Uota Akifumi, Okuno Yosuke, Fukuhara Atsunori, Sasaki Shugo, Kobayashi Sachiko, Shimomura Iichiro
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
J Biol Chem. 2024 Dec;300(12):107953. doi: 10.1016/j.jbc.2024.107953. Epub 2024 Nov 2.
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.
SREBF1在脂质代谢中起核心作用。已知未与SCAP结合的全长SREBF1（无SCAP的SREBF1）会被主动降解，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途径，但ARMC5在脂肪细胞中的作用尚未得到研究。在本研究中，生成了脂肪细胞特异性Armc5基因敲除小鼠。在这些小鼠的白色脂肪组织中，所有的硬脂酰辅酶A去饱和酶（Scd）都大幅下调。相应地，不饱和脂肪酸减少，饱和脂肪酸增加。全长SREBF1的蛋白量增加，但在Armc5基因敲除小鼠的白色脂肪组织中，Scd1基因座周围SREBF1结合位点的ATAC-Seq峰明显减少。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的减少。Scap的过表达抑制了ARMC5介导的全长SREBF1的降解，并且在存在外源性SCAP的情况下，Armc5的过表达增加了核SREBF1/全长SREBF1的比率和SREBF1的转录活性。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，因此对于体内脂肪酸去饱和至关重要。
