SREBF1 plays the central role in lipid metabolism. It has been known that full-length SREBF1 that did not associate with SCAP (SCAP-free SREBF1) is actively degraded, but its molecular mechanism and its biological meaning remain unclear. ARMC5–CUL3 complex was recently identified as E3 ubiquitin ligase of full-length SREBF. Although ARMC5 was involved in SREBF pathway in adrenocortical cells, the role of ARMC5 in adipocytes has not been investigated. In this study, adipocyte-specific Armc5 KO mice were generated. In the white adipose tissue of these mice, all the stearoyl-CoA desaturase (Scd) were drastically downregulated. Consistently, unsaturated fatty acids were decreased and saturated fatty acids were increased. The protein amount of full-length SREBF1 was increased, but ATAC-Seq peaks at the SREBF1-binding sites were markedly diminished around the Scd1 locus in the WAT of Armc5 KO mice. Armc5-deficient 3T3-L1 adipocytes also exhibited downregulation of Scd. Mechanistically, disruption of Armc5 restored decreased full-length SREBF1 in CHO cells deficient for Scap. Overexpression of Scap inhibited ARMC5-mediated degradation of full-length SREBF1, and overexpression of Armc5 increased nuclear SREBF1/full-length SREBF1 ratio and SREBF1 transcriptional activity in the presence of exogenous SCAP. These results demonstrated that ARMC5 selectively removes SCAP-free SREBF1 and stimulates SCAP-mediated SREBF1 processing, hence is essential for fatty acid desaturation in vivo.

中文翻译：

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ARMC5 选择性降解无 SCAP 的 SREBF1，对脂肪细胞中的脂肪酸去饱和至关重要


SREBF1 在脂质代谢中起着核心作用。众所周知，与 SCAP 无关的全长 SREBF1 （SCAP-free SREBF1） 正在主动降解，但其分子机制和生物学意义仍不清楚。ARMC5-CUL3 复合物最近被鉴定为全长 SREBF 的 E3 泛素连接酶。尽管 ARMC5 参与肾上腺皮质细胞中的 SREBF 通路，但尚未研究 ARMC5 在脂肪细胞中的作用。在这项研究中，产生了脂肪细胞特异性 Armc5 KO 小鼠。在这些小鼠的白色脂肪组织中，所有硬脂酰辅酶 A 去饱和酶 （Scd） 都急剧下调。一致地，不饱和脂肪酸减少，饱和脂肪酸增加。在 Armc5 KO 小鼠的 WAT 中，全长 SREBF1 蛋白质量增加，但 SREBF1 结合位点处 SREBF1 结合位点的 ATAC-Seq 峰显著减少。Armc5 缺陷的 3T3-L1 脂肪细胞也表现出 Scd 的下调。从机制上讲，Armc5 的破坏恢复了 Scap 缺陷的 CHO 细胞中全长 SREBF1 的降低。Scap 的过表达抑制了 ARMC5 介导的全长 SREBF1 降解，在外源性 SCAP 存在下，Armc5 的过表达增加了核 SREBF1/全长 SREBF1 比率和 SREBF1 转录活性。这些结果表明，ARMC5 选择性地去除无 SCAP 的 SREBF1 并刺激 SCAP 介导的 SREBF1 加工，因此对体内脂肪酸去饱和 至关重要。