Centre de Référence des Maladies Héréditaires du Métabolisme, Institut Imagine des Maladies Génétiques, Laboratoire de génétique des maladies autoinflammatoires monogéniques, INSERM UMR1163, Université Paris Descartes et Hôpital Necker-Enfants malades (Assistance publique - Hôpitaux de Paris), Paris, France
Laboratoire de Biogenèse Membranaire-UMR 5200, CNRS, Université de Bordeaux, Villenave d'Ornon, France.
J Lipid Res. 2017 Dec;58(12):2348-2364. doi: 10.1194/jlr.P075440. Epub 2017 Oct 6.
Lipin-1 is a Mg-dependent phosphatidic acid phosphatase (PAP) that in mice is necessary for normal glycerolipid biosynthesis, controlling adipocyte metabolism, and adipogenic differentiation. Mice carrying inactivating mutations in the gene display the characteristic features of human familial lipodystrophy. Very little is known about the roles of lipin-1 in human adipocyte physiology. Apparently, fat distribution and weight is normal in humans carrying inactivating mutations, but a detailed analysis of adipose tissue appearance and functions in these patients has not been available so far. In this study, we performed a systematic histopathological, biochemical, and gene expression analysis of adipose tissue biopsies from human patients harboring biallelic inactivating mutations and affected by recurrent episodes of severe rhabdomyolysis. We also explored the adipogenic differentiation potential of human mesenchymal cell populations derived from lipin-1 defective patients. White adipose tissue from human mutant patients displayed a dramatic decrease in lipin-1 protein levels and PAP activity, with a concomitant moderate reduction of adipocyte size. Nevertheless, the adipose tissue develops without obvious histological signs of lipodystrophy and with normal qualitative composition of storage lipids. The increased expression of key adipogenic determinants such as , , and shows that specific compensatory phenomena can be activated in vivo in human adipocytes with deficiency of functional lipin-1.
脂肪分化相关蛋白 1（Lipin-1）是一种依赖镁的磷酸脂酸磷酸酶（PAP），在小鼠中，它对于正常甘油酯的生物合成、调节脂肪细胞代谢和脂肪生成分化是必需的。在基因中携带失活突变的小鼠表现出人类家族性脂肪营养不良的特征。关于 Lipin-1 在人类脂肪细胞生理学中的作用，人们知之甚少。显然，在携带失活突变的人类中，脂肪分布和体重是正常的，但迄今为止，还没有对这些患者的脂肪组织外观和功能进行详细分析。在这项研究中，我们对携带双等位基因失活突变并反复发生严重横纹肌溶解症的人类患者的脂肪组织活检进行了系统的组织病理学、生化和基因表达分析。我们还探索了源自 Lipin-1 缺陷患者的人类间充质细胞群体的脂肪生成分化潜力。人类 突变患者的白色脂肪组织中 Lipin-1 蛋白水平和 PAP 活性显著降低，同时伴随着脂肪细胞体积的适度减小。然而，脂肪组织的发育没有明显的脂肪营养不良的组织学迹象，并且储存脂质的定性组成正常。关键脂肪生成决定因素如 、 、 和 的表达增加表明，在体内缺乏功能性 Lipin-1 的人类脂肪细胞中可以激活特定的代偿现象。
