Calcyphosine-like (CAPSL) is regulated in Multiple Symmetric Lipomatosis and is involved in Adipogenesis
Calcyphosine-like (CAPSL) is regulated in Multiple Symmetric Lipomatosis and is involved in Adipogenesis
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DOI：
10.1038/s41598-019-44382-1
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发表时间：
2019-06-11
影响因子：
4.6
通讯作者：
Schreml, Julia
中科院分区：
文献类型：
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作者：
Lindner, Angie;Marbach, Felix;Schreml, Julia
关于脂肪组织疾病（家族性）多发性对称性脂肪增多症（MSL）的病因和发病机制知之甚少。在一个四代的MSL家族中，我们对3个受影响的个体和1个专性携带者进行了全外显子组测序（WES），并将钙调素样（CAPSL）确定为该家族最有希望的候选基因。21名独立患者的筛选排除了CAPSL编码序列变异作为常见的单基因病因，但使用免疫组化，我们发现CAPSL不仅在索引患者的脂肪组织中下调，而且在10名独立的散发性MSL患者中下调。这表明CAPSL在散发性MSL中受到调节，而与潜在的遗传/多因素原因无关。此外，我们培养了来自MSL患者的前脂肪细胞，并产生了基于3 T3-L1的Capsl敲除和过表达细胞模型，其显示出改变的自噬、脂肪生成、脂肪生成和Sirtuin-1（SIRT 1）表达。CAPSL似乎参与脂肪细胞生物学，自噬的扰动是MSL发病机制中的潜在机制。CAPSL的下调和UCP 1的上调是MSL脂肪的共同特征，而已知的MSL基因MFN 2和LIPE没有显示出一致的改变。CAPSL免疫染色可以作为MSL临床护理的第一诊断工具，有可能改善诊断时间和医疗保健选择。
Little is known on the causes and pathogenesis of the adipose tissue disorder (familial) Multiple Symmetric Lipomatosis (MSL). In a four-generation MSL-family, we performed whole exome sequencing (WES) in 3 affected individuals and 1 obligate carrier and identified Calcyphosine-like (CAPSL) as the most promising candidate gene for this family. Screening of 21 independent patients excluded CAPSL coding sequence variants as a common monogenic cause, but using immunohistochemistry we found that CAPSL was down-regulated in adipose tissue not only from the index patient but also in 10 independent sporadic MSL-patients. This suggests that CAPSL is regulated in sporadic MSL irrespective of the underlying genetic/multifactorial cause. Furthermore, we cultivated pre-adipocytes from MSL-patients and generated 3T3-L1-based Capsl knockout and overexpressing cell models showing altered autophagy, adipogenesis, lipogenesis and Sirtuin-1 (SIRT1) expression. CAPSL seems to be involved in adipocyte biology and perturbation of autophagy is a potential mechanism in the pathogenesis of MSL. Downregulation of CAPSL and upregulation of UCP1 were common features in MSL fat while the known MSL genes MFN2 and LIPE did not show consistent alterations. CAPSL immunostainings could serve as first diagnostic tools in MSL clinical care with a potential to improve time to diagnosis and healthcare options.