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Loft, A. ; Schmidt, S.F. ; Caratti, G.* ; Stifel, U.* ; Havelund, J.F.* ; Sekar, R. ; Kwon, Y. ; Sulaj, A.* ; Chow, K.K. ; Alfaro, A.J. ; Schwarzmayr, T. ; Rittig, N.* ; Svart, M.* ; Tsokanos, F.-F. ; Maida, A. ; Blutke, A. ; Feuchtinger, A. ; Møller, N.* ; Blüher, M. ; Nawroth, P.* ; Szendrödi, J.* ; Færgeman, N.J.* ; Zeigerer, A. ; Tuckermann, J.* ; Herzig, S.

A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis.

Cell Metab. 34, 473-486.e9 (2022)
DOI
Free by publisher: Publ. Version/Full Text online available 04/2023
Fasting metabolism and immunity are tightly linked; however, it is largely unknown how immune cells contribute to metabolic homeostasis during fasting in healthy subjects. Here, we combined cell-type-resolved genomics and computational approaches to map crosstalk between hepatocytes and liver macrophages during fasting. We identified the glucocorticoid receptor (GR) as a key driver of fasting-induced reprogramming of the macrophage secretome including fasting-suppressed cytokines and showed that lack of macrophage GR impaired induction of ketogenesis during fasting as well as endotoxemia. Mechanistically, macrophage GR suppressed the expression of tumor necrosis factor (TNF) and promoted nuclear translocation of hepatocyte GR to activate a fat oxidation/ketogenesis-related gene program, cooperatively induced by GR and peroxisome proliferator-activated receptor alpha (PPARα) in hepatocytes. Together, our results demonstrate how resident liver macrophages directly influence ketogenesis in hepatocytes, thereby also outlining a strategy by which the immune system can set the metabolic tone during inflammatory disease and infection.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Fasting ; Genomics ; Glucocorticoid Receptor ; Hepatocyte ; Ketogenesis ; Liver ; Macrophage ; Nuclear Receptor ; Transcripional Regulation ; Tumor Necrosis Factor; Necrosis-factor-alpha; Hepatic Steatosis; Acid Homeostasis; Gene-expression; Tnf-alpha; Liver; Cells; Gluconeogenesis; Suppression; Deficiency
ISSN (print) / ISBN 1550-4131
e-ISSN 1932-7420
Journal Cell Metabolism
Quellenangaben Volume: 34, Issue: 3, Pages: 473-486.e9 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
Institute of Human Genetics (IHG)
Research Unit Analytical Pathology (AAP)
Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Grants ProtrainU grant from Ulm University
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through the Collaborative Research Center (CRC)
Danish National Research Foundation (DNRF)
Novo Nordisk Foundation
Danish Independent Research Council | Medical Sciences
EMBO Long-Term Fellowship
DZD grant NEXT
EFSD/Lilly
Medical Faculty of Ulm University
German Research Foundation (DFG)