Sphingomyelinase treatment of rat hepatocytes inhibits cell‐swelling‐stimulated glycogen synthesis by causing cell shrinkage

Abstract

Breakdown of plasma-membrane sphingomyelin caused by TNF-a is known to inhibit glucose metabolism and insulin signalling in muscle and fat cells. In hepatocytes, conversion of glucose to glycogen is strongly activated by amino acid-induced cell swelling. In order to find out whether breakdown of plasma-membrane sphingomyelin also inhibits this insulin-independent process, the effect of addition of sphingomyelinase was studied in rat hepatocytes.Sphingomyelinase (but not ceramide) inhibited glycogen synthesis, caused cell shrinkage, decreased the activity of glycogen synthase a, but had no effect on phosphorylase a. Cell integrity was not affected by sphingomyelinase addition as gluconeogenesis and the intracellular concentration of ATP were unchanged. As a control, glycogen synthesis was studied in HepG2 cells. In these cells, the basal rate of glycogen production was high, could not be stimulated by amino acids, nor be inhibited by sphingomyelinase.Regarding the mechanism responsible for the inhibition of glycogen synthase a, sphingomyelinase did not affect amino acid-induced, PtdIns 3-kinase-dependent, phosphorylation of p70S6 kinase, but caused an increase in intracellular chloride, which is known to inhibit glycogen synthase phosphatase.It is concluded that the decrease in cell volume, following the breakdown of sphingomyelin in the plasma membrane of the hepatocyte, may contribute to the abnormal metabolism of glucose when TNF-a levels are high.

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…Ugcg inhibitors may exert their effect on hepatocytes independently of GSLs (157,161,173). A preventive effect of GSL deficiency on the development of liver steatosis after an HFD was not observed.…”

“…Alcohol-related liver disease (ALD) is also associated with altered Cer profiles, steatohepatitis, insulin resistance, disruptions in lipid metabolism in hepatocytes, increased proinflammatory cytokines, dysregulated lipid metabolism, ER, and oxidative stress (53, 169,173). Altered lipid metabolism promotes Cer accumulation and oxidative stress, and these can result in a "lipotoxic state" in which there is activation of ER-stress pathways, inflammation, and insulin resistance (54,143,147).…”

“…The Cer inhibitor myriocin reduces the severity of ASH by decreasing the abundance and size of lipid droplets and mitochondria and limiting inflammation, thereby improving the architecture of the ER. Myriocin-mediated reductions in hepatic Cer levels enhance insulin signaling through the insulin receptor with a reduced hepatic oxidative stress and modulated ER stress (53, 169,173).…”

“…Inhibition of de novo SL synthesis increases ABCA1-mediated cholesterol efflux independent of SM, increasing antiatherogenic lipoproteins and decreasing atherosclerosis in mice (159,179,183). Breakdown of plasma membrane SM by TNF-␣ inhibits glucose metabolism and insulin signaling in muscle and fat cells (160,173,177).…”

Accumulation of Free Oligosaccharides and Tissue Damage in Cytosolic α-Mannosidase (Man2c1)-deficient Mice

“…because of increased cytosolic sugar content. This interpretation would be in line with the high glycogen amounts because hepatocyte swelling (next to ER stress) is a documented strong activator of converting glucose into the osmotically less critical glycogen polymer form (37,38). Therefore, the high protein turnover characteristic of liver parenchyma may be the ultimate reason for mannosyl compound accumulation by ERAD defects.…”