Effect of rosiglitazone on peroxisome proliferator-activated receptor γ gene expression in human adipose tissue is limited by antiretroviral drug - Induced mitochondrial dysfunction

Patrick W.G. Mallon, Rebecca Sedwell, Gary Rogers, David Nolan, Patrick Unemori, Jennifer Hoy, Katherine Samaras, Anthony Kelleher, Sean Emery, David A. Cooper, Andrew Carr

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25 Citations (Scopus)

Abstract

Background. Treatment of human immunodeficiency virus (HIV)-1 with thymidine-analogue nucleoside reverse-transcriptase inhibitors (tNRTIs) causes lipoatrophy, mitochondrial toxicity, and lower adipose tissue expression of peroxisome proliferator-activated receptor γ(PPARγ[PPARG gene]) . Rosiglitazone (RSG), a PPARγagonist, improves congenital lipoatrophy but not HIV lipoatrophy. Methods. Serial fat biopsies were taken from HIV-infected, lipoatrophic men randomized to receive RSG or placebo for 48 weeks. Adipose tissue mitochondrial and nuclear gene expression and mitochondrial DNA content were quantified by real-time polymerase chain reaction. Nonparametric analyses were applied. Results. Subjects receiving tNRTI-containing antiretroviral therapy had lower baseline mitochondrial RNA expression and DNA content. In subjects receiving tNRTIs, exposure to RSG did not affect PPARG expression at either week 2 or 48. At week 2, RSG increased PPARG expression only in subjects not treated with tNRTIs, whereas at week 48, increased PPARG expression was observed in subjects not treated with tNRTIs, regardless of RSG use. Similar findings were observed for the PPARG-responsive gene fatty acid- binding protein 4. Changes in PPARG expression were associated with increases in limb fat mass. Conclusions. These data suggest that in HIV-infected, lipoatrophic men, adipose PPARG expression and function are dependent on intact mitochondrial function. These data support a direct link between mitochondrial toxicity and adipose tissue PPARG expression and help explain the poor clinical response to RSG observed in clinical trials.

Original languageEnglish
Pages (from-to)1794-1803
Number of pages10
JournalJournal of Infectious Diseases
Volume198
Issue number12
DOIs
Publication statusPublished - 15 Dec 2008

Cite this

Mallon, Patrick W.G. ; Sedwell, Rebecca ; Rogers, Gary ; Nolan, David ; Unemori, Patrick ; Hoy, Jennifer ; Samaras, Katherine ; Kelleher, Anthony ; Emery, Sean ; Cooper, David A. ; Carr, Andrew. / Effect of rosiglitazone on peroxisome proliferator-activated receptor γ gene expression in human adipose tissue is limited by antiretroviral drug - Induced mitochondrial dysfunction. In: Journal of Infectious Diseases. 2008 ; Vol. 198, No. 12. pp. 1794-1803.
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abstract = "Background. Treatment of human immunodeficiency virus (HIV)-1 with thymidine-analogue nucleoside reverse-transcriptase inhibitors (tNRTIs) causes lipoatrophy, mitochondrial toxicity, and lower adipose tissue expression of peroxisome proliferator-activated receptor γ(PPARγ[PPARG gene]) . Rosiglitazone (RSG), a PPARγagonist, improves congenital lipoatrophy but not HIV lipoatrophy. Methods. Serial fat biopsies were taken from HIV-infected, lipoatrophic men randomized to receive RSG or placebo for 48 weeks. Adipose tissue mitochondrial and nuclear gene expression and mitochondrial DNA content were quantified by real-time polymerase chain reaction. Nonparametric analyses were applied. Results. Subjects receiving tNRTI-containing antiretroviral therapy had lower baseline mitochondrial RNA expression and DNA content. In subjects receiving tNRTIs, exposure to RSG did not affect PPARG expression at either week 2 or 48. At week 2, RSG increased PPARG expression only in subjects not treated with tNRTIs, whereas at week 48, increased PPARG expression was observed in subjects not treated with tNRTIs, regardless of RSG use. Similar findings were observed for the PPARG-responsive gene fatty acid- binding protein 4. Changes in PPARG expression were associated with increases in limb fat mass. Conclusions. These data suggest that in HIV-infected, lipoatrophic men, adipose PPARG expression and function are dependent on intact mitochondrial function. These data support a direct link between mitochondrial toxicity and adipose tissue PPARG expression and help explain the poor clinical response to RSG observed in clinical trials.",
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Effect of rosiglitazone on peroxisome proliferator-activated receptor γ gene expression in human adipose tissue is limited by antiretroviral drug - Induced mitochondrial dysfunction. / Mallon, Patrick W.G.; Sedwell, Rebecca; Rogers, Gary; Nolan, David; Unemori, Patrick; Hoy, Jennifer; Samaras, Katherine; Kelleher, Anthony; Emery, Sean; Cooper, David A.; Carr, Andrew.

In: Journal of Infectious Diseases, Vol. 198, No. 12, 15.12.2008, p. 1794-1803.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Effect of rosiglitazone on peroxisome proliferator-activated receptor γ gene expression in human adipose tissue is limited by antiretroviral drug - Induced mitochondrial dysfunction

AU - Mallon, Patrick W.G.

AU - Sedwell, Rebecca

AU - Rogers, Gary

AU - Nolan, David

AU - Unemori, Patrick

AU - Hoy, Jennifer

AU - Samaras, Katherine

AU - Kelleher, Anthony

AU - Emery, Sean

AU - Cooper, David A.

AU - Carr, Andrew

PY - 2008/12/15

Y1 - 2008/12/15

N2 - Background. Treatment of human immunodeficiency virus (HIV)-1 with thymidine-analogue nucleoside reverse-transcriptase inhibitors (tNRTIs) causes lipoatrophy, mitochondrial toxicity, and lower adipose tissue expression of peroxisome proliferator-activated receptor γ(PPARγ[PPARG gene]) . Rosiglitazone (RSG), a PPARγagonist, improves congenital lipoatrophy but not HIV lipoatrophy. Methods. Serial fat biopsies were taken from HIV-infected, lipoatrophic men randomized to receive RSG or placebo for 48 weeks. Adipose tissue mitochondrial and nuclear gene expression and mitochondrial DNA content were quantified by real-time polymerase chain reaction. Nonparametric analyses were applied. Results. Subjects receiving tNRTI-containing antiretroviral therapy had lower baseline mitochondrial RNA expression and DNA content. In subjects receiving tNRTIs, exposure to RSG did not affect PPARG expression at either week 2 or 48. At week 2, RSG increased PPARG expression only in subjects not treated with tNRTIs, whereas at week 48, increased PPARG expression was observed in subjects not treated with tNRTIs, regardless of RSG use. Similar findings were observed for the PPARG-responsive gene fatty acid- binding protein 4. Changes in PPARG expression were associated with increases in limb fat mass. Conclusions. These data suggest that in HIV-infected, lipoatrophic men, adipose PPARG expression and function are dependent on intact mitochondrial function. These data support a direct link between mitochondrial toxicity and adipose tissue PPARG expression and help explain the poor clinical response to RSG observed in clinical trials.

AB - Background. Treatment of human immunodeficiency virus (HIV)-1 with thymidine-analogue nucleoside reverse-transcriptase inhibitors (tNRTIs) causes lipoatrophy, mitochondrial toxicity, and lower adipose tissue expression of peroxisome proliferator-activated receptor γ(PPARγ[PPARG gene]) . Rosiglitazone (RSG), a PPARγagonist, improves congenital lipoatrophy but not HIV lipoatrophy. Methods. Serial fat biopsies were taken from HIV-infected, lipoatrophic men randomized to receive RSG or placebo for 48 weeks. Adipose tissue mitochondrial and nuclear gene expression and mitochondrial DNA content were quantified by real-time polymerase chain reaction. Nonparametric analyses were applied. Results. Subjects receiving tNRTI-containing antiretroviral therapy had lower baseline mitochondrial RNA expression and DNA content. In subjects receiving tNRTIs, exposure to RSG did not affect PPARG expression at either week 2 or 48. At week 2, RSG increased PPARG expression only in subjects not treated with tNRTIs, whereas at week 48, increased PPARG expression was observed in subjects not treated with tNRTIs, regardless of RSG use. Similar findings were observed for the PPARG-responsive gene fatty acid- binding protein 4. Changes in PPARG expression were associated with increases in limb fat mass. Conclusions. These data suggest that in HIV-infected, lipoatrophic men, adipose PPARG expression and function are dependent on intact mitochondrial function. These data support a direct link between mitochondrial toxicity and adipose tissue PPARG expression and help explain the poor clinical response to RSG observed in clinical trials.

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JO - Journal of Infectious Diseases

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SN - 0022-1899

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