Department of Plastic Surgery, Wound Repair and Regeneration, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Department of Plastic and Reconstructive Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Int J Mol Sci. 2021 Feb 20;22(4):2114. doi: 10.3390/ijms22042114.
Lipodystrophy is a common complication in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART). Previous studies demonstrated that endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) is involved in lipodystrophy; however, the detailed mechanism has not been fully described in human adipogenic cell lineage. We utilized adipose tissue-derived stem cells (ADSCs) obtained from human subcutaneous adipose tissue, and atazanavir (ATV), a protease inhibitor (PI), was administered to ADSCs and ADSCs undergoing adipogenic conversion. Marked repression of adipogenic differentiation was observed when ATV was administered during 10 days of ADSC culture in adipogenic differentiation medium. Although ATV had no effect on ADSCs, it significantly induced apoptosis in differentiating adipocytes. ATV treatment also caused the punctate appearance of CCAAT-enhancer-binding (C/EBP) protein homologous protein (CHOP), and altered expression of CHOP and GRP78/Bip, which are the representation of ER stress, only in differentiating adipocytes. Administration of UPR inhibitors restored adipogenic differentiation, indicating that ER stress-mediated UPR was induced in differentiating adipocytes in the presence of ATV. We also observed autophagy, which was potentiated in differentiating adipocytes by ATV treatment. Thus, adipogenic cell atrophy leads to ATV-induced lipodystrophy, which is mediated by ER stress-mediated UPR and accelerated autophagy, both of which would cause adipogenic apoptosis. As our study demonstrated for the first time that ADSCs are unsusceptible to ATV and its deleterious effects are limited to the differentiating adipocytes, responsible target(s) for ATV-induced lipodystrophy may be protease(s) processing adipogenesis-specific protein(s).
脂肪营养不良是接受高效抗逆转录病毒治疗（HAART）或抗逆转录病毒治疗（ART）的人类免疫缺陷病毒（HIV）感染患者的常见并发症。先前的研究表明，内质网（ER）应激介导的未折叠蛋白反应（UPR）参与脂肪营养不良；然而，在人类脂肪生成细胞谱系中，其详细机制尚未完全描述。我们利用从人皮下脂肪获得的脂肪组织源性干细胞（ADSCs），并给予 ADCS 和正在进行脂肪生成转化的 ADCS 阿扎那韦（ATV），一种蛋白酶抑制剂（PI）。当在脂肪生成分化培养基中培养 ADCS 10 天时给予 ATV 时，观察到明显抑制脂肪生成分化。尽管 ATV 对 ADCS 没有影响，但它在分化的脂肪细胞中显著诱导细胞凋亡。ATV 处理还导致 CCAAT 增强子结合（C / EBP）蛋白同源蛋白（CHOP）点状出现，以及内质网应激的代表性蛋白 CHOP 和 GRP78 / Bip 的表达改变，仅在分化的脂肪细胞中。UPR 抑制剂的给药恢复了脂肪生成分化，表明在存在 ATV 的情况下，分化的脂肪细胞中诱导了 ER 应激介导的 UPR。我们还观察到自噬，ATV 处理增强了分化的脂肪细胞中的自噬。因此，脂肪生成细胞萎缩导致 ATV 诱导的脂肪营养不良，这是由 ER 应激介导的 UPR 和加速自噬介导的，这两者都会导致脂肪生成细胞凋亡。正如我们的研究首次表明的那样，ADSCs 不易受 ATV 影响，其有害影响仅限于正在分化的脂肪细胞，因此 ATV 诱导的脂肪营养不良的责任靶标可能是处理脂肪生成特异性蛋白的蛋白酶。
