Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance
Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance
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DOI：
10.1016/s0140-6736(02)08094-7
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发表时间：
2002-03-23
期刊：
影响因子：
168.9
通讯作者：
Capeau, J
中科院分区：
文献类型：
--
作者：
Bastard, JP;Caron, M;Capeau, J
背景：脂肪营养不良是抗逆转录病毒治疗的一个主要副作用，但其病理生理机制仍不清楚。体外研究表明，HIV-1蛋白抑制剂对脂肪细胞分化的影响较早，主要涉及类固醇调节元件结合蛋白-1(SREBP1)，但体内研究较少。方法比较26例HIV-1感染患者和18例HIV-1血清阴性健康对照腹部皮下脂肪组织中脂肪形态、主要脂肪细胞分化标志物和细胞因子的mRNA和蛋白表达，发现患者脂肪中含有较高比例的小脂肪细胞，而成脂分化因子CCAAT-EBPβ和α的mRNA浓度较低。过氧化物酶体增殖物激活受体(PPAR)γ和SREBP1的1c亚型，后者的中位数下降了93%。SREBP1蛋白浓度增加了2.6倍，而PPAR-γ蛋白浓度降低了70%。脂肪细胞特异性标志物，包括瘦素，在患者脂肪中的表达低于对照组脂肪，而肿瘤坏死因子α的表达高于对照组，且与SREBP1c及其下游成脂因子的表达呈负相关。SREBP1c mRNA浓度与血糖和胰岛素抵抗呈负相关，而与胰岛素抵抗呈正相关，但与血脂变量无关。解释HIV-1感染抗逆转录病毒诱导的脂肪萎缩患者外周脂肪细胞分化状态的改变与SREBP1c表达显著降低有关。由于分化因子SREBP1在体外能迅速被蛋白酶抑制剂靶向，我们的结果表明SREBP1c可能是这种情况下外周脂肪萎缩的重要介质，导致代谢变化，如胰岛素抵抗。
Background Lipodystrophy is a major side-effect of antiretroviral therapy but its pathophysiology remains elusive. In-vitro studies show that HIV-1-protease inhibitors affect adipocyte differentiation at an early step involving sterol-regulatory-element-binding-protein-1 (SREBP1), but in-vivo studies are lacking.Methods We compared fat morphology and mRNA and protein expression of major adipocyte differentiation markers and cytokines in subcutaneous abdominal adipose tissue from 26 HIV-1-infected patients who developed peripheral lipoatrophy while on protease inhibitors and from 18 HIV-1-seronegative healthy controls.Findings Patients' fat contained a higher proportion of small adipocytes than control fat, together with lower mRNA concentrations of the adipogenic differentiation factors CCAAT-enhancer binding protein (C/EBP) beta and alpha, peroxisome proliferator-activated receptor (PPAR) gamma, and the 1c isoform of SREBP1, with a median decrease of 93% in the latter. The SREBP1 protein concentration was increased 2.6-fold, whereas the PPAR-gamma protein concentration was decreased by 70%. The expression of adipocyte-specific markers, including leptin, was lower in fat from patients than in fat from controls, whereas expression of tumour necrosis factor (TNF) alpha was higher and correlated negatively with the expression of SREBP1c and downstream adipogenic factors. SREBP1c mRNA concentrations correlated negatively, and TNFalpha mRNA concentrations positively, with glycaemia and insulin resistance, but did not correlate with lipid variables.Interpretation The altered differentiation status of peripheral adipocytes in HIV-1-infected patients with antiretroviral-induced lipoatrophy is associated with greatly reduced SREBP1c expression. Since the differentiation factor SREBP1 is rapidly targeted by protease inhibitors in vitro, our results suggest that SREBP1c could be an important mediator of peripheral lipoatrophy in this setting, leading to metabolic alterations such as insulin resistance.