In vivo, nucleoside reverse-transcriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA
ABSTRACT Nucleoside reverse-transcriptase inhibitors (NRTIs), which are used to treat human immunodeficiency virus (HIV) infection, can cause mitochondrial dysfunction and have been associated with lipoatrophy. The effects of this mitochondrial dysfunction on lipid metabolism, at a molecular level in vivo, have not been described.
We examined early changes (by 2 weeks after initiation of therapy) in expression of mitochondrial and nuclear genes in adipose tissue from 20 HIV-negative subjects randomized to receive dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) for 6 weeks.
We observed decreased transcription of mitochondrial (mt) RNA without significant depletion of mtDNA. Decreases in mtRNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mtRNA (NRF1 and TFAM) and oxidation of fatty acids (PPARA and LPL), whereas PPARG, which is important for differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC1), suggesting a central role for PGC1 in nuclear responses to mitochondrial dysfunction. Expression of peripheral blood monocyte mtRNA also decreased, suggesting that monocytes may be surrogates for NRTI-induced mitochondrial dysfunction in other tissues.
Independent of HIV, NRTIs decrease transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase- gamma , whereas disruption of expression of lipid metabolism genes offers an explanation for NRTI-induced lipoatrophy.
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ABSTRACT: Increased plasma lactate levels can indicate the presence of metabolic disorders in HIV infected individuals. Objective: To determine whether a portable analyzer is valid for measuring cerebrospinal fluid (CSF) and plasma lactate levels in HIV infected individuals. Method: CSF and plasma were collected from 178 subjects. Samples tested by the Accutrend® portable analyzer were compared to those tested by a reference device (SYNCHRON LX® 20). Results: The portable analyzer had in plasma sensitivity of 0.95 and specificity 0.87. For CSF the specificity was 0.95; the sensitivity 0.33; the negative predictive value was 95% and the positive predictive value 33%. Conclusions: These findings support the validity of the portable analyzer in measuring lactate concentrations in CSF that fall within the normal range. The relatively poor positive predictive value indicates that a result above the reference range may represent a "false positive test", and should be confirmed by the reference device before concluding abnormality.Arquivos de Neuro-Psiquiatria 07/2014; 72(7):500-505. DOI:10.1590/0004-282X20140076 · 1.01 Impact Factor
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ABSTRACT: Gene expression studies of subcutaneous adipose tissue may help to better understand the mechanisms underneath body fat changes in HIV-infected patients who initiate antiretroviral therapy (ART). Here we evaluated early changes in adipose tissue gene expression and their relationship with fat changes in ART-naïve HIV-infected patients randomly assigned to initiate therapy with emtricitabine/tenofovir plus efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r). This was a substudy of a randomized clinical trial (LIPOTAR-NCT00759070). Patients had abdominal subcutaneous adipose tissue biopsies at baseline and week 16 and dual-energy-X-ray absorptiometry at baseline, week 16 and 48. mRNA changes of eleven genes involved in adipogenesis, lipid and glucose metabolism, mitochondrial energy and inflammation were assessed through RT-qPCR. Additionally, correlations between gene expression changes and fat changes were evaluated. Fat increased preferentially in the trunk with EFV and in the limbs with LPV/r (p<0.05). After 16 weeks of exposure to the drug regimen, transcripts of CEBP/A, ADIPOQ, GLUT4, LPL and COXIV were significantly down-expressed in EFV arm compared to LPV/r (p<0.05). Significant correlations were observed between LPL expression change and trunk fat change at week 16 in both arms, and CEBP/A or COXIV changes and trunk fat change at the same time-point only in EFV arm and not in LPV/r. When combined with emtricitabine/tenofovir as standard backbone therapy, EFV or LPV/r induced differential early expression of genes involved in adipogenesis and energy metabolism. Moreover, these mRNA expression changes correlated with trunk fat change in the EFV arm.Antimicrobial Agents and Chemotherapy 08/2014; 58(11). DOI:10.1128/AAC.03481-14 · 4.45 Impact Factor
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ABSTRACT: To study the effect of concurrent use of second-generation antipsychotics (SGAs) on metabolic syndrome (MetS) components conferring increased cardiovascular risk in a sample of human immunodeficiency virus (HIV)-infected adults taking antiretroviral therapy (ART). A retrospective study of participants consecutively recruited at the UCSD HIV Neurobehavioral Research Program examined effects of combined ART and SGAs on body mass index (BMI), nonfasting serum lipids, diabetes mellitus (DM) incidence, and mean arterial pressure (MAP). Metabolic outcome variables and covariates were compared using t-tests, Chi-squared or Fisher's exact tests. Linear and logistic multivariable models explored metabolic outcomes for participants taking (SGA+) or not taking (SGA-) concomitant SGAs, after controlling for demographic and HIV disease- and ART-related covariates. Of 2229 HIV-infected participants, 12% (N=258) were treated with SGAs. In multivariable models adjusted for relevant covariates, the SGA+ group had significantly higher mean triglycerides, significantly higher odds of DM, significantly higher MAPs and marginally higher BMI. The use of SGAs in HIV-infected adults taking ART was independently associated with worse indicators of MetS and cardiovascular risk. Aggressive monitoring for the metabolic complications from concurrent SGA and ART is indicated in all patients receiving these medication combinations.04/2014; 218(1-2). DOI:10.1016/j.psychres.2014.04.015