| First Author | Beer AJ | Year | 2020 |
| Journal | Sci Rep | Volume | 10 |
| Issue | 1 | Pages | 13110 |
| PubMed ID | 32753644 | Mgi Jnum | J:298936 |
| Mgi Id | MGI:6457734 | Doi | 10.1038/s41598-020-69901-3 |
| Citation | Beer AJ, et al. (2020) Reduced Mrp2 surface availability as PI3Kgamma-mediated hepatocytic dysfunction reflecting a hallmark of cholestasis in sepsis. Sci Rep 10(1):13110 |
| abstractText | Sepsis-associated liver dysfunction manifesting as cholestasis is common during multiple organ failure. Three hepatocytic dysfunctions are considered as major hallmarks of cholestasis in sepsis: impairments of microvilli covering canalicular membranes, disruptions of tight junctions sealing bile-collecting canaliculae and disruptions of Mrp2-mediated hepatobiliary transport. PI3Kgamma loss-of-function was suggested as beneficial in early sepsis. Yet, the PI3Kgamma-regulated cellular processes in hepatocytes remained largely unclear. We analysed all three sepsis hallmarks for responsiveness to massive PI3K/Akt signalling and PI3Kgamma loss-of-function, respectively. Surprisingly, neither microvilli nor tight junctions were strongly modulated, as shown by electron microscopical studies of mouse liver samples. Instead, quantitative electron microscopy proved that solely Mrp2 surface availability, i.e. the third hallmark, responded strongly to PI3K/Akt signalling. Mrp2 plasma membrane levels were massively reduced upon PI3K/Akt signalling. Importantly, Mrp2 levels at the plasma membrane of PI3Kgamma KO hepatocytes remained unaffected upon PI3K/Akt signalling stimulation. The effect explicitly relied on PI3Kgamma's enzymatic ability, as shown by PI3Kgamma kinase-dead mice. Keeping the surface availability of the biliary transporter Mrp2 therefore is a cell biological process that may underlie the observation that PI3Kgamma loss-of-function protects from hepatic excretory dysfunction during early sepsis and Mrp2 should thus take center stage in pharmacological interventions. |
