Acid sphingomyelinase plays important roles in ceramide homeostasis, which has been proposed to be linked to insulin resistance. To test this association in vivo, acid sphingomyelinase deletion (asm ؊/؊ ) was transferred to mice lacking the low density lipoprotein receptor (ldlr ؊/؊ ), and then offsprings were placed on control or modified (enriched in saturated fat and cholesterol) diets for 10 weeks. The modified diet caused hypercholesterolemia in all genotypes; however, in contrast to asm ؉/؉ /ldlr ؊/؊ , the acid sphingomyelinase-deficient littermates did not display hepatic triacylglyceride accumulation, although sphingomyelin and other sphingolipids were substantially elevated, and the liver was enlarged. asm ؊/؊ /ldlr ؊/؊ mice on a modified diet did not accumulate body fat and were protected against diet-induced hyperglycemia and insulin resistance. Experiments with hepatocytes revealed that acid sphingomyelinase regulates the partitioning of the major fatty acid in the modified diet, palmitate, into two competitive and inversely related pools, triacylglycerides and sphingolipids, apparently via modulation of serine palmitoyltransferase, a rate-limiting enzyme in de novo sphingolipid synthesis. These studies provide evidence that acid sphingomyelinase activity plays an essential role in the regulation of glucose metabolism by regulating the hepatic accumulation of triacylglycerides and sphingolipids during consumption of a diet rich in saturated fats.
E vidence has consistently indicated that activation of sphingomyelinases and/or ceramide synthases and the resulting accumulation of ceramide mediate cellular responses to stressors such as lipopolysaccharide, interleukin 1`, tumor necrosis factor _, serum deprivation, irradiation and various antitumor treatments. Recent studies had identified the genes encoding most of the enzymes responsible for the generation of ceramide and ongoing research is aimed at characterizing their individual functions in cellular response to stress. This chapter discusses the seminal and more recent discoveries in regards to the pathways responsible for the accumulation of ceramide during stress and the mechanisms by which ceramide affects cell functions. The former group includes the roles of neutral sphingomyelinase 2, serine palmitoyltransferase, ceramide synthases, as well as the secretory and endosomal/lysosomal forms of acid sphingomyelinase. The latter summarizes the mechanisms by which ceramide activate its direct targets, PKCc, PP2A and cathepsin D. The ability of ceramide to affect membrane organization is discussed in the light of its relevance to cell signaling. Emerging evidence to support the previously assumed notion that ceramide acts in a strictly structure-specific manner are also included. These findings are described in the context of several physiological and pathophysiological conditions, namely septic shock, obesity-induced insulin resistance, aging and apoptosis of tumor cells in response to radiation and chemotherapy.
Acid sphingomyelinase (ASMase) has been proposed to mediate lipopolysaccharide (LPS) signaling in various cell types. This study shows that ASMase is a negative regulator of LPS-induced tumor necrosis factor ␣ (TNF␣) secretion in macrophages. ASMase-deficient (asm ؊/؊ ) mice and isolated peritoneal macrophages produce severalfold more TNF␣ than their wildtype (asm ؉/؉ ) counterparts when stimulated with LPS, whereas the addition of exogenous ceramides or sphingomyelinase reduces the differences. The underlying mechanism for these effects is not transcriptional but post-translational. The TNF␣-converting enzyme (TACE) catalyzes the maturation of the 26-kDa precursor (pro-TNF␣) to an active 17-kDa form (soluble (s)TNF␣). In mouse peritoneal macrophages, the activity of TACE was the rate-limiting factor regulating TNF␣ production. A substantial portion of the translated pro-TNF␣ was not processed to sTNF␣; instead, it was rapidly internalized and degraded in the lysosomes. Production of tumor necrosis factor ␣ (TNF␣), 3 the major mediator of the innate immune response, is tightly regulated by transcriptional, post-transcriptional, and post-translational mechanisms. Dysregulation of TNF␣ synthesis and/or turnover has been linked to various disease conditions, including rheumatoid arthritis, sepsis, and cancer (1-3). Lipopolysaccharide (LPS), a component of the bacterial cell wall, is a potent inducer of TNF␣ production and the underlying signaling mechanisms are well understood. LPS binding to its cognitive receptor, MD-2, induces dimerization of the signaling Toll-like receptor-4 (TLR-4) and activation of interleukin-1 receptor-associated kinase-1 (IRAK-1) in a myeloid differentiation factor 88 (MyD88)-dependent manner. Ultimately, the nuclear translocation of nuclear factor B (4, 5), AP-1, Ets, and Elk-1 (6 -8) transcription factors results in multifold induction of TNF␣ mRNA synthesis. LPS also regulates mRNA stability through AU-rich elements at the 3Ј-untranslated region of TNF␣ mRNA (9, 10).In mice, TNF␣ mRNA is translated into a 26-kDa precursor protein (pro-TNF␣), part of which is immediately N-glycosylated (11). pro-TNF␣ is selected as a cargo for the Golgin p230-positive vesicles (12) and transported to the plasma membrane via Rab11 recycling vesicles (13,14). pro-TNF␣ is integrated in the plasma membrane as a type II membrane protein (15); its ectodomain is cleaved by TNF␣-converting enzyme (TACE) (16) and released as a biologically active 17-kDa soluble form (sTNF␣). TACE is a member of the a disintegrin and metalloproteinase family of proteases. In addition to TNF␣, TACE also processes the two TNF␣ receptors (p55 and p75), transforming growth factor ␣, L-selectin, and other secretory proteins (17)(18)(19)(20).The regulation of TNF␣ mRNA transcription has been extensively studied, and it is well understood. In contrast, evidence for a regulatory role of TACE has emerged only recently. It was reported that a substantial portion of pro-TNF␣ is not immediately processed by TACE but is rapidly internalized a...
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