Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients.
OBJECTIVE
To examine the in vivo effects of highly active antiretroviral therapy (HAART) regimens on adipose tissue mitochondrial DNA (mtDNA) depletion, mitochondrial organellar proliferation, and markers of adipocyte differentiation and phenotype.


METHODS
DNA and mRNA quantification using real-time PCR methods was performed on adipose tissue samples from 31 HIV-infected individuals, of whom 11 were treatment-naive and 20 were receiving HAART. mtDNA depletion was measured as mtDNA copies/cell, and mitochondrial proliferation by quantification of mitochondrial protein mass. Regulation of mitochondrial biogenesis was assessed by NRF-1 and mtTFA mRNA. PPARgamma, UCP2 and UCP1 mRNA expression was used to assess adipocyte differentiation and phenotype.


RESULTS
Stavudine-based HAART recipients (n=10) displayed significant mtDNA depletion (12.8% of control, P<0.001), mildly increased mitochondrial protein mass (2.6-fold of control, P=0.032) and decreased expression of PPARgamma (53.9% of control, P=0.021), UCP2 (62.2% of control, P=0.024) and UCP3 (51.8% of control, P=0.047) mRNA compared with controls. Zidovudine-based HAART recipients (n=7) also displayed significant mtDNA depletion (34.45% of control, P=0.031), increased mitochondrial protein mass (5.7-fold of control, P=0.009), and markedly increased UCP1 (18-fold of control, P=0.009) mRNA. Elevated UCP1 mRNA expression was found to be associated with non-stavudine (zidovudine or abacavir), protease inhibitor (PI)-containing HAART (95-fold of non-stavudine, non-PI-containing HAART, P=0.006).


CONCLUSIONS
Differential effects of stavudine and zidovudine therapy on mtDNA depletion and expression of adipocyte differentiation markers PPARgamma and UCP2 were observed, consistent with increased adipose tissue toxicity associated with stavudine therapy. Increased UCP1 mRNA, a marker of brown adipose tissue phenotype, was associated with non-stavudine, PI-containing HAART, and may represent an adaptive response to the increased fatty acid flux associated with PI therapy, and may contribute to the increased resting energy expenditure reported in such patients.
D017667:Adipocytes / Q000166:cytology*; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D002454:Cell Differentiation; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D015224:Dideoxynucleosides / Q000009:adverse effects; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000473:pathology / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects; D018119:Stavudine / Q000009:adverse effects; D015215:Zidovudine / Q000009:adverse effects; D000099227:Abacavir
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D015224:Dideoxynucleosides; D017320:HIV Protease Inhibitors; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D015215:Zidovudine; D000099227:Abacavir