Endotoxin and Cytokines Increase Hepatic Sphingolipid Biosynthesis and Produce Lipoproteins Enriched in Ceramides and Sphingomyelin

Abstract

Abstract-Alterations in triglyceride and cholesterol metabolism often accompany inflammatory diseases and infections.We studied the effects of endotoxin (lipopolysaccharide [LPS]) and cytokines on hepatic sphingolipid synthesis, activity of serine palmitoyltransferase (SPT), the first and rate-limiting enzyme in sphingolipid synthesis, and lipoprotein sphingolipid content in Syrian hamsters. Administration of LPS induced a 2-fold increase in hepatic SPT activity. The increase in activity first occurred at 16 hours, peaked at 24 hours, and was sustained for at least 48 hours. Low doses of LPS produced maximal increases in SPT activity, with half-maximal effect seen at Ϸ0.3 g LPS/100 g body weight.LPS increased hepatic SPT mRNA levels 2-fold, suggesting that the increase in SPT activity was due to an increase in SPT mRNA. LPS treatment also produced 75% and 2.5-fold increases in hepatic sphingomyelin and ceramide synthesis, respectively. Many of the metabolic effects of LPS are mediated by cytokines. Interleukin 1 (IL-1), but not tumor necrosis factor, increased both SPT activity and mRNA levels in the liver of intact animals, whereas both IL-1 and tumor necrosis factor increased SPT mRNA levels in HepG2 cells. IL-1 produced a 3-fold increase in SPT mRNA in HepG2 cells, and the half-maximal dose was 2 ng/mL. IL-1 also increased the secretion of sphingolipids into the medium. Increased hepatic fatty acid synthesis, as well as increased adipose tissue lipolysis, provides the fatty acid substrate for increased triglyceride production.3 High doses of LPS do not stimulate hepatic VLDL secretion 3 but inhibit the clearance of triglyceride-rich lipoproteins by decreasing lipoprotein lipase activity in heart, muscle, and adipose tissue and in postheparin plasma. In rodents, LPS treatment increases serum cholesterol levels; however, this effect is delayed in onset compared with the increase in serum triglyceride levels and is primarily accounted for by an increase in LDL cholesterol.4 LPS increases hepatic cholesterol synthesis and the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. 4Increased transcription of the HMG-CoA reductase gene leads to increased mRNA and protein levels, which account for the increase in hepatic HMG-CoA reductase activity. 5This effect of LPS on hepatic HMG-CoA reductase is specific, because mRNA levels of other important enzymes in cholesterol synthesis, such as HMG-CoA synthase, farnesyl pyrophosphate synthase, and squalene synthase, are not increased. 5,6 In addition, LPS decreases the activity and mRNA levels of cholesterol 7␣-hydroxylase, the rate-limiting enzyme in bile acid synthesis.7 A decrease in bile acid synthesis would increase the availability of cholesterol for lipoprotein production. Finally, LPS has minimal or no effect on LDL receptor protein or mRNA levels in the liver, the organ primarily responsible for LDL clearance. 4 These results suggest that the increased production of lipoproteins rather

Innate and acquired immunity intersect in a global view of the acute-phase response

“…3E). In contrast, and consistent with previous reports (18,19), increased expression of sphingolipid and ganglioside synthetic genes was observed (Fig. 3F).…”

Regulation of the Activity and Fatty Acid Specificity of Lecithin-Cholesterol Acyltransferase by Sphingomyelin and Its Metabolites, Ceramide and Ceramide Phosphate

“…Since both ceramide and SM are present in the same lipoprotein particle (7,8), this observation could have physiological (30,31). It is therefore possible that ceramide offsets the inhibitory effect of SM by 'liberating' the SM-sequestered cholesterol to accept the acyl group in the LCAT reaction.…”

De Novo Sphingolipid Biosynthesis: A Necessary, but Dangerous, Pathway

“…11) perhaps by down-regulation of SPT by sphingoid base 1-phosphates (27). Regulation at a transcriptional level has been seen with a number of agents, including endotoxin and cytokines (28), UVB irradiation (29), retinoic acid (30), and other agents (31). Induction of both SPT1 and SPT2 occurs in balloon-injured rat carotid artery (32).…”