Genetic and Metabolic Basis of Familial Lipodystrophies

家族性脂肪营养不良的遗传和代谢基础

基本信息

批准号：
8044804
负责人：
Abhimanyu Garg
金额：
$ 58.3万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-05-15 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8044804
关键词：
AKT2 gene Acanthosis Nigricans Acyltransferase Adipose tissue Affect BSCL2 gene Biochemical Biological Biological Process Body fat Clinical Cultured Cells Defect Development Diabetes Mellitus Disease Dyslipidemias Dysplasia Etiology Familial generalized lipodystrophy Familial partial lipodystrophy Fatty Liver Fatty acid glycerol esters Functional disorder Gene Mutation Genes Genetic Health Homologous Gene Human Hyperglycemia Hyperinsulinism Hypertriglyceridemia In Vitro Insulin Resistance Knockout Mice Laboratories Lamin Type A Lead Light Lipodystrophy Mental Depression Metabolic Metalloproteases Molecular Morbidity - disease rate Mus Mutation Neonatal Nonesterified Fatty Acids Obesity Oncogenes PPARG gene Patients Peripheral Peroxisome Proliferator-Activated Receptors Phenotype Process Protein Isoforms Proteins Proto-Oncogene Proteins c-akt Relative (related person)Research Personnel Role Serum Skeletal Muscle Teething Testing Thymoma Triglycerides Variant Wiedemann-Rautenstrauch syndrome Zinc adipocyte biology base early onset genetic pedigree impaired glucose tolerance inorganic phosphate insight lipid biosynthesis mouse model positional cloning programs

项目摘要

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.

描述（由申请人提供）：肥胖仍然是美国的一个主要健康问题，并导致糖尿病、血脂异常和胰岛素抵抗等代谢并发症。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，这种单基因疾病的特征是部分（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）体内脂肪缺乏。在过去的几年里，常染色体隐性遗传的几个基因，即1-酰基甘油-3-磷酸O-酰基转移酶2（AGPAT2）和Berardinelli-Seip先天性脂肪营养不良2（BSCL2）；核纤层蛋白 A/C (LMNA)、过氧化物酶体增殖物激活受体-D (PPARG) 和常染色体显性 FPL 的 v-AKT 鼠胸腺瘤癌基因同源物 2 (AKT2)； LMNA 和锌金属蛋白酶 (ZMPSTE24) 已被鉴定用于治疗下颌骨发育不良相关的脂肪营养不良。然而，来自许多谱系的受影响受试者在这些基因中缺乏突变，这表明存在其他基因座。此外，许多与 SHORT 和新生儿早衰综合症相关的极其罕见的脂肪营养不良品种的遗传基础仍然未知。因此，该提案的首要目的是鉴定参与导致脂肪营养不良的脂肪细胞生物学、发育和分化的其他基因。我们的实验室还一直在体外或通过开发敲除小鼠模型来研究 AGPAT 的各种亚型（主要是 AGPAT1 和 2）的功能作用。 Agpat2-/-小鼠再现了人类CGL的许多特征，例如体脂极度缺乏、早发性高血糖、高胰岛素血症、高甘油三酯血症和肝脂肪变性。有趣的是，我们的研究表明，在这些无效小鼠中，饮食中的甘油三酯是导致肝脂肪变性的主要因素。 Agpatl-/- 小鼠也严重缺乏体脂，但详细的表型仍有待表征。此外，BSCL2编码蛋白seipin的生物学功能仍然未知，因此BSCL2突变如何导致脂肪营养不良仍然令人费解。因此，该提案的第二个目的是进一步表征Agpat2-/-和Agpatl-/-小鼠，并开发Bscl2敲除小鼠模型，以深入了解与广泛性脂肪营养不良有关的各种基因的生物学作用，并了解因果关系中涉及的分子机制胰岛素抵抗及其相关疾病的研究。