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LIPE-related lipodystrophic syndrome: clinical features and disease modeling using adipose stem cells.

LIPE相关的脂肪营养不良综合征: 使用脂肪干细胞的临床特征和疾病建模。

  • 影响因子:5.04
  • DOI:10.1530/EJE-20-1013
  • 作者列表:"Sollier C","Capel E","Aguilhon C","Smirnov V","Auclair M","Douillard C","Ladsous M","Defoort-Dhellemmes S","Gorwood J","Braud L","Motterlini R","Vatier C","Lascols O","Renard E","Vigouroux C","Jéru I
  • 发表时间:2021-01-01
Abstract

Objective:The term Multiple Symmetric Lipomatosis (MSL) describes a heterogeneous group of rare monogenic disorders and multifactorial conditions, characterized by upper-body adipose masses. Biallelic variants in LIPE encoding hormone-sensitive lipase (HSL), a key lipolytic enzyme, were implicated in three families worldwide. We aimed to further delineate LIPE-related clinical features and pathophysiological determinants. Methods:A gene panel was used to identify pathogenic variants. The disease features were reviewed at the French lipodystrophy reference center. The immunohistological, ultrastructural, and protein expression characteristics of lipomatous tissue were determined in surgical samples from one patient. The functional impact of variants was investigated by developing a model of adipose stem cells (ASCs) isolated from lipomatous tissue. Results:We identified new biallelic LIPE null variants in three unrelated patients referred for MSL and/or partial lipodystrophy. The hallmarks of the disease, appearing in adulthood, included lower-limb lipoatrophy, upper-body and abdominal pseudo-lipomatous masses, diabetes and/or insulin resistance, hypertriglyceridemia, liver steatosis, high blood pressure, and neuromuscular manifestations. Ophthalmological investigations revealed numerous auto-fluorescent drusen-like retinal deposits in all patients. Lipomatous tissue and patient ASCs showed loss of HSL and decreased expression of adipogenic and mature adipocyte markers. LIPE-mutated ASCs displayed impaired adipocyte differentiation, decreased insulin response, defective lipolysis, and mitochondrial dysfunction. Conslusions:Biallelic LIPE null variants result in a multisystemic disease requiring multidisciplinary care. Loss of HSL expression impairs adipocyte differentiation, consistent with the lipodystrophy/MSL phenotype and associated metabolic complications. Detailed ophthalmological examination could reveal retinal damage, further pointing to the nervous tissue as an important disease target.

摘要

目的: 多发性对称性脂肪瘤病 (MSL) 一词描述了一组罕见的单基因疾病和多因素疾病的异质性,其特征是上身脂肪块。编码激素敏感脂肪酶 (HSL) 的LIPE的双等位基因变异体,一种关键的脂解酶,在世界范围内涉及三个家族。我们旨在进一步描述LIPE相关的临床特征和病理生理决定因素。 方法: 使用基因面板来鉴定致病变体。在法国脂肪营养不良参考中心审查了疾病特征。在来自一名患者的手术样品中测定脂肪瘤组织的免疫组织学、超微结构和蛋白质表达特征。通过开发从脂肪瘤组织分离的脂肪干细胞 (asc) 模型来研究变体的功能影响。 结果: 我们在3例不相关的MSL和/或部分脂肪营养不良患者中发现了新的双等位基因LIPE无效变体。该病在成年期出现的标志包括下肢脂肪萎缩、上半身和腹部假性脂肪瘤样肿块、糖尿病和/或胰岛素抵抗、高甘油三酯血症、肝脂肪变性、高血压和神经肌肉表现。眼科检查显示所有患者中有大量自体荧光玻璃疣样视网膜沉积物。脂肪瘤组织和患者ASCs显示出HSL的丢失以及成脂和成熟脂肪细胞标志物的表达降低。LIPE突变的asc表现出脂肪细胞分化受损、胰岛素反应降低、脂肪分解缺陷和线粒体功能障碍。 结论: 双等位基因LIPE无效变异导致多系统疾病,需要多学科护理。HSL表达的缺失损害脂肪细胞分化,与脂肪营养不良/MSL表型和相关的代谢并发症一致。详细的眼科检查可以揭示视网膜损伤,进一步指出神经组织是重要的疾病目标。

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发表时间:2021-02-01
DOI:10.1080/14656566.2020.1814255
作者列表:["Sawada H","Oeda T","Kohsaka M","Tomita S","Umemura A","Park K","Yamamoto K","Kiyohara K"]

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发表时间:2021-03-24
DOI:10.1007/s11033-021-06299-9
作者列表:["Louvrier A","Terranova L","Meyer C","Meyer F","Euvrard E","Kroemer M","Rolin G"]

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