Sphingolipid de novo biosynthesis is essential for intestine cell survival and barrier function (original) (raw)
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Hepatology (Baltimore, Md.), 2016
Serine palmitoyltransferase (SPT) is the key enzyme in sphingolipid biosynthesis. Mice lacking SPT are embryonic lethal. We prepared liver-specific Sptlc2 deficient mice using an albumin-Cre approach, we found that the deficient mice have severe jaundice. Moreover, the deficiency impairs hepatocyte polarity, attenuates liver regeneration after hepatectomy, and promotes tumorigenesis. Importantly, we show that the deficiency significantly reduces sphingomyelin but not other sphingolipids in hepatocyte plasma membrane, greatly reduces cadherin, the major protein in adherens junctions, on the membrane and greatly induces cadherin phosphorylation, an indication for its degradation. The deficiency affects cellular distribution of β-catenin, the central component of the canonical Wnt pathway. Furthermore, such a defect can be partially corrected by sphingomyelin supplementation in vivo and in vitro. Our results, for the first time, show that plasma membrane sphingomyelin level is one of t...
Physiological functions and clinical implications of sphingolipids in the gut
Journal of Digestive Diseases, 2011
Studies of sphingolipids have become one of the most rapidly advancing fields in the last two decades. These highly diverse lipids have been known to have multiple physiological functions and clinical implications in several diseases, including tumorigenesis, inflammation, atherosclerosis and neural degenerative diseases. Unlike other organs, sphingolipids in the intestinal tract are present not only as lipid constitu-ents in the cells but also as dietary compositions for digestion in the lumen. The present review focuses on the presence of sphingolipids and their catalytic enzymes in the gut; the metabolism and the signaling effects of the metabolites and their impacts on barrier functions, cholesterol absorption, inflammatory diseases and tumor development in the gut.
Metabolism of sphingolipids in the gut and its relation to inflammation and cancer development
Progress in Lipid Research, 2009
Sphingolipids are abundant in the microvillar membrane of intestinal epithelial cells where they are essential for structural integrity and may act as receptors for toxins, virus and bacteria. Metabolism of dietary and membrane sphingolipids in the intestine generates ceramide, sphingosine, sphingosine-1-phosphate, and ceramide-1phosphate, via the action of alkaline sphingomyelinase, neutral ceramidase, sphingosine-1-kinase, and ceramide-1-kinase. These intermediary metabolites act as bioactive lipid messengers, influencing numerous cellular functions including growth, differentiation and apoptosis of both epithelial and immunocompetent cells in the gastrointestinal tract, and also the progress of inflammation and responsiveness of the mucosal cells to pathogens. This review summarizes background and recent progress in the metabolism of dietary and endogenous sphingolipids in the gut and its pathophysiological implications.
PubMed, 2001
Sphingolipid consumption suppresses colon carcinogenesis, but the specific genetic defect(s) that can be bypassed by these dietary components are not known. Colon tumors often have defect(s) in the adenomatous polyposis coli (APC)/beta-catenin regulatory system. Therefore, C57Bl/6J(Min/+) mice with a truncated APC gene product were fed diets supplemented with ceramide, sphingomyelin, glucosylceramide, lactosylceramide, and ganglioside G(D3) (a composition similar in amount and type to that of dairy products) to determine whether tumorigenesis caused by this category of genetic defect is suppressed. Sphingolipid feeding reduced the number of tumors in all regions of the intestine, and caused a marked redistribution of beta-catenin from a diffuse (cytosolic plus membrane) pattern to a more "normal" localization at mainly intercellular junctions between intestinal epithelial cells. The major digestion product of complex sphingolipids is sphingosine, and treatment of two human colon cancer cell lines in culture (SW480 and T84) with sphingosine reduced cytosolic and nuclear beta-catenin, inhibited growth, and induced cell death. Ceramides, particularly long-chain ceramides, also had effects. Thus, dietary sphingolipids, presumably via their digestion products, bypass or correct defect(s) in the APC/beta-catenin regulatory pathway. This may be at least one mechanism whereby dietary sphingolipids inhibit colon carcinogenesis, and might have implications for dietary intervention in human familial adenomatous polyposis and colon cancer.
Colon Cancer and Perturbations of the Sphingolipid Metabolism
International Journal of Molecular Sciences, 2019
The development and progression of colon cancer (CRC), a major cause of cancer-related death in the western world, is accompanied with alterations of sphingolipid (SL) composition in colon tumors. A number of enzymes involved in the SL metabolism have been found to be deregulated in human colon tumors, in experimental rodent studies, and in human colon cancer cells in vitro. Therefore, the enzymatic pathways that modulate SL levels have received a significant attention, due to their possible contribution to CRC development, or as potential therapeutic targets. Many of these enzymes are associated with an increased sphingosine-1-phosphate/ceramide ratio, which is in turn linked with increased colon cancer cell survival, proliferation and cancer progression. Nevertheless, more attention should also be paid to the more complex SLs, including specific glycosphingolipids, such as lactosylceramides, which can be also deregulated during CRC development. In this review, we focus on the pote...
2013
The involvement of ceramide in death receptor-mediated apoptosis has been widely examined with most studies focusing on the role of ceramide generated from sphingomyelin hydrolysis. We now analyze the effect of the ceramide acyl chain length by studying tumor necrosis factor a receptor-1 (TNFR1)-mediated apoptosis in a ceramide synthase 2 (CerS2) null mouse, which cannot synthesize very-long acyl chain ceramides. CerS2 null mice were resistant to lipopolysaccharide/galactosaminemediated fulminant hepatic failure even though TNFa secretion from macrophages was unaffected. Cultured hepatocytes were also insensitive to TNFa-mediated apoptosis. In addition, in both liver and in hepatocytes, caspase activities were not elevated, consistent with inhibition of TNFR1 pro-apoptotic signaling. In contrast, Fas receptor activation resulted in the death of CerS2 null mice. Caspase activation was blocked because of the inability of CerS2 null mice to internalize the TNFR1; whereas Fc-TNFa was internalized to a perinuclear region in hepatocytes from wild-type mice, no internalization was detected in CerS2 null mice.
Serine palmitoyltransferase (SPT) deficient mice absorb less cholesterol☆
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2009
Serine palmitoyltransferase (SPT) is the key enzyme for the biosynthesis of sphingolipids. It has been reported that oral administration of myriocin (an SPT inhibitor) decreases plasma sphingomyelin (SM) and cholesterol levels, and reduces atherosclerosis in apoE knockout (KO) mice. We studied cholesterol absorption in myriocin-treated WT or apoE KO animals and found that, after myriocin treatment, the mice absorbed significantly less cholesterol than controls, with no observable pathological changes in the small intestine. More importantly, we found that heterozygous Sptlc1 (a subunit of SPT) KO mice also absorbed significantly less cholesterol than controls. To understand the mechanism, we measured protein levels of Niemann-Pick C1-like 1 (NPC1L1), ABCG5, and ABCA1, three key factors involved in intestinal cholesterol absorption. We found that NPC1L1 and ABCA1 were decreased, whereas ABCG5 was increased in the SPT deficient small intestine. SM levels on the apical membrane were also measured and they were significantly decreased in SPT deficient mice, compared with controls. In conclusion, SPT deficiency might reduce intestinal cholesterol absorption by altering NPC1L1 and ABCG5 protein levels in the apical membranes of enterocytes through lowering apical membrane SM levels. This may be also true for ABCA1 which locates on basal membrane of enterocytes. Manipulation of SPT activity could thus provide a novel alternative treatment for dyslipidemia.
Characterization of Serine Palmitoyltransferase in Normal Human Tissues
Journal of Histochemistry & Cytochemistry, 2003
S U M M A R Y Sphingolipids serve as structural elements of cells and as lipid second messengers. They regulate cellular homeostasis, mitogenesis, and apoptosis. Sphingolipid signaling may also be important in various pathophysiologies such as vascular injury, inflammation, and cancer. Serine palmitoyltransferase (SPT) catalyzes the condensation of serine with palmitoyl-CoA, the first, rate-limiting step in de novo sphingolipid biosynthesis. This integral microsomal membrane protein consists of at least two subunits, SPT1 and SPT2. In this study we analyzed the expression of SPT1 and SPT2 in normal human tissues. Strong SPT1 and SPT2 expression was observed in pyramidal neurons in the brain, in colon epithelium, and in mucosal macrophages. However, SPT2 expression was more prominent than SPT1 in the colon mucosal macrophages, the adrenomedullary chromaffin cells and endothelium, and in the uterine endothelium. SPT2 was localized in both nuclei and cytoplasm of the adrenomedullary chromaffin cells, whereas SPT1 was primarily cytoplasmic. These observations link enhanced SPT expression to proliferating cells, such as the lung, stomach, intestinal epithelium, and renal proximal tubular epithelium, and to potentially activated cells such as neurons, chromaffin cells, and mucosal macrophages. A baseline expression of SPT, established by this study, may serve as a measure for aberrant expression in various disease states. (J Histochem Cytochem 51:687-696, 2003)