1. Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis.
- Author
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Ursino, Gloria, Ramadori, Giorgio, Höfler, Anna, Odouard, Soline, Teixeira, Pryscila D. S., Visentin, Florian, Veyrat-Durebex, Christelle, Lucibello, Giulia, Firnkes, Raquel, Ricci, Serena, Vianna, Claudia R., Jia, Lin, Dirlewanger, Mirjam, Klee, Philippe, Elmquist, Joel K., Roth, Johannes, Vogl, Thomas, Schwitzgebel, Valérie M., Jornayvaz, François R., and Boland, Andreas
- Subjects
HYPERGLYCEMIA ,TUBEROUS sclerosis ,INSULIN therapy ,TOLL-like receptors ,KETOACIDOSIS ,DIABETES complications - 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. Excess ketogenesis can lead to ketoacidosis, a serious complication in patients with diabetes. Here the authors report an insulin independent pathway, the hepatic nonparenchymal S100A9-TLR4-mTORC1 axis, that is able to normalize diabetic ketogenesis and pre-clinical data to suggest potential for development of S100A9 based adjunctive therapy to insulin. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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