College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China; Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA; Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou, China.
J Biol Chem. 2022 Oct;298(10):102339. doi: 10.1016/j.jbc.2022.102339. Epub 2022 Aug 2.
Family with sequence similarity 83 A (FAM83A) is a newly discovered proto-oncogene that has been shown to play key roles in various cancers. However, the function of FAM83A in other physiological processes is not well known. Here, we report a novel function of FAM83A in adipocyte differentiation. We used an adipocyte-targeting fusion oligopeptide (FITC-ATS-9R) to deliver a FAM83A-sgRNA/Cas9 plasmid to knockdown Fam83a (ATS/sg-FAM83A) in white adipose tissue in mice, which resulted in reduced white adipose tissue mass, smaller adipocytes, and mitochondrial damage that was aggravated by a high-fat diet. In cultured 3T3-L1 adipocytes, we found loss or knockdown of Fam83a significantly repressed lipid droplet formation and downregulated the expression of lipogenic genes and proteins. Furthermore, inhibition of Fam83a decreased mitochondrial ATP production through blockage of the electron transport chain, associated with enhanced apoptosis. Mechanistically, we demonstrate FAM83A interacts with casein kinase 1 (CK1) and promotes the permeability of the mitochondrial outer membrane. Furthermore, loss of Fam83a in adipocytes hampered the formation of the TOM40 complex and impeded CK1-driven lipogenesis. Taken together, these results establish FAM83A as a critical regulator of mitochondria maintenance during adipogenesis.
家族性序列相似性 83A（FAM83A）是一种新发现的原癌基因，已被证明在多种癌症中发挥关键作用。然而，FAM83A 在其他生理过程中的功能尚不清楚。在这里，我们报告了 FAM83A 在脂肪细胞分化中的一个新功能。我们使用脂肪细胞靶向融合寡肽（FITC-ATS-9R）将 FAM83A-sgRNA/Cas9 质粒递送到小鼠白色脂肪组织中以敲低 Fam83a（ATS/sg-FAM83A），导致白色脂肪组织质量减少、脂肪细胞变小和线粒体损伤，高脂肪饮食加重了这种损伤。在培养的 3T3-L1 脂肪细胞中，我们发现 Fam83a 的缺失或敲低显着抑制了脂滴形成，并下调了脂肪生成基因和蛋白的表达。此外，抑制 Fam83a 通过阻断电子传递链减少线粒体 ATP 产生，与增强的细胞凋亡相关。在机制上，我们证明 FAM83A 与酪蛋白激酶 1（CK1）相互作用并促进线粒体外膜的通透性。此外，脂肪细胞中 Fam83a 的缺失阻碍了 TOM40 复合物的形成，并阻碍了 CK1 驱动的脂肪生成。总之，这些结果确立了 FAM83A 作为脂肪生成过程中线粒体维持的关键调节剂。
