Year-end Sale % OFF 
Abstract
Although hypoglycemia has been documented as a major cause of high mortality in the setting of septic shock, the mechanism of hypoglycemia in infection has not been clearly determined. Hepatic gluconeogenesis serves as an important mechanism to maintain glucose levels under physiological conditions and CREB coactivator CRTC2 plays an important role in regulating gluconeogenic gene expression. Here, we show that triggering of the Toll-like receptor 4 pathway in response to endotoxin lipopolysaccharide (LPS) inhibits gluconeogenic gene expression and hepatic glucose output by blocking CRTC2 activation. Interleukin-1β (IL-1β) is found to disrupt gluconeogenic gene expression via the activation of the E3 ubiquitin ligase TRAF6, a key component of the Toll-like receptor 4 signaling pathway that associates with and ubiquitinates CRTC2. TRAF6 promotes the K63-linked ubiquitination of CRTC2, a modification that blocks binding of calcineurin at an adjacent calcineurin-binding site, thereby disrupting CRTC2 dephosphorylation in response to glucagon signals. Mutation of TRAF6-binding sites or ubiquitination site in CRTC2 rescues hepatic gluconeogenesis in LPS-challenged mice. These results suggest that pro-inflammatory signals intersect with the CRTC2 pathway in liver, thus contributing to hypoglycemia caused by infection.
Highlights
Hypoglycemia is a cause of considerable morbidity and mortality in the setting of septic shock both in experimental animals and in humans [1,2,3,4]
Our results unveil a novel mechanism by which pro-inflammatory signals intersect with the CRTC2 pathway in liver and this mechanism contributes to the hypoglycemia caused by infection
constitutive photomorphogenic protein 1 (COP1) mediates CRTC2 K48 ubiquitination at Lys628 and promotes CRTCs degradation under feeding signal such as insulin stimulation, which serves as a mechanism for insulin-mediated suppression of gluconeogenesis [12]
Summary
Hypoglycemia is a cause of considerable morbidity and mortality in the setting of septic shock both in experimental animals and in humans [1,2,3,4]. Overexpression of wild-type TRAF6 but not catalytically inactive (C70A) TRAF6 reduced gluconeogenic gene (G6pase, Pck1) expression and glucose output as well as CRTC2 occupancy over the G6pase promoter in hepatocytes exposed to glucagon (Supplementary Figure S4a–d), while RNAi-mediated depletion of TRAF6 increased it (Supplementary Figure S4e–h) Taken together, these results indicate that IL-1β inhibits CRTC2 signaling through TRAF6. LPS administration (i.p.) decreased G6pase-luc activity as well as gluconeogenic gene expression (G6pase and Pck1) and circulating blood glucose concentrations in fasted mice; these effects were potentiated by overexpression of wild type but not catalytically inactive C70A mutant TRAF6 (Figure 3a–d). Exposure to IL-1β reduced G6pase gene expression as well as glucose output induced by wild-type CRTC2 but not PVIVIT mutant CRTC2 in primary hepatocytes (Figure 5f and g) These results demonstrate that pro-inflammatory stimuli disrupt signaling through the CRTC2 pathway in part via the TRAF6-mediated ubiquitination and inhibition of CRTC2 dephosphorylation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
