接受高效抗逆转录病毒治疗的HIV阳性患者皮下脂肪组织中的线粒体增殖、DNA耗竭与脂肪细胞分化

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

作者信息

Pace Craig S, Martin Annalise M, Hammond Emma L, Mamotte Cyril D, Nolan David A, Mallal Simon A

机构信息

Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Western Australia.

出版信息

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

PMID:14518702

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.

摘要

目的

研究高效抗逆转录病毒治疗（HAART）方案对脂肪组织线粒体DNA（mtDNA）耗竭、线粒体细胞器增殖以及脂肪细胞分化和表型标志物的体内影响。

设计与方法

采用实时PCR方法对31例HIV感染个体的脂肪组织样本进行DNA和mRNA定量分析，其中11例未接受过治疗，20例正在接受HAART治疗。mtDNA耗竭以mtDNA拷贝数/细胞来衡量，线粒体增殖通过线粒体蛋白质量的定量分析来评估。通过NRF-1和mtTFA mRNA评估线粒体生物发生的调控。PPARγ、UCP2和UCP1 mRNA表达用于评估脂肪细胞分化和表型。

结果

接受基于司他夫定的HAART治疗的患者（n = 10）表现出显著的mtDNA耗竭（为对照组的12.8%，P < 0.001），线粒体蛋白质量轻度增加（为对照组的2.6倍，P = 0.032），PPARγ（为对照组的53.9%，P = 0.021）、UCP2（为对照组的62.2%，P = 0.024）和UCP3（为对照组的51.8%，P = 0.047）mRNA表达降低；与对照组相比，接受基于齐多夫定的HAART治疗的患者（n = 7）也表现出显著的mtDNA耗竭（为对照组的34.45%，P = 0.031），线粒体蛋白质量增加（为对照组的5.7倍，P = 0.009），UCP1 mRNA显著增加（为对照组的18倍，P = 0.009）。发现UCP1 mRNA表达升高与不含司他夫定（齐多夫定或阿巴卡韦）、含蛋白酶抑制剂（PI）的HAART治疗相关（是不含司他夫定、不含PI的HAART治疗的95倍，P = 0.006）。

结论

观察到司他夫定和齐多夫定治疗对mtDNA耗竭以及脂肪细胞分化标志物PPARγ和UCP2表达的不同影响，这与司他夫定治疗相关的脂肪组织毒性增加一致。UCP1 mRNA增加是棕色脂肪组织表型的标志物，与不含司他夫定、含PI的HAART治疗相关，可能代表对PI治疗相关脂肪酸通量增加的一种适应性反应，并且可能导致此类患者静息能量消耗增加。