Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 May;1864(5):715-732. doi: 10.1016/j.bbalip.2019.02.002. Epub 2019 Feb 8.
Monogenic lipodystrophies are a heterogeneous group of rare disorders characterized by a lack of adipose tissue (AT), all of which predispose patients to the development of insulin resistance and its related metabolic sequelae. The extent of AT loss ranges from partial, as in familial partial lipodystrophy (FPLD), to a total absence of metabolically active AT in congenital generalized lipodystrophy (CGL) and is generally associated with the severity of metabolic complications. Significant genetic, allelic, phenotypic, and clinical heterogeneity exists among the lipodystrophies. Patients with FPLD3 due to mutations in the PPARG gene, which encodes a key transcriptional regulator of adipocyte development and function, provide a particularly striking example of this heterogeneity. We will present several gene-gene and gene-environment factors and mechanisms that are critical for adequate PPARγ expression and activity in AT and discuss how these interactions potentially contribute to the observed spectrum of FPLD3 phenotypes. Comparable mechanisms may play a role in other types of lipodystrophies too, and their elucidation may further improve our molecular understanding of AT dysfunction.
单基因脂肪营养不良是一组罕见疾病，其特征为脂肪组织（AT）缺失，所有这些疾病都使患者易发生胰岛素抵抗及其相关代谢后果。AT 丧失的程度从部分缺失（如家族性部分脂肪营养不良（FPLD））到先天性全身性脂肪营养不良（CGL）中代谢活跃的 AT 完全缺失不等，且通常与代谢并发症的严重程度相关。脂肪营养不良症存在显著的遗传、等位基因、表型和临床异质性。由于编码脂肪细胞发育和功能的关键转录调节剂的 PPARG 基因突变导致的 FPLD3 患者，提供了这种异质性的一个特别显著的例子。我们将介绍几个对 AT 中 PPARγ表达和活性至关重要的基因-基因和基因-环境因素和机制，并讨论这些相互作用如何可能导致观察到的 FPLD3 表型谱。类似的机制可能在其他类型的脂肪营养不良症中也起作用，阐明这些机制可能进一步提高我们对 AT 功能障碍的分子理解。
