Genetic and Metabolic Basis of Familial Lipodystrophies

家族性脂肪营养不良的遗传和代谢基础

• 批准号: 7992512
• 负责人: Abhimanyu Garg
• 金额: $ 9.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992512
• 关键词: 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; 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

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(申请人提供)：肥胖在美国仍然是一个主要的健康问题，并会导致代谢并发症，如糖尿病、血脂异常和胰岛素抵抗。类似的并发症也发生在家族性脂营养不良的患者中，单基因疾病的特征是部分(家族性部分脂营养不良，FPL)或几乎完全(先天性全身性脂营养不良，CGL)缺乏体脂。近年来，与常染色体隐性遗传性CGL相关的基因有1-酰基甘油-3-磷酸O-酰基转移酶2(AGPAT2)和Berardinelli-Seip先天性脂营养不良症2(BSCL2)；与常染色体显性脂肪营养不良相关的LMNA(lamin A/C)、过氧化物酶体增殖物激活受体D(PPARG)和v-AKT小鼠胸腺瘤癌基因同源物2(AKT2)；与下颌骨发育不良相关的脂营养不良症的LMNA和锌金属蛋白酶(ZMPSTE24)。然而，来自许多家系的受影响受试者在这些基因中缺乏突变，表明存在额外的基因座。此外，许多极罕见的脂肪营养不良与短和新生儿黄体综合征相关的遗传基础仍不清楚。因此，这项建议的第一个目的是确定与脂肪细胞生物学、发育和分化有关的导致脂肪营养不良的额外基因(S)。我们的实验室也一直在体外或通过建立基因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-/-小鼠复制了许多人类CGL的特征，如极度缺乏体脂、早发性高血糖、高胰岛素血症、高甘油三酯血症和肝脏脂肪变性。有趣的是，我们的研究表明，在这些空白小鼠中，饮食中的甘油三酯是肝脏脂肪变性的主要贡献者。Agpatl-/-小鼠也严重缺乏体脂，但具体表型尚不清楚。此外，BSCL2编码的蛋白质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困惑。因此，这项建议的第二个目的是进一步研究AGPAT2-/-和Agpat1-/-小鼠的特征，并建立Bscl2基因敲除小鼠模型，以深入了解各种基因在全身性脂肪营养不良中的生物学作用，并了解胰岛素抵抗及其相关疾病的分子机制。