Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation
Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation
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DOI：
10.1038/s41598-020-59982-5
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发表时间：
2020-02-24
影响因子：
4.6
通讯作者：
Rochford, Justin J.
中科院分区：
文献类型：
--
作者：
Sim, M. F. Michelle;Persiani, Elisa;Rochford, Justin J.
Seipin缺乏导致严重的先天性全身性脂肪营养不良（CGL）和代谢疾病。然而，seipin如何调节脂肪细胞的发育和功能仍不完全清楚。我们之前的研究表明，seipin作为AGPAT2的支架蛋白，其破坏也会导致CGL。最近，有报道称seipin通过直接抑制GPAT3促进脂肪形成，这提示GPAT抑制剂可能为CGL提供新的治疗方法。本文研究了seipin与GPAT3和AGPAT2之间的相互作用。我们发现seipin和GPAT3通过直接相互作用结合，并且seipin可以同时结合GPAT3和AGPAT2。抑制seipin、AGPAT2或GPAT3的表达导致培养细胞中脂肪细胞分化早期标志物的诱导受损。然而，与GPAT3缺失小鼠的正常脂肪量一致，GPAT3抑制并未阻止成熟脂肪细胞的形成。尽管如此，缺乏sepin的前脂肪细胞中GPAT3的缺失加剧了这些细胞中脂肪形成的失败。因此，我们的数据表明GPAT3在脂肪形成中发挥适度的积极作用，并反对GPAT抑制剂在CGL2中挽救白色脂肪组织块的潜力。总的来说，我们的研究揭示了由seipin或AGPAT2突变引起的严重脂肪营养不良的分子发病机制。
Seipin deficiency causes severe congenital generalized lipodystrophy (CGL) and metabolic disease. However, how seipin regulates adipocyte development and function remains incompletely understood. We previously showed that seipin acts as a scaffold protein for AGPAT2, whose disruption also causes CGL. More recently, seipin has been reported to promote adipogenesis by directly inhibiting GPAT3, leading to the suggestion that GPAT inhibitors could offer novel treatments for CGL. Here we investigated the interactions between seipin, GPAT3 and AGPAT2. We reveal that seipin and GPAT3 associate via direct interaction and that seipin can simultaneously bind GPAT3 and AGPAT2. Inhibiting the expression of seipin, AGPAT2 or GPAT3 led to impaired induction of early markers of adipocyte differentiation in cultured cells. However, consistent with normal adipose mass in GPAT3-null mice, GPAT3 inhibition did not prevent the formation of mature adipocytes. Nonetheless, loss of GPAT3 in seipin-deficient preadipocytes exacerbated the failure of adipogenesis in these cells. Thus, our data indicate that GPAT3 plays a modest positive role in adipogenesis and argue against the potential of GPAT inhibitors to rescue white adipose tissue mass in CGL2. Overall, our study reveals novel mechanistic insights regarding the molecular pathogenesis of severe lipodystrophy caused by mutations in either seipin or AGPAT2.