Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients.

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Pace CS, Martin AM, Hammond EL, Mamotte CD, Nolan DA, Mallal SA

Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients.

Antivir Ther. 2003 Aug;8(4):323-31.

PubMed ID

14518702 [ View in PubMed

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Abstract

OBJECTIVES: 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. DESIGN AND 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). CONCLUSION: 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.

DrugBank Data that Cites this Article

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Abacavir	Approved Investigational	UCP1	7350	upregulated	abacavir results in increased expression of UCP1 mRNA	4q31.1
Stavudine	Approved Investigational	PPARG	5468	downregulated	Stavudine results in decreased expression of PPARG mRNA	3p25.2
Stavudine	Approved Investigational	UCP2	7351	downregulated	Stavudine results in decreased expression of UCP2 mRNA	11q13
Stavudine	Approved Investigational	UCP3	7352	downregulated	Stavudine results in decreased expression of UCP3 mRNA	11q13.4
Zidovudine	Approved	UCP1	7350	upregulated	Zidovudine results in increased expression of UCP1 mRNA	4q31.1