ENDOTOXIN AND CYTOKINES INCREASE HEPATIC SPHINGOLIPID BIOSYNTHESIS AND PRODUCE LIPOPROTEINS ENRICHED IN CERAMIDES AND SPHINGOMYELIN

Alterations in triglyceride and cholesterol metabolism often accompany inflammatory diseases and infections. We studied the effects of endot oxin (lipopolysaccharide [LPS]) and cytokines on hepatic sphingolipid synthesis, activity of serine palmitoyltransferase (SPT), the first an d rate-limiting enzyme in sphingolipid synthesis, and lipoprotein sphi ngolipid 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 le ast 48 hours. Low doses of LPS produced maximal increases in SPT activ ity, with half-maximal effect seen at approximate to 0.3 mu g LPS/100 g body weight. LPS increased hepatic SPT mRNA levels 2-fold, suggestin g 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 sp hingomyelin and ceramide synthesis, respectively. Many of the metaboli c 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-fo ld increase in SPT rnRNA in HepG2 cells, and the half-maximal dose was 2 ng/mL. IL-1 also increased the secretion of sphingolipids into the medium. Analysis of serum lipoprotein fractions demonstrated that very low density lipoprotein, intermediate density lipoprotein, and low de nsity lipoprotein isolated from animals treated with LPS contained sig nificantly higher amounts of ceramide, glucosylceramide, and sphingomy elin. Taken together, these results indicate that LPS and cytokines st imulate hepatic sphingolipid synthesis, which results in an altered st ructure of circulating lipoproteins and may promote atherogenesis.