磷脂酶A/酰基转移酶3（PLAAT3）缺失会导致PPARγ信号传导受损，从而引发脂肪营养不良和神经系统综合征，这一成果由比利时根特大学医院Bart Dermaut团队经过不懈努力而取得。该项研究成果发表在2023年11月2日出版的《自然-遗传学》上。

研究人员从四个无血缘关系的近亲家庭中发现了七名患者，他们都有PLAAT3的同源功能缺失变异，表现为脂肪营养不良综合征，具有部分到全身不等的脂肪损失，并伴有代谢并发症，以及不同的神经系统特征，包括脱髓鞘神经病变和智力障碍。对小鼠Plaat3^-/-和患者衍生的白色脂肪组织（WAT）进行的多组学分析发现，这些样品具有含花生四烯酸的膜磷脂富集、过氧化物酶体增殖激活受体γ（PPARγ）信号转导强烈下降，而PPARγ是脂肪细胞分化的主要调节因子。

因此，CRISPR-Cas9介导的人脂肪干细胞PLAAT3失活诱导产生胰岛素抵抗，改变了脂肪细胞的分化，减少了脂滴的形成，并降低了成脂和成熟脂肪细胞标志物（包括PPARγ）的表达。这些发现表明PLAAT3缺乏症是一种遗传性脂肪营养不良综合征，具有神经系统表现，其是由PPARγ依赖性脂肪细胞分化和功能缺陷造成。

据介绍，PLAAT3是一种主要在神经和WAT中表达的磷脂修饰酶。它是代谢综合征的潜在治疗靶点，因为小鼠缺失Plaat3可防止饮食引起的肥胖。

附：英文原文

Title: Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling

Author: Schuermans, Nika, El Chehadeh, Salima, Hemelsoet, Dimitri, Gautheron, Jrmie, Vantyghem, Marie-Christine, Nouioua, Sonia, Tazir, Meriem, Vigouroux, Corinne, Auclair, Martine, Bogaert, Elke, Dufour, Sara, Okawa, Fumiya, Hilbert, Pascale, Van Doninck, Nike, Taquet, Marie-Caroline, Rosseel, Toon, De Clercq, Griet, Debackere, Elke, Van Haverbeke, Carole, Cherif, Ferroudja Ramdane, Urtizberea, Jon Andoni, Chanson, Jean-Baptiste, Funalot, Benoit, Authier, Franois-Jrme, Kaya, Sabine, Terryn, Wim, Callens, Steven, Depypere, Bernard, Van Dorpe, Jo, Poppe, Bruce, Impens, Francis, Mizushima, Noboru, Depienne, Christel, Jru, Isabelle, Dermaut, Bart

Issue&Volume: 2023-11-02

Abstract: Phospholipase A/acyltransferase 3 (PLAAT3) is a phospholipid-modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome, as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3/ and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipocyte differentiation. Accordingly, CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function.

DOI: 10.1038/s41588-023-01535-3

Source: https://www.nature.com/articles/s41588-023-01535-3