factors (18 –20), suggesting that an initial lack of adipogenesis or a loss in adipose tissue may be involved in insulin resistance and metabolic complications
To investigate the functional consequences of SREBP-1c down-regulation by efavirenz, we examined the effects of the nonnucleoside reverse transcriptase inhibitors (NNRTI) on the expression of typical SREBP-1c target genes, such as those coding for fatty acid synthase (FAS) [22,23,24] and stearoyl-CoA desaturase-1 (SCD-1) [67]
Summary
The widespread use of highly active antiretroviral therapy (HAART) has radically transformed the prognosis of HIVinfected patients in the developed countries [1, 2]. Long term HAART has been associated with a unique and unexpected lipodystrophic syndrome involving altered body fat distribution and disturbances of glucose and lipid metabolism (6 – 8). Most patients receiving this treatment develop metabolic abnormalities, which include dyslipidemia (elevated plasma triglycerides and cholesterol), increased visceral and dorsocervical adipose tissue, and peripheral lipoatrophy. Glycemic and lipidic disturbances are observed in genetic syndromes of generalized or partial lipodystrophy [17] and in transgenic models of lipoatrophy resulting from manipulation of major adipogenic transcription factors (18 –20), suggesting that an initial lack of adipogenesis or a loss in adipose tissue may be involved in insulin resistance and metabolic complications. PPAR␥, C/EBP␣, and SREBP-1c act in concert to induce and maintain the adipocyte phenotype
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