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Ludzki, A.C.* ; Hansen, M.* ; Zareifi, D.* ; Jalkanen, J.* ; Huang, Z.* ; Omar-Hmeadi, M.* ; Renzi, G.* ; Klingelhuber, F. ; Boland, S.* ; Ambaw, Y.A.* ; Wang, N.* ; Damdimopoulos, A.E.* ; Liu, J.* ; Jernberg, T.* ; Petrus, P.* ; Arner, P.* ; Krahmer, N. ; Fan, R.* ; Treuter, E.* ; Gao, H.* ; Rydén, M.* ; Mejhert, N.*

Transcriptional determinants of lipid mobilization in human adipocytes.

Sci. Adv. 10:eadi2689 (2024)
DOI PMC
Creative Commons Lizenzvertrag
Defects in adipocyte lipolysis drive multiple aspects of cardiometabolic disease, but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human adipocytes. Our analyses identified 37 transcriptional regulators of lipid mobilization, which we classified as (i) transcription factors, (ii) histone chaperones, and (iii) mRNA processing proteins. On the basis of its strong relationship with multiple readouts of lipolysis in patient samples, we performed mechanistic studies on one hit, ZNF189, which encodes the zinc finger protein 189. Using mass spectrometry and chromatin profiling techniques, we show that ZNF189 interacts with the tripartite motif family member TRIM28 and represses the transcription of an adipocyte-specific isoform of phosphodiesterase 1B (PDE1B2). The regulation of lipid mobilization by ZNF189 requires PDE1B2, and the overexpression of PDE1B2 is sufficient to attenuate hormone-stimulated lipolysis. Thus, our work identifies the ZNF189-PDE1B2 axis as a determinant of human adipocyte lipolysis and highlights a link between chromatin architecture and lipid mobilization.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adipose Triglyceride Lipase; Hormone-sensitive Lipase; Chromatin-structure; Gene-expression; Lipolysis; Fat; Cell; Promotes; Isoform; Package
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Journal Science Advances
Quellenangaben Volume: 10, Issue: 1, Pages: , Article Number: eadi2689 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC [u.a.]
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Grants Novo Nordisk Postdoctoral fellowship
DFG Emmy Noether
DFG BAtenergy
EFSN/Lilly research fellowship
ERC- SyG SPHERES
European Foundation
Knut & Alice Wallenberg's Foundation
Margareta af Uggla's Foundation
NovoNordisk Foundation MeRIAD
NovoNordisk Foundation
Stockholm County Council
Strategic Research Program in Diabetes at Karolinska Institutet
Swedish Diabetes Foundation
Swedish Research Council
CIMED