Nucleosides reduce PPAR-gamma: a role for rosiglitazone without thymidine analogues?
31 January 2005. Related: Conference reports, Lipodystrophy Workshop (IWADRW) 6th Washington 2004.
Simon Collins, HIV i-Base
Even earlier changes in gene-expression implicated in lipoatrophy were presented by Paddy Mallon and colleagues from St Vincent’s Hospital, Sydney, who described changes in mitochondrial and nuclear gene expression in adipose tissue in 20 HIV-negative volunteers, randomised to standard dose dual nucleoside therapy (AZT/3TC or d4T/3TC) for 6 weeks. [1, 2, 3]
This group observed inhibition of mitochondrial RNA after 2 weeks that coincided with upregulation of genes relating to mt transcription by 25-83% (mtTFA, NRF1, PCG1) and fatty acid oxidation by 50-55% (PPAR-alpha and LPL) and down regulation of PPAR-gamma (which is responsible for adipocyte differentiation and insulin responses) by 50%. It is notable that these changes occurred without significant changes in mtDNA appearance or depletion.
Monocyte mtRNA expression (COX1) also decreased by –38% to week 6 and persisted for a further 6 weeks after stopping study drugs.
These results showing an early change both in genetic expression both on production and development of fat cells on the one hand, and upregulation of mitochondrial transcription on the other, explain the link between nucleoside therapy and lipoatropy, and also the increased rates of lipoatrophy when protease inhibitors (which also down regulate PPAR-gamma) are used in combinations with nucleosides.
The affect of thymidine analogues on PPAR-gamma may also explain the disappointing results given the theoretical promise of using rosiglitazone, a PPAR-gamma agonist, was used to treat lipoatrophy. [4] In a double-blinded randomised placebo study of 4mg rosiglitazone twice-daily showed no benefit over 48 weeks of the original study, or when follow-up was extended to 84 weeks.
Comment
An understanding that nucleosides could be acting at a later step to block any benefit from rosiglitazone, suggests that the rosiglitazone could perhaps be restudied without use of thymidine analogues.
References:
- Mallon PWG, Unemori P, Carr A et al. In vivo nucleoside reverse transcriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes independent to HIV infection. 6th Lipodystrophy Workshop (6th IWADRLH), Washington. Abstract 15. Antiviral Therapy 2004; 9:L11.
http://www.aegis.org/DisaplayConf/?Abstract=87271 - Mallon PWG, Sedwell R, Unemori U et al. Changes in nuclear gene expression resulting from NRTI-induced inhibition of mitochondrial transcription reveal links between mitochondrial dysfunction and lipid metabolism. 6th Lipodystrophy Workshop (6th IWADRLH), Washington. Abstract 97. Antiviral Therapy 2004; 9:L56.
http://www.aegis.org/DisaplayConf/?Abstract=87189 - Mallon PWG, Sedwell R, Unemori U et al. Nucleoside reverse transcriptase inhibitors (NRTI) decrease adipocyte and monocyte mitochondrial (mt) messenger RNA transcription in the absence of changes in mtDNA or cell morphology. 6th Lipodystrophy Workshop (6th IWADRLH), Washington. Abstract 98. Antiviral Therapy 2004; 9:L56.
http://www.aegis.org/DisaplayConf/?Abstract=87188 - Carey D, Workman C, Rogers G et al. Rosiglitazone for HIV lipoatrophy: 84 weeks follow-up. 6th Lipodystrophy Workshop (6th IWADRLH), Washington. Abstract 78. Antiviral Therapy 2004; 9:L46.
http://www.aegis.org/DisaplayConf/?Abstract=87208