Boothby Meg, McGee Kirsty C, Tomlinson Jeremy W, Gathercole Laura L, McTernan Philip G, Shojaee-Moradie Fariba, Umpleby A Margot, Nightingale Peter, Shahmanesh Mohsen
University Hospital Birmingham, HIV Medicine, Birmingham, UK.
Antivir Ther. 2009;14(8):1089-100. doi: 10.3851/IMP1457.
Abnormal lipid metabolism and cell oxidative mechanisms are reported in patients on antiretroviral treatment. We compared the expression of several key adipocyte genes in HIV-infected patients randomized to antiretroviral regimens containing zidovudine (AZT) or tenofovir disoproxil fumarate (TDF).
Subcutaneous fat was sampled from 32 HIV-positive treatment-naive patients before and 6 months after randomization to AZT/lamivudine/efavirenz (n=15) or TDF/emtricitabine/efavirenz (n=17) plus 15 HIV-negative matched controls. Expression of genes involved in adipocyte differentiation, lipid metabolism, mitochondrial function and glucocorticoid generation were profiled using real-time PCR. Lipoprotein lipase and hepatic lipase activity were assessed.
Before treatment, 11beta-hydroxysteroid dehydrogenase expression was down-regulated compared with controls. Following 6 months treatment with AZT, there was a significant increase in visceral adipose tissue (VAT; P=0.02) and the ratio of VAT to subcutaneous adipose tissue (P=0.008), down-regulation of cytochrome B (P=0.003) and cytochrome oxidase (COX)-3 gene expression (P=0.03), up-regulation of NADH dehydrogenase (P=0.008) and nuclear-encoded COX-4 (complex IV) gene expression (P=0.012). Genes involved with adipocyte cortisol generation, fatty acid metabolism and the tricarboxylic acid cycle were up-regulated. In the TDF-treated patients, there was no significant change in regional body fat or mitochondrial genes compared with pretreatment values. Changes in the expression of genes involved with cortisol and fatty acid metabolism were less marked with TDF.
Interference with the mitochondrial electron transport chain appears to occur early in an AZT-containing regimen and occurs at a time when there is increased visceral fat and up-regulation of genes involved with adipocyte differentiation and fatty acid flux.
据报道，接受抗逆转录病毒治疗的患者存在脂质代谢异常和细胞氧化机制异常。我们比较了随机接受含齐多夫定（AZT）或替诺福韦酯（TDF）的抗逆转录病毒方案治疗的HIV感染患者中几种关键脂肪细胞基因的表达情况。
从32例未接受过治疗的HIV阳性患者中采集皮下脂肪，在随机分组接受AZT/拉米夫定/依非韦伦（n = 15）或TDF/恩曲他滨/依非韦伦（n = 17）治疗前及治疗6个月后进行采样，并选取15例匹配的HIV阴性对照。使用实时PCR分析参与脂肪细胞分化、脂质代谢、线粒体功能和糖皮质激素生成的基因表达情况。评估脂蛋白脂肪酶和肝脂肪酶活性。
治疗前，与对照组相比，11β-羟基类固醇脱氢酶表达下调。接受AZT治疗6个月后，内脏脂肪组织（VAT）显著增加（P = 0.02），VAT与皮下脂肪组织的比值增加（P = 0.008），细胞色素B（P = 0.003）和细胞色素氧化酶（COX）-3基因表达下调（P = 0.03），烟酰胺腺嘌呤二核苷酸脱氢酶（P = 0.008）和核编码的COX-4（复合体IV）基因表达上调（P = 0.012）。参与脂肪细胞皮质醇生成、脂肪酸代谢和三羧酸循环的基因上调。在接受TDF治疗的患者中，与治疗前相比，局部体脂或线粒体基因无显著变化。TDF治疗后，与皮质醇和脂肪酸代谢相关的基因表达变化较小。
在含AZT的治疗方案中，线粒体电子传递链的干扰似乎在早期就会出现，且此时内脏脂肪增加，参与脂肪细胞分化和脂肪酸通量的基因上调。
