Effects of HAART on expression (mRNA) of PPAR-gamma, UCP2, UCP1, mitochondrial DNA depletion and proliferation
Pace, C., Martin, A., Mamotte, C., Hammond, E., Nolan, D. and Mallal, S. (2003) Effects of HAART on expression (mRNA) of PPAR-gamma, UCP2, UCP1, mitochondrial DNA depletion and proliferation. In: 10th Conference on Retroviruses and Opportunistic Infections, 10 - 14 February 2003, Boston, U.S.A.
Background: Much debate currently exists regarding the contribution of NRTIs and PIs to the development of HIV-associated lipodystrophy, with evidence the cytotoxicity exerted by NRTIs and PIs occur via distinct mechanisms. NRTIs have the intrinsic ability to inhibit mitochondrial DNA (mtDNA) replication and PIs have been demonstrated to inhibit adipocyte differentiation. However, there also appears to be distinct mechanisms of toxicity within each class. In this study, we sought to examine the effect of NRTIs and PIs as a class, and the effects of stavudine and zidovudine specifically, on mitochondrial DNA depletion, mitochondrial proliferation and expression of adipocyte differentiation markers; PPAR?, UCP2 and UCP1 in vivo.
Methods: Twenty-three (23) HIV+, HAART recipients and 11 HIV+ treatment naïve individuals who had previously had a subcutaneous adipose tissue biopsy were selected. Ten (10) patients (pts) were receiving NRTI/PI combination therapy, of which 5 were stavudine-based therapy and 5 were zidovudine-based. Of the 13 PI naïve individuals, 8 were receiving stavudine-based therapy and 5 were receiving zidovudine-based therapy. Eleven (11) HIV+, ART naïve, age- and BMI-matched individuals were used as controls. Quantification of mRNA expression and mtDNA depletion was performed by real-time RT-PCR on the PE7700. Mitochondrial protein mass (proliferation) was determined by the Bradford method.
Results: Stavudine-based HAART recipients displayed significant mtDNA depletion (13.4% of control, p = 0.002), mild mitochondrial proliferation (2.6-fold, p = 0.112) and decreased expression of PPAR? (40% of control, p = 0.039) and UCP2 mRNA (35% of control, p = 0.015). Zidovudine-based HAART recipients displayed marked, but non-significant mtDNA depletion (37% of control, p = 0.215) and increased expression of UCP2 (1.5-fold, p = 0.053) and UCP1 mRNA (19-fold, p = 0.010). PI-containing HAART recipients displayed significant mitochondrial proliferation (4.2-fold, p = 0.015); however, this appeared to be due to stavudine-based, PI-containing HAART recipients.
Conclusions: Stavudine-based HAART is associated with mtDNA depletion, mitochondrial proliferation, and decreased expression of adipocyte differentiation markers PPAR? and UCP2. Zidovudine-based HAART is associated with increased expression of UCP2 and the brown adipocyte-specific marker UCP1. Caution should be exercised in interpreting quantification of mRNA as this was performed on whole tissue, not isolated adipocytes.
|Publication Type:||Conference Item|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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