Regulation of sphingolipid and glycosphingolipid metabolism in extrahepatic tissues by endotoxin

Riaz A Memon,Walter M Holleran,Yoshikazu Uchida,Arthur H Moser,Carl Grunfeld,Kenneth R Feingold

doi:10.1016/s0022-2275(20)31670-9

Riaz A Memon, Walter M Holleran + Show 4 more

Open Access

https://doi.org/10.1016/s0022-2275(20)31670-9

Copy DOI

Abstract

The host response to infection and inflammation is associated with multiple alterations in lipid metabolism. We have shown that endotoxin [lipopolysaccharide (LPS)] stimulates hepatic sphingolipid synthesis and increases ceramide and glucosylceramide (GlcCer) content in circulating lipoproteins in Syrian hamsters. LPS also increases the activity and mRNA levels of serine palmitoyltransferase (SPT) and GlcCer synthase, the committed enzymes in sphingolipid and glycosphingolipid (GSL) synthesis, respectively, in the liver. To determine whether sphingolipid and GSL metabolism are regulated in other tissues during the host response to infection, we examined the effect of LPS on the regulation of SPT and GlcCer synthase in extrahepatic tissues in Syrian hamsters. LPS significantly increased SPT activity in spleen and kidney after 16 h of treatment, but had no effect on SPT activity in lung and brain, suggesting that the effect of LPS on sphingolipid metabolism is tissue specific. LPS also increased SPT mRNA levels in spleen and kidney by ~3-fold, suggesting that the increase in SPT activity is due to an increase in SPT mRNA expression. LPS significantly increased GlcCer synthase activity in spleen and kidney, and produced 4- and 15-fold increases in GlcCer synthase mRNA levels in spleen and kidney, respectively. LPS treatment increased GlcCer content by 1.3-fold in spleen and by 6.2-fold in kidney. LPS also increased the content of ceramide trihexoside by 1.7-fold in spleen. These results suggest that LPS regulates sphingolipid and GSL metabolism in spleen and kidney. An increase in GSL metabolites in spleen and kidney during the host response to infection and inflammation may be required for modulation of immune responses and regulation of cell growth. —Memon, R. A., W. M. Holleran, Y. Uchida, A. H. Moser, C. Grunfeld, and K. R. Feingold. Regulation of sphingolipid and glycosphingolipid metabolism in extrahepatic tissues by endotoxin.

Highlights

The host response to infection and inflammation is associated with multiple alterations in lipid metabolism
The data show that LPS increased serine palmitoyltransferase (SPT) mRNA levels by 2.8-fold in spleen and by 2.9-fold in kidney
Our previous studies have shown that LPS significantly increases SPT activity and mRNA levels in Syrian hamster liver, with the maximal increase observed at 16 h [12]

Summary

Introduction

The host response to infection and inflammation is associated with multiple alterations in lipid metabolism. Previous studies by our laboratory and others have shown that the acute-phase response (APR) induced by infection or inflammation results in several alterations in lipid and lipoprotein metabolism, such as increased serum triglyceride and cholesterol levels, stimulation of fatty acid and cholesterol synthesis, enhanced lipolysis, and decreased ketogenesis [7,8,9,10]. These metabolic alterations can be induced by endotoxin [lipopolysaccharide (LPS)] treatment, which mimicks gram-negative infections [11]. Sphingolipids are important components of the cell membranes of all eukaryotic cells and exert a wide range of functions including regulation of cell growth, differen-

Methods

Results

Conclusion