Badralmaa Yunden, Natarajan Ven
Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
J Biol Chem. 2025 Jan;301(1):108057. doi: 10.1016/j.jbc.2024.108057. Epub 2024 Dec 9.
Obesity is one of the main clinical characteristics associated with the heterogeneous genetic disorder Bardet-Biedl syndrome (BBS). Leucine zipper transcription factor like 1 (LZTFL1) is a member of the BBS gene family. Our work showed that Lztfl1knockout (LZKO) mice display the obesity phenotype as early as 3 months of age. Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into various cell types, including adipocytes. To understand the role of LZTFL1 in adipogenesis, we analyzed MSCs isolated from LZKO mouse compact bones (CB-MSCs). Compared to wildtype (WT), LZKO CB-MSCs had elongated primary cilia with tapered tips and increased levels of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor that favors adipogenesis, and nuclear glucocorticoid receptor (GR), a transcription factor involved in Pparg activation. Also, LZKO CB-MSCs had a lower level of total β-catenin, a core factor of the antiadipogenic canonical Wnt/b-catenin signaling pathway involved in limiting the nuclear localization of GR. Interaction between caveolin1 (CAV1) and LRP6, the main receptor for canonical Wnt signaling, is known to be critical for Wnt pathway activation and β-catenin stabilization. Compared to WT cells, LZKO cells had elevated total, cell-surface, and lipid-raft-associated LRP6 and reduced CAV1, strongly indicating alterations in the components of the Wnt-signaling pathway. We show that in the absence of LZTFL1, adipogenesis-restraining Wnt/β-catenin signaling is inhibited, and adipogenesis-favorable factors are stimulated in CB-MSCs, leading to enhanced adipogenesis. Evidence provided here could help in understanding the mechanism and molecular basis of obesity in LZTFL1-defective patients.
肥胖是与异质性遗传疾病巴德-比埃尔综合征（BBS）相关的主要临床特征之一。亮氨酸拉链转录因子样1（LZTFL1）是BBS基因家族的成员。我们的研究表明，Lztfl1基因敲除（LZKO）小鼠早在3月龄时就表现出肥胖表型。间充质干细胞（MSC）是多能干细胞，可分化为包括脂肪细胞在内的多种细胞类型。为了解LZTFL1在脂肪生成中的作用，我们分析了从LZKO小鼠致密骨中分离出的间充质干细胞（CB-MSC）。与野生型（WT）相比，LZKO CB-MSC的初级纤毛伸长且尖端变细，过氧化物酶体增殖物激活受体γ（PPARγ，一种促进脂肪生成的关键转录因子）和核糖皮质激素受体（GR，一种参与Pparg激活的转录因子）水平升高。此外，LZKO CB-MSC的总β-连环蛋白水平较低，β-连环蛋白是抗脂肪生成的经典Wnt/β-连环蛋白信号通路的核心因子，参与限制GR的核定位。已知小窝蛋白1（CAV1）与经典Wnt信号的主要受体低密度脂蛋白受体相关蛋白6（LRP6）之间的相互作用对于Wnt通路激活和β-连环蛋白稳定至关重要。与WT细胞相比，LZKO细胞的总LRP6、细胞表面LRP6和脂筏相关LRP6水平升高，而CAV1水平降低，这强烈表明Wnt信号通路的成分发生了改变。我们发现，在缺乏LZTFL1的情况下，抑制脂肪生成的Wnt/β-连环蛋白信号受到抑制，而促进脂肪生成的因子在CB-MSC中受到刺激，导致脂肪生成增强。本文提供的证据有助于理解LZTFL1缺陷患者肥胖的机制和分子基础。
