Unit of Bologna, CNR-National Research Council of Italy, Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", 40136 Bologna, Italy.
IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
Cells. 2023 Nov 7;12(22):2586. doi: 10.3390/cells12222586.
Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient's neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies.
2 型家族性部分脂肪营养不良（FPLD2）是一种罕见的脂肪营养不良，由基因突变引起，其特征是躯干和四肢的皮下脂肪丧失，颈部和面部脂肪组织过度积聚。几项研究表明，盐皮质激素受体（MR）在脂肪组织分化和功能中发挥着重要作用。我们之前曾报道过，从 FPLD2 患者颈部分离出的棕色前体细胞异常分化为白色谱系。由于这种情况可能与 MR 激活有关，我们怀疑 FPLD2 中的 MR 动力学发生改变。尽管对照棕色脂肪细胞的细胞质 MR 定位，但在 FPLD2 棕色脂肪细胞核中观察到 MR 的保留。此外，野生型或突变型前纤层蛋白 A 的过表达导致 GFP-MR 募集到 HEK293 细胞的核膜，而药物诱导的前纤层蛋白 A 在人前体细胞中与内源性 MR 共定位。基于计算机分析和原位蛋白连接测定，我们可以推测前纤层蛋白 A 和 MR 之间存在相互作用，这种相互作用似乎被盐皮质激素受体拮抗剂抑制。重要的是，MR 拮抗剂螺内酯将 FPLD2 前体细胞分化为棕色谱系，避免形成增大和畸形的脂滴。最后，在接受螺内酯治疗的 FPLD2 患者中观察到棕色脂肪组织活性的有益影响。这些发现将 MR 鉴定为新的 lamin A 相互作用蛋白和 lamin A 相关脂肪营养不良的新参与者。
