Genetic and Metabolic Basis of Familial Lipodystrophies

描述（由申请人提供）：肥胖仍然是美国的主要健康问题，并导致代谢并发症，如糖尿病、血脂异常和胰岛素抵抗。类似的并发症也发生在患有家族性脂肪营养不良的患者中，家族性脂肪营养不良是以部分（家族性部分脂肪营养不良，FPL）或几乎完全（先天性全身性脂肪营养不良，CGL）缺乏体脂为特征的单基因疾病。在过去的几年中，几个基因，即1-酰基甘油-3-磷酸O-酰基转移酶2（AGPAT 2）和Berardinelli-Seip先天性脂肪营养不良2（BSCL 2），用于常染色体隐性遗传，CGL;核纤层蛋白A/C（LMNA），过氧化物酶体增殖物激活受体-D（PPARG），和v-AKT鼠胸腺瘤癌基因同源物2（AKT 2），用于常染色体显性FPL;和LMNA和锌金属蛋白酶（ZMPSTE 24）用于下颌骨肢端发育不良相关的脂肪营养不良。然而，来自许多家系的受影响的受试者缺乏这些基因的突变，这表明存在其他基因座。此外，与SHORT和新生儿早老综合征相关的许多极其罕见的脂肪营养不良的遗传基础仍然未知。因此，该建议的第一个目的是鉴定参与脂肪细胞生物学、发育和分化的引起脂肪营养不良的其他基因。我们的实验室也一直在研究AGPAT的各种亚型（主要是AGPAT 1和2）的功能作用，无论是在体外还是通过开发敲除小鼠模型。Agpat 2-/-小鼠再现了人CGL的许多特征，例如极度缺乏体脂肪、早发性高血糖症、高胰岛素血症、高胆固醇血症和肝脂肪变性。有趣的是，我们的研究表明，在这些无效小鼠中，饮食甘油三酯是肝脂肪变性的主要贡献者。Agpatl-/-小鼠也严重缺乏体脂，但详细的表型仍有待表征。此外，BSCL 2编码的蛋白质seipin的生物学功能仍然未知，因此BSCL 2突变如何引起脂肪代谢障碍仍然令人困惑。因此，本建议的第二个目的是进一步表征Agpat 2- /-和Agpat 1-/-小鼠，并开发Bscl 2敲除小鼠模型，以深入了解全身性脂肪营养不良中涉及的各种基因的生物学作用，并了解胰岛素抵抗及其相关发病率的分子机制。

DESCRIPTION (provided by applicant): Obesity remains a major health problem in US and causes metabolic complications such as diabetes, dyslipidemia and insulin resistance. Similar complications also occur in patients with familial lipodystrophies, monogenic disorders characterized by partial (familial partial lipodystrophy, FPL) or almost complete (congenital generalized lipodystrophy, CGL) lack of body fat. In the last few years, several genes, namely, 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2), for the autosomal recessive, CGL; lamin A/C (LMNA), peroxisome proliferator-activated receptor-D (PPARG), and v-AKT murine thymoma oncogene homolog 2 (AKT2) for the autosomal dominant FPL; and LMNA and zinc metalloproteinase (ZMPSTE24) for mandibuloacral dysplasia associated lipodystrophies have been identified. However, affected subjects from many pedigrees lack mutations in these genes suggesting additional loci. Furthermore, the genetic basis of many extremely rare varieties of lipodystrophies associated with SHORT and neonatal progeroid syndromes remains unknown. Thus, the first aim of this proposal is to identify additional gene(s) involved in adipocyte biology, development and differentiation that cause lipodystrophies. Our laboratory has also been studying the functional role of various isoforms of AGPAT (mainly AGPAT1 and 2) either in vitro or by developing knockout mouse models. The Agpat2-/- mice reproduce many features of human CGL such as extreme lack of body fat, early onset hyperglycemia, hyperinsulinemia, hypertriglyceridemia and hepatic steatosis. Interestingly, our studies reveal that in these null mice, dietary triglycerides are major contributors to hepatic steatosis. The Agpatl-/- mice also have profound lack of body fat but the detailed phenotype remains to be characterized. Furthermore, the biological function of BSCL2-encoded protein, seipin, still remains unknown and thus how BSCL2 mutations cause lipodystrophy remains puzzling. Therefore, the second aim of this proposal is to further characterize Agpat2- /- and Agpatl-/- mice and to develop Bscl2 knockout mouse model to gain insights into biological role of various genes implicated in generalized lipodystrophies and to understand molecular mechanisms involved in causation of insulin resistance and its associated morbidities.