Abstract
The host response to infection is associated with multiple alterations in lipid and lipoprotein metabolism. We have shown recently that endotoxin (lipopolysaccharide (LPS)) and cytokines enhance hepatic sphingolipid synthesis, increase the activity and mRNA levels of serine palmitoyltransferase, the first committed step in sphingolipid synthesis, and increase the content of sphingomyelin, ceramide, and glucosylceramide (GlcCer) in circulating lipoproteins in Syrian hamsters. Since the LPS-induced increase in GlcCer content of lipoproteins was far greater than that of ceramide or sphingomyelin, we have now examined the effect of LPS and cytokines on glycosphingolipid metabolism. LPS markedly increased the mRNA level of hepatic GlcCer synthase, the enzyme that catalyzes the first glycosylation step of glycosphingolipid synthesis. The LPS-induced increase in GlcCer synthase mRNA levels was seen within 2 h, sustained for 8 h, and declined to base line by 24 h. LPS-induced increase in GlcCer synthase mRNA was partly accounted for by an increase in its transcription rate. LPS produced a 3-4-fold increase in hepatic GlcCer synthase activity and significantly increased the content of GlcCer (the immediate product of GlcCer synthase reaction) as well as ceramide trihexoside and ganglioside GM3 (products distal to the GlcCer synthase step) in the liver. Moreover, both tumor necrosis factor-alpha and interleukin-1beta, cytokines that mediate many of the metabolic effects of LPS, increased hepatic GlcCer synthase mRNA levels in vivo as well as in HepG2 cells in vitro, suggesting that these cytokines can directly stimulate glycosphingolipid metabolism. These results indicate that LPS and cytokines up-regulate glycosphingolipid metabolism in vivo and in vitro. An increase in GlcCer synthase mRNA levels and activity leads to the increase in hepatic GlcCer content and may account for the increased GlcCer content in circulating lipoproteins during the acute phase response.
Highlights
The host response to infection is associated with multiple alterations in lipid and lipoprotein metabolism
The effects of LPS are in turn mediated by cytokines, including tumor necrosis factor-␣ (TNF-␣) and interleukin-1 (IL-1), and it has been shown that many of the metabolic effects of infection, inflammation, and trauma can be induced by these cytokines
It is of note that the increases in GlcCer levels (19-fold in VLDL and 7.3-fold in LDL) were greater than the increases in ceramide (3.7- and 2.2-fold in VLDL and LDL, respectively) and sphingomyelin, suggesting that GlcCer synthesis may be regpopolysaccharide; TNF, tumor necrosis factor; IL, interleukin; SPT, serine palmitoyltransferase; GlcCer, glucosylceramide; BW, body weight; LDL, low density lipoprotein; VLDL, very low density lipoprotein; MOPS, 4-morpholinepropanesulfonic acid; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; PBS, phosphatebuffered saline; GM1, Gal1,3GalNAc1,4(NeuAc␣2,3)Gal1,4Glc-Cer; GM3, NeuAc␣2,3Gal1,4Glc-Cer; GD1a, NeuAc␣2,3Gal1,3GalNAc1, 4(NeuAc␣2,3)Gal1,4Glc-Cer
Summary
Vol 274, No 28, Issue of July 9, pp. 19707–19713, 1999 Printed in U.S.A. Regulation of Glycosphingolipid Metabolism in Liver during the Acute Phase Response*. LPS produced a 3– 4-fold increase in hepatic GlcCer synthase activity and significantly increased the content of GlcCer (the immediate product of GlcCer synthase reaction) as well as ceramide trihexoside and ganglioside GM3 (products distal to the GlcCer synthase step) in the liver Both tumor necrosis factor-␣ and interleukin-1, cytokines that mediate many of the metabolic effects of LPS, increased hepatic GlcCer synthase mRNA levels in vivo as well as in HepG2 cells in vitro, suggesting that these cytokines can directly stimulate glycosphingolipid metabolism. The acute phase response is accompanied by several changes in lipid and lipoprotein metabolism that include stimulation of fatty acid and cholesterol synthesis and a marked increase in serum triglyceride and cholesterol levels [6] These metabolic alterations can be induced by endotoxin (lipopolysaccharide (LPS)) treatment, which mimics Gram-negative infections [7]. It is of note that the increases in GlcCer levels (19-fold in VLDL and 7.3-fold in LDL) were greater than the increases in ceramide (3.7- and 2.2-fold in VLDL and LDL, respectively) and sphingomyelin (no change in VLDL and 84% increase in LDL), suggesting that GlcCer synthesis may be regpopolysaccharide; TNF, tumor necrosis factor; IL, interleukin; SPT, serine palmitoyltransferase; GlcCer, glucosylceramide; BW, body weight; LDL, low density lipoprotein; VLDL, very low density lipoprotein; MOPS, 4-morpholinepropanesulfonic acid; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; PBS, phosphatebuffered saline; GM1, Gal1,3GalNAc1,4(NeuAc␣2,3)Gal1,4Glc-Cer; GM3, NeuAc␣2,3Gal1,4Glc-Cer; GD1a, NeuAc␣2,3Gal1,3GalNAc1, 4(NeuAc␣2,3)Gal1,4Glc-Cer
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