自由基衍生的氧化甾醇：调节脂肪前体细胞脂肪生成分化的新型脂肪因子。

Free Radical-derived Oxysterols: Novel Adipokines Modulating Adipogenic Differentiation of Adipose Precursor Cells.

作者信息

Murdolo Giuseppe, Piroddi Marta, Tortoioli Cristina, Bartolini Desirée, Schmelz Martin, Luchetti Francesca, Canonico Barbara, Papa Stefano, Zerbinati Chiara, Iuliano Luigi, Galli Francesco

机构信息

Department of Internal Medicine (G.M.), Assisi Hospital, 06081 Assisi (Perugia), Italy; Department of Internal Medicine, Section of Internal Medicine, Endocrine and Metabolic Sciences (G.M., C.T.), University of Perugia, 06126 Perugia Italy; Department of Pharmaceutical Sciences (M.P., D.B., F.G.), University of Perugia, 06126 Perugia, Italy; Department of Anesthesiology and Intensive Care Medicine Mannheim (M.S.), Heidelberg University, 69117 Heidelberg, Germany; Department of Earth, Life and Environmental Sciences (F.L., B.C., S.P.), University Carlo Bo, 61029 Urbino, Italy; and Department of Medico-Surgical Sciences and Biotechnologies, Unit of Vascular Medicine (C.Z., L.I.), Sapienza University of Rome, 00185 Latina, Italy.

出版信息

J Clin Endocrinol Metab. 2016 Dec;101(12):4974-4983. doi: 10.1210/jc.2016-2918. Epub 2016 Oct 6.

DOI:10.1210/jc.2016-2918

PMID:27710239

Abstract

CONTEXT

Increased oxidative stress in adipose tissue emerges as an inducer of obesity-linked insulin resistance. Here we tested whether free-radical derived oxysterols are formed by, and accumulate in, human adipocytes. Moreover, we asked whether increased accumulation of oxysterols characterizes the adipose cells of obese patients with type 2 diabetes (T2D) (OBT2D) compared with lean, nondiabetic controls (CTRLs). Finally, we studied the effects of the free radical-derived oxysterols on adipogenic differentiation of adipose-derived stem cells (ASCs).

MAIN OUTCOME MEASURES

Adipocytes and ASCs were isolated from sc abdominal adipose tissue biopsy in four OBT2D and four CTRL subjects. Oxysterols in adipocytes were detected by gas chromatography/mass spectrometry. The cellular and molecular effects of oxysterols were then evaluated on primary cultures of ASCs focusing on cell viability, adipogenic differentiation, and "canonical" WNT and MAPK signaling pathways.

RESULTS

7-ketocholesterol (7κ-C) and 7β-hydroxycholesterol were unambiguously detected in adipocytes, which showed higher oxysterol accumulation (P < .01) in OBT2D, as compared with CTRL individuals. Notably, the accumulation of oxysterols in adipocytes was predicted by the adipose cell size of the donor (R = 0.582; P < .01). Challenging ASCs with free radical-derived type I (7κ-C) and type II (5,6-Secosterol) oxysterols led to a time- and concentration-dependent decrease of cell viability. Meaningfully, at a non-toxic concentration (1μM), these bioactive lipids hampered adipogenic differentiation of ASCs by sequential activation of WNT/β-catenin, p38-MAPK, ERK1/2, and JNK signaling pathways.

CONCLUSION

Free radical-derived oxysterols accumulate in the "diabetic" fat and may act as novel adipokines modulating the adipogenic potential of undifferentiated adipose precursor cells.

摘要

背景

脂肪组织中氧化应激增加成为肥胖相关胰岛素抵抗的诱因。在此，我们测试了自由基衍生的氧化甾醇是否由人类脂肪细胞形成并在其中积累。此外，我们还询问与瘦的非糖尿病对照组（CTRLs）相比，氧化甾醇积累增加是否是2型糖尿病肥胖患者（OBT2D）脂肪细胞的特征。最后，我们研究了自由基衍生的氧化甾醇对脂肪来源干细胞（ASCs）成脂分化的影响。

主要观察指标

从4名OBT2D和4名CTRL受试者的腹部皮下脂肪组织活检中分离脂肪细胞和ASCs。通过气相色谱/质谱法检测脂肪细胞中的氧化甾醇。然后以细胞活力、成脂分化以及“经典”WNT和MAPK信号通路为重点，评估氧化甾醇对ASCs原代培养物的细胞和分子效应。

结果

在脂肪细胞中明确检测到7-酮胆固醇（7κ-C）和7β-羟基胆固醇，与CTRL个体相比，OBT2D患者的脂肪细胞中氧化甾醇积累更高（P <.01）。值得注意的是，供体脂肪细胞大小可预测氧化甾醇在其中的积累（R = 0.582；P <.01）。用自由基衍生的I型（7κ-C）和II型（5,6-甾醇）氧化甾醇刺激ASCs会导致细胞活力呈时间和浓度依赖性下降。有意义的是，在无毒浓度（1μM）下，这些生物活性脂质通过依次激活WNT/β-连环蛋白、p38-MAPK、ERK1/2和JNK信号通路，阻碍了ASCs的成脂分化。