ArticleNature communications2022
Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
What it found
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Who cites it
15 citing papers in PubMed, 22 citations in OpenAlex.
- Hepatic translational rewiring in insulin deficiency identifies Reg3α as an insulin-independent glucoregulatory factor.Endocrinology · 2026Article
- A Nutrient-Sensitive ZRF1-Dependent Secretory Network Involving S100A9 Contributes to Neutrophil Plasticity in Triple-Negative Breast Cancer.ACS pharmacology & translational science · 2026Article
- Exploring the mechanism of endothelial Pim-1 upregulation of tissue factor to initiate the hypercoagulable state in sepsis.Molecular medicine (Cambridge, Mass.) · 2026Article
- Harnessing Distinct Tissue-Resident Immune Niches via S100A9/TLR4 Improves Ketone, Lipid, and Glucose Metabolism.Endocrinology · 2025Article
- Neutrophil Mobilization Triggers Microglial Functional Change to Exacerbate Cerebral Ischemia-Reperfusion Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Spontaneous and pharmacologically induced hypothermia protect mice against endotoxic shock.British journal of pharmacology · 2025Article
- TARGETING S100A9-TLR2 AXIS CONTROLS MACROPHAGE NLRP3 INFLAMMASOME ACTIVATION IN FATTY LIVER ISCHEMIA REPERFUSION INJURY.Shock (Augusta, Ga.) · 2025Article
- Potential diagnostic markers and therapeutic targets for DM2 and periodontitis based on bioinformatics analysis.PloS one · 2025Article
- Atractylenolide-I restore intestinal barrier function by targeting the S100A9/AMPK/mTOR signaling pathway.Frontiers in pharmacology · 2025Article
- Advances in the study of S100A9 in cardiovascular diseases.Cell proliferation · 2024Review
- mTOR: Its Critical Role in Metabolic Diseases, Cancer, and the Aging Process.International journal of molecular sciences · 2024Review
- Polyploidy and mTOR signaling: a possible molecular link.Cell communication and signaling : CCS · 2024Review
- MDSC-derived S100A8/9 contributes to lupus pathogenesis by promoting TLR7-mediated activation of macrophages and dendritic cells.Cellular and molecular life sciences : CMLS · 2024Article
- S100A9 exerts insulin-independent antidiabetic and anti-inflammatory effects.Science advances · 2024Article
- Hepatocyte Toll-Like Receptor 4 Mediates Alcohol-Induced Insulin Resistance in Mice.Biomolecules · 2023Article
Corrections and comments
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Authors and funding
21 authors at 4 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.