Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis

Gloria Ursino, Giorgio Ramadori, Anna Höfler, Soline Odouard, Pryscila D.S. Teixeira, Florian Visentin, Christelle Veyrat-Durebex, Giulia Lucibello, Raquel Firnkes, Serena Ricci, Claudia R. Vianna, Lin Jia, Mirjam Dirlewanger, Philippe Klee, Joel K. Elmquist, Johannes Roth, Thomas Vogl, Valérie M. Schwitzgebel, François R. Jornayvaz, Andreas BolandRoberto Coppari

Research output: Contribution to journalArticlepeer-review

Abstract

Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis. By generating insulin deficient male mice lacking or re-expressing Toll-Like Receptor 4 (TLR4) only in liver or hepatocytes, we demonstrate that hepatic TLR4 in non-parenchymal cells mediates the ketogenesis-suppressing action of S100A9. Mechanistically, S100A9 acts extracellularly to activate the mechanistic target of rapamycin complex 1 (mTORC1) in a TLR4-dependent manner. Accordingly, hepatic-restricted but not hepatocyte-restricted loss of Tuberous Sclerosis Complex 1 (TSC1, an mTORC1 inhibitor) corrects insulin-deficiency-induced hyperketonemia. Therapeutically, recombinant S100A9 administration restrains ketogenesis and improves hyperglycemia without causing hypoglycemia in diabetic mice. Also, circulating S100A9 in patients with ketoacidosis is only marginally increased hence unveiling a window of opportunity to pharmacologically augment S100A9 for preventing unrestrained ketogenesis. In summary, our findings reveal the hepatic S100A9-TLR4-mTORC1 axis in non-parenchymal cells as a promising therapeutic target for restraining diabetic ketogenesis.

Original languageEnglish (US)
Article number4107
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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