Bastard Jean Philippe, Caron Martine, Vidal Hubert, Jan Véronique, Auclair Martine, Vigouroux Corinne, Luboinski Jacqueline, Laville Martine, Maachi Mustapha, Girard Pierre Marie, Rozenbaum Willy, Levan Philippe, Capeau Jacqueline
INSERM Research Unit 402, Faculty of Medicine Saint-Antoine, Paris, France.
Lancet. 2002 Mar 23;359(9311):1026-31. doi: 10.1016/S0140-6736(02)08094-7.
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.
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.
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 PPARgamma 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.
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.
脂肪代谢障碍是抗逆转录病毒治疗的主要副作用，但其病理生理学仍不清楚。体外研究表明，HIV-1蛋白酶抑制剂在涉及固醇调节元件结合蛋白-1（SREBP1）的早期阶段影响脂肪细胞分化，但缺乏体内研究。
我们比较了26例在接受蛋白酶抑制剂治疗时出现外周脂肪萎缩的HIV-1感染患者与18例HIV-1血清阴性健康对照者腹部皮下脂肪组织的脂肪形态、主要脂肪细胞分化标志物及细胞因子的mRNA和蛋白表达。
患者的脂肪中小脂肪细胞比例高于对照脂肪，同时脂肪生成分化因子CCAAT增强子结合蛋白（C/EBP）β和α、过氧化物酶体增殖物激活受体（PPAR）γ以及SREBP1的1c亚型的mRNA浓度较低，后者中位数下降93%。SREBP1蛋白浓度增加2.6倍，而PPARγ蛋白浓度下降70%。包括瘦素在内的脂肪细胞特异性标志物在患者脂肪中的表达低于对照脂肪，而肿瘤坏死因子（TNF）α的表达较高，且与SREBP1c及下游脂肪生成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，TNFα mRNA浓度与血糖和胰岛素抵抗呈正相关，但与脂质变量无关。
抗逆转录病毒治疗诱导脂肪萎缩的HIV-1感染患者外周脂肪细胞分化状态改变与SREBP1c表达大幅降低有关。由于分化因子SREBP1在体外被蛋白酶抑制剂迅速靶向，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，导致胰岛素抵抗等代谢改变。
