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

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.

Hepatocyte Toll-Like Receptor 4 Mediates Alcohol-Induced Insulin Resistance in Mice

“…To investigate the sufficiency of hepatocyte TLR4 in alcohol-induced insulin resistance, we used a mouse model that is conditionally null for TLR4 (Tlr4 LoxTB ) [ 24 ]. The utility of this mouse model has been widely tested [ 24 , 25 , 26 ]. To re-express Tlr4 selectively in hepatocytes, we crossed the Tlr4 LoxTB mice to Alb-Cre mice (Tlr4 LoxTB × Alb-Cre).…”

“…The generation and validation of Tlr4 fl/fl [ 19 , 22 , 23 ] and Tlr4 LoxTB [ 24 , 25 , 26 ] mice have been previously reported. Albumin-Cre transgenic mice (Alb-Cre, JAX:003574) were crossed with Tlr4 fl/fl animals to produce mice lacking TLR4 in hepatocytes (Tlr4 LKO ) [ 19 , 24 ].…”

MDSC-derived S100A8/9 contributes to lupus pathogenesis by promoting TLR7-mediated activation of macrophages and dendritic cells

“…However, we did not further investigate the mechanism by which S100A9 promotes IFN-γ secretion in Mφ, but continued to investigate the effect of IFN-γ on TLR7-mediated activation of Mφ. S100A8/9 are known to possess proinflammatory functions consistent with those of the complex as a TLR4 ligand [ 45 , 46 ]. Interestingly, several studies have shown that activation of TLR4 signaling can promote the secretion of IFN-γ in Mφ [ 47 , 48 ].…”

The role of alternative splicing and splicing factors in diabetes: Current status and future perspectives

“…Fasting causes liver to produce more ketone bodies (ketogenesis), which provide distant organs with energy sources (Owen, 2005). In rodents, mTORC1 regulates ketogenesis in response to fasting (Ursino et al, 2022). A marked defect in the generation of ketone bodies has been observed in the liver by the hyperactivation of mTORC1 (Ursino et al, 2022).…”

“…In rodents, mTORC1 regulates ketogenesis in response to fasting (Ursino et al, 2022). A marked defect in the generation of ketone bodies has been observed in the liver by the hyperactivation of mTORC1 (Ursino et al, 2022). Inhibition of mTORC1 activity is required for fasting‐induced activation of peroxisome proliferator activated receptor α (PPARα), the master transcriptional activator of ketogenic genes (Laffel, 1999; Owen, 2005; Ursino et al, 2022).…”