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. 2022 Jun 8;606(7916):968–975. doi: 10.1038/s41586-022-04787-x

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — a, Left, biosynthesis of 9-OAHSA in vitro by affinity-purified WT ATGL-288 (ATGL) and the cofactor CGI-58 from 9-HSA and acyl-donor TG(18:1) and inhibition with atglistatin (50 µM). Right, inhibition of the transacylation activity of affinity-purified full-length ATGL (ATGL_full) by the indicated doses of atglistatin. b, c, WT ATGL-288 catalysed biosynthesis of 9-C17:1HSA from 9-HSA and acyl donors TG(C17:1) and C17:1(FFA) (b) and biosynthesis of 9-PA-D₂₀HSA and 9-OA-D₂₀HSA from D₂₀-9-HSA and acyl donor TG(C16:0/18:1/18:1) (c). d, WT ATGL-288 and ATGL-288(S47A) transacylation activity catalysed 9-FAHFA biosynthesis from acyl donors: TG(18:2), TG(16:1), TG(18:1), DG(C18:1/18:1/0:0), phosphatidylcholine (PC(18:1/18:1/0:0)) and 18:1-CoA. e, Lipase activity of WT ATGL-288 (ATGL) and ATGL-288(S47A) enzymes as measured by OA release during the FAHFA biosynthesis assay with the substrate TG(18:1) in d. f, 9-OAHSA biosynthesis from TG(18:1) and D₂₀-9-HSA in human SQ WAT lysates. g, 9-FAHFA biosynthesis in human SVF adipocytes incubated with D₂₀-9-HSA or vehicle (0.025% DMSO). (n = 3, mean ± s.e.m. a–g), *P < 0.0001 versus no enzyme, #P < 0.0001 versus ATGL/CGI-58 and @P < 0.0001 versus ATGL (one-way ANOVA, a, d). $P < 0.02, $$P < 0.008 versus no enzyme (t-test, two-tailed c). AT-Atgl-KO and littermate Atgl^fl/fl female mice were used for h–v. h–k, Total endogenous PAHSA (h) and PAHSA isomer levels in SQ WAT (i), PG WAT (j), BAT (k), liver (l) and serum (m). n–q, Total TG-esterified PAHSA (n) and TG-esterified PAHSA isomer levels in SQ WAT (o), PG WAT (p) and liver (q). r, Adipose tissue and liver total triglyceride levels. AT-Atgl-KO and Atgl^fl/fl mice were injected with D₂₀-9-HSA (5 mg kg⁻¹) intraperitoneally and euthanized 4 h later (s–v). s, PG WAT, liver and serum levels of newly synthesized 9-PA-D₂₀HSA. t–v, 9-PA-D₂₀HSA enrichment (9-PA-D₂₀HSA per cent of total 9-PAHSA) (t), levels of newly synthesized TG-esterified 9-PA-D₂₀HSA (u), endogenous HSA substrate level (v, left) and enrichment of D₂₀-9-HSA (v, right) in PG WAT. n = 6 mice for all tissues in h–r; n = 5 mice for serum in h, m and s–v; mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus Atgl^fl/fl mice t-test, two-tailed (h–v). White error bars are shown within the bars in o, p. Only levels above the quantification limit are shown with white circles.

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