AGMO inhibitor reduces 3T3-L1 adipogenesis

  • Alkylglycerol monooxygenase (AGMO) is a tetrahydrobiopterin (BH4)-dependent enzyme with major expression in the liver and white adipose tissue that cleaves alkyl ether glycerolipids. The present study describes the disclosure and biological characterization of a candidate compound (Cp6), which inhibits AGMO with an IC50 of 30–100 µM and 5–20-fold preference of AGMO relative to other BH4-dependent enzymes, i.e., phenylalanine-hydroxylase and nitric oxide synthase. The viability and metabolic activity of mouse 3T3-L1 fibroblasts, HepG2 human hepatocytes and mouse RAW264.7 macrophages were not affected up to 10-fold of the IC50. However, Cp6 reversibly inhibited the differentiation of 3T3-L1 cells towards adipocytes, in which AGMO expression was upregulated upon differentiation. Cp6 reduced the accumulation of lipid droplets in adipocytes upon differentiation and in HepG2 cells exposed to free fatty acids. Cp6 also inhibited IL-4-driven differentiation of RAW264.7 macrophages towards M2-like macrophages, which serve as adipocyte progenitors in adipose tissue. Collectively, the data suggest that pharmacologic AGMO inhibition may affect lipid storage.

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Author:Caroline Fischer, Annett Wilken-Schmitz, Victor Hernandez-OlmosORCiD, Ewgenij ProschakORCiDGND, Holger StarkORCiDGND, Ingrid FlemingORCiD, Andreas WeigertORCiDGND, Manuela Thurn, Martine HofmannORCiD, Ernst R. Werner, Gerd GeisslingerORCiDGND, Ellen Niederberger, Katrin WatschingerORCiD, Irmgard TegederORCiD
Parent Title (English):Cells
Place of publication:Basel
Document Type:Article
Date of Publication (online):2021/05/01
Date of first Publication:2021/05/01
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/08/18
Tag:macrophage polarization
3T3-L1 mouse fibroblasts; AGMO; adipocytes; compound screen; enzyme activity assay; tetrahydrobiopterin
Issue:5, art. 1081
Page Number:20
First Page:1
Last Page:20
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0