Contribution of Nucleoside-Analogue Reverse Transcriptase Inhibitor Therapy to Lipoatrophy from the Population to the Cellular Level
Contribution of Nucleoside-Analogue Reverse Transcriptase Inhibitor Therapy to Lipoatrophy from the Population to the Cellular Level
复制标题
核苷类似物逆转录酶抑制剂治疗对从人群到细胞水平的脂肪萎缩的贡献
作者：
D. Nolan;E. Hammond;I. James;E. McKinnon;S. Mallal
目的 有人提出，核苷类似物逆转录酶抑制剂 (NRTI) 治疗对皮下脂肪消耗的贡献涉及脂肪组织特异性线粒体 DNA 毒性。我们研究了西澳大利亚 HIV 队列白种男性研究参与者中 NRTI 疗法、脂肪细胞线粒体 DNA 含量、脂肪组织毒性证据和脂肪消耗之间的关系。方法：对接受初始司他夫定或齐多夫定高效抗逆转录病毒治疗 (HAART) 的个体进行脂肪消耗的纵向混合效应分析（n = 49, 149 DEXA 测量）。还根据当前的 NRTI 疗法，对来自 69 名 HIV 阳性个体和 7 名健康对照的 92 例皮下脂肪活检进行了脂肪细胞线粒体 DNA (mtDNA) 消耗的评估，结果与接受初始含司他夫定或齐多夫定的 HAART 的活检数据的一部分患者的脂肪消耗相关（n = 22, 103 DEXA 测量）。对开始/转换 NRTI 治疗之前和之后获得的 22 个活检样本进行共聚焦显微镜检查。结果 在独立分析中，与齐多夫定治疗相比，司他夫定治疗与更严重的脂肪细胞线粒体 DNA 耗竭 (P<0.001) 和随时间推移的脂肪消耗 (P=0.002) 相关。在同时进行活检和纵向 DEXA 数据的患者中，脂肪消耗与 NRTI 治疗持续时间 (P=0.001) 和脂肪细胞 mtDNA 拷贝/细胞 (P=0.01) 相关。在此分析中，司他夫定与齐多夫定的选择与脂肪消耗之间的显着相关性 (P=0.03) 在调整 mtDNA 消耗的影响后消失 (P=0.13)。共聚焦分析提供了脂肪组织毒性严重程度与线粒体 DNA 消耗之间关系的直接证据。这些分析中没有检测到 HIV 蛋白酶抑制剂治疗的显着效果。结论 皮下脂肪消耗的严重程度主要取决于 NRTI 疗法的选择（司他夫定与齐多夫定）以及暴露于相关 NRTI 的持续时间。在细胞水平上，有证据表明这种效应是通过 NRTI 诱导的线粒体 DNA 耗竭来体现的。
Objectives It has been proposed that the contribution of nucleoside-analogue reverse transcriptase inhibitor (NRTI) therapy to subcutaneous fat wasting involves adipose tissue-specific mitochondrial DNA toxicity. We have investigated the relationships between NRTI therapy, adipocyte mitochondrial DNA content, evidence of toxicity in adipose tissue and fat wasting in Caucasian male Western Australian HIV Cohort study participants. Methods: Longitudinal mixed effects analysis of fat wasting was undertaken in individuals receiving initial stavudine- or zidovudine-containing highly active anti-retroviral therapy (HAART) (n=49, 149 DEXA measurements). Adipocyte mitochondrial DNA (mtDNA) depletion was also assessed according to current NRTI therapy in 92 subcutaneous fat biopsies from 69 HIV-positive individuals and seven healthy controls, and results were correlated with fat wasting among a subset of patients with biopsy data receiving initial stavudine-or zidovudine-containing HAART (n=22, 103 DEXA measurements). Confocal microscopy was performed in 22 biopsy samples obtained before and after initiating/switching NRTI therapy. Results Stavudine therapy was associated with more severe adipocyte mitochondrial DNA depletion (P<0.001) and fat wasting over time (P=0.002) compared with zidovudine therapy in independent analyses. Among patients with concurrent biopsy and longitudinal DEXA data, fat wasting was associated with duration of NRTI therapy (P=0.001) and adipocyte mtDNA copies/cell (P=0.01). In this analysis, the significant association between choice of stavudine versus zidovudine and fat wasting (P=0.03) was lost after adjustment for the effect of mtDNA depletion (P=0.13). Confocal analysis provided direct evidence of a relationship between severity of adipose tissue toxicity and mitochondrial DNA depletion. No significant effects of HIV protease inhibitor therapy were detected in these analyses. Conclusions Severity of subcutaneous fat wasting is primarily determined by choice of NRTI therapy (stavudine versus zidovudine) and by duration of exposure to the relevant NRTI. At the cellular level, evidence is provided that this effect manifests through NRTI-induced mitochondrial DNA depletion.
影响因子：
7.7
作者：
Woerle, IJ;Mariuz, PR;Gerich, JE
通讯作者：
Gerich, JE