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.
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http://dx.doi.org/10.1016/j.jbc.2024.107953 | DOI Listing |
J Biol Chem
November 2024
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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.
View Article and Find Full Text PDFJCI Insight
August 2022
Department of Metabolic Medicine and.
Inactivating mutations of ARMC5 are responsible for the development of bilateral macronodular adrenal hyperplasia (BMAH). Although ARMC5 inhibits adrenocortical tumor growth and is considered a tumor-suppressor gene, its molecular function is poorly understood. In this study, through biochemical purification using SREBF (SREBP) as bait, we identified the interaction between SREBF and ARMC5 through its Armadillo repeat.
View Article and Find Full Text PDFMol Cell Biochem
January 2020
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
Insulin stimulates de novo lipid synthesis in the liver and in cultured hepatocytes via its ability to activate sterol regulatory element-binding protein 1c (SREBP-1c). Although PI3K-AKT-mTORC1-p70S6K-signaling kinases are known to drive feed-forward expression of SREBP-1c, the identity of the phosphorylated amino acid residue(s) putatively involved in insulin-stimulated de novo lipogenesis remains elusive. We obtained in silico and mass spectrometry evidence, that was combined with siRNA strategies, to discover that insulin-induced phosphorylation of serine 418, serine 419, and serine 422 in rat SREBP-1c was most likely mediated by p70S6 kinase.
View Article and Find Full Text PDFJ Lipid Res
March 2015
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. Electronic address:
Cells produce two cholesteryl ester transfer protein (CETP) isoforms, full-length and a shorter variant produced by alternative splicing. Blocking synthesis of both isoforms disrupts lipid metabolism and storage. To further define the role of CETP in cellular lipid metabolism, we stably overexpressed full-length CETP in SW872 cells.
View Article and Find Full Text PDFExp Cell Res
December 2011
Laboratoire du Stress et Pathologies du Cytosquelette, Université Paris Diderot-Paris 7, CNRS, Institut de Biologie Fonctionnelle et Adaptative, 4 rue M.A. Lagroua Weill Halle, 75205 Paris cedex 13, France.
Lamins A and C are nuclear intermediate filament proteins expressed in most differentiated somatic cells. Previous data suggested that prelamin A, the lamin A precursor, accumulates in some lipodystrophy syndromes caused by mutations in the lamin A/C gene, and binds and inactivates the sterol regulatory element binding protein 1 (SREBP1). Here we show that, in vitro, the tail regions of prelamin A, lamin A and lamin C bind a polypeptide of SREBP1.
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