Cell Volume, the Serum and Glucocorticoid Inducible Kinase 1 and the Liver

Abstract

In virtually all cells including hepatocytes cell volume regulation is accomplished during cell swelling by cellular ion release (activation of K (+) channels and/or anion channels, KCl-cotransport, parallel activation of K (+)/H (+) exchange and Cl (-)/HCO (3)(-) exchange) and following cell shrinkage by cellular ion uptake (activation of Na (+), K (+), 2Cl (-) cotransport, Na (+)/H (+) exchange in parallel to Cl (-)/HCO (3)(-) exchange and Na (+)-channels). Moreover, cell shrinkage triggers the cellular accumulation of organic osmolytes (e. g., myoinositol, betaine, phosphorylcholine, taurine). Cell volume is a powerful regulator of hepatic metabolism. Cell shrinkage stimulates and cell swelling inhibits proteolysis and glycogenolysis. Moreover, cell volume influences the generation of and sensitivity to oxidants. Cell volume regulatory mechanisms furthermore do play a role in fibrosing disease. Kinases stimulating cell volume regulatory mechanisms include the serum and glucocorticoid inducible kinase SGK1, which is expressed in the liver, is genomically up-regulated by cell shrinkage, stimulates a wide variety of channels and transporters including Na (+), K (+), 2Cl (-) cotransport and Na (+)/H (+) exchange and is known to participate in the stimulation of fibrosis. Accordingly, excessive SGK1 expression is observed in liver cirrhosis. The case is made that SGK1 participates in the regulation of liver cell volume and thus in the regulation of hepatic metabolism.

Requirement of translocated lysosomal V1 H+-ATPase for activation of membrane acid sphingomyelinase and raft clustering in coronary endothelial cells

“…It was reported that in hepatocytes, hyperosmotic exposure induces an almost instantaneous acidification of ASM-containing endosomal compartment, which is followed by an increase in the intracellular ceramide concentration (Reinehr and Haussinger, 2007; Lang et al , 2011). Moreover, inhibition of the vacuolar-type H + -ATPase abolishes not only endosomal acidification and subsequent ceramide generation, but also hyperosmotically induced generation of ROS by NADPH oxidase.…”

The Emerging Role of SGK1 (Serum- and Glucocorticoid-Regulated Kinase 1) in Major Depressive Disorder: Hypothesis and Mechanisms

“…Ion channel physiology and pathophysiology of membrane polarization appear to play an important role in cell proliferation, although rigorous scientific demonstrations are still lacking (Zhang et al, 2014;Zhou et al, 2015b). Taken together, all these information underline that SGK1, originally studied as a kinase responsible for regulating several cellular ion channels and pumps (Wulff et al, 2002;Lang et al, 2011;Chraïbi and Renauld, 2014), can indeed have a role in oncology and immunology as well (Lang et al, 2006;Sobiesiak et al, 2009;Wu C. et al, 2013). SGK1 function is directly dependent on mTOR phosphorylation.…”

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

“…Several proteins of the mTOR pathway are now known to mediate survival and chemo-radio resistance among these SGK1 [16,17]. The serum-and glucocorticoid-regulated kinase 1 (SGK1) mediates signals of cell survival and proliferation [18,19]. SGK1 is a serine/threonine kinase that shares structural and functional similarities with the AKT family of kinases [20].…”