Absorption and lipoprotein transport of sphingomyelin
2005; Elsevier BV; Volume: 47; Issue: 1 Linguagem: Inglês
10.1194/jlr.m500357-jlr200
ISSN1539-7262
Autores Tópico(s)Lysosomal Storage Disorders Research
ResumoDietary sphingomyelin (SM) is hydrolyzed by intestinal alkaline sphingomyelinase and neutral ceramidase to sphingosine, which is absorbed and converted to palmitic acid and acylated into chylomicron triglycerides (TGs). SM digestion is slow and is affected by luminal factors such as bile salt, cholesterol, and other lipids. In the gut, SM and its metabolites may influence TG hydrolysis, cholesterol absorption, lipoprotein formation, and mucosal growth. SM accounts for ∼20% of the phospholipids in human plasma lipoproteins, of which two-thirds are in LDL and VLDL. It is secreted in chylomicrons and VLDL and transferred into HDL via the ABCA1 transporter. Plasma SM increases after periods of large lipid loads, during suckling, and in type II hypercholesterolemia, cholesterol-fed animals, and apolipoprotein E-deficient mice. SM is thus an important amphiphilic component when plasma lipoprotein pools expand in response to large lipid loads or metabolic abnormalities. It inhibits lipoprotein lipase and LCAT as well as the interaction of lipoproteins with receptors and counteracts LDL oxidation. The turnover of plasma SM is greater than can be accounted for by the turnover of LDL and HDL particles. Some SM must be degraded via receptor-mediated catabolism of chylomicron and VLDL remnants and by scavenger receptor class B type I receptor-mediated transfer into cells. Dietary sphingomyelin (SM) is hydrolyzed by intestinal alkaline sphingomyelinase and neutral ceramidase to sphingosine, which is absorbed and converted to palmitic acid and acylated into chylomicron triglycerides (TGs). SM digestion is slow and is affected by luminal factors such as bile salt, cholesterol, and other lipids. In the gut, SM and its metabolites may influence TG hydrolysis, cholesterol absorption, lipoprotein formation, and mucosal growth. SM accounts for ∼20% of the phospholipids in human plasma lipoproteins, of which two-thirds are in LDL and VLDL. It is secreted in chylomicrons and VLDL and transferred into HDL via the ABCA1 transporter. Plasma SM increases after periods of large lipid loads, during suckling, and in type II hypercholesterolemia, cholesterol-fed animals, and apolipoprotein E-deficient mice. SM is thus an important amphiphilic component when plasma lipoprotein pools expand in response to large lipid loads or metabolic abnormalities. It inhibits lipoprotein lipase and LCAT as well as the interaction of lipoproteins with receptors and counteracts LDL oxidation. The turnover of plasma SM is greater than can be accounted for by the turnover of LDL and HDL particles. Some SM must be degraded via receptor-mediated catabolism of chylomicron and VLDL remnants and by scavenger receptor class B type I receptor-mediated transfer into cells. Sphingomyelin (SM) in mammalian cells is colocalized with cholesterol mainly in the plasma membrane and in lysosomal and Golgi membranes. It interacts strongly with cholesterol, and the regulation of SM and cholesterol metabolism are in part coordinated (1Slotte J.P. Sphingomyelin-cholesterol interactions in biological and model membranes.Chem. Phys. Lipids. 1999; 102: 13-27Google Scholar, 2Ridgway N.D. Interactions between metabolism and intracellular distribution of cholesterol and sphingomyelin.Biochim. Biophys. Acta. 2000; 1484: 129-141Google Scholar). In plasma lipoproteins, SM is the second most abundant polar lipid after phosphatidylcholine (PC). The size of the plasma lipoprotein SM pool in humans is 1–1.5 g, of which approximately two-thirds are in apolipoprotein B (apoB)-containing triglyceride (TG)-rich lipoproteins and LDL. The SM content in most extraneural tissues is 1–2 g/kg. Factors regulating plasma SM concentration have received little attention. It was early shown that the level of SM is increased in hypercholesterolemia and that SM-rich lipoproteins accumulate in arteriosclerotic lesions (3Portman O.W. Alexander M. Metabolism of sphingolipids by normal and atherosclerotic aorta of squirrel monkeys.J. Lipid Res. 1970; 11: 23-30Google Scholar, 4Portman O.W. Illingworth D.R. Arterial metabolism in primates.Primates Med. 1976; 9: 145-223Google Scholar, 5Stein O. Eisenberg S. Stein Y. Aging of aortic smooth muscle cells in rats and rabbits. A morphologic and biochemical study.Lab. Invest. 1969; 21: 386-397Google Scholar). Plasma SM is thus a risk factor for ischemic heart disease (6Jiang X.C. Paultre F. Pearson T.A. Reed R.G. Francis C.K. Lin M. Berglund L. Tall A.R. Plasma sphingomyelin level as a risk factor for coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2614-2618Google Scholar), and the apoE-deficient (apoE−/−) mouse, which accumulates SM-rich remnant particles in blood (7Jeong T. Schissel S.L. 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This review focuses on the absorption and transport of SM and on the biological effects of SM and its metabolites that may be exerted during these processes. Humans on an ordinary Western diet ingest 0.3–0.4 g of sphingolipids per day, of which SM in meat, milk, egg products, and fish (21Vesper H. Schmelz E.M. Nikolova-Karakashian M.N. Dillehay D.L. Lynch D.V. Merrill Jr., A.H. Sphingolipids in food and the emerging importance of sphingolipids to nutrition.J. Nutr. 1999; 129: 1239-1250Scopus (358) Google Scholar, 22Zeisel S.H. Char D. Sheard N.F. Choline, phosphatidylcholine and sphingomyelin in human and bovine milk and infant formulas.J. Nutr. 1986; 116: 50-58Scopus (133) Google Scholar, 23Zeisel S.H. Mar M.H. Howe J.C. Holden J.M. Concentrations of choline-containing compounds and betaine in common foods.J. Nutr. 2003; 133: 1302-1307Scopus (564) Google Scholar) is a large part. The suckling baby ingesting milk consumes only ∼150 mg of SM per day. SM accounts for ∼2% of the phospholipids in human bile, which means that 100–200 mg is delivered to the gut every day (24Alvaro D. Cantafora A. Attili A.F. Ginanni Corradini S. De Luca C. Minervini G. Di Biase A. Angelico M. Relationships between bile salts hydrophilicity and phospholipid composition in bile of various animal species.Comp. Biochem. Physiol. B. 1986; 83: 551-554Google Scholar), mainly the palmitoyl and stearoyl species (25Nibbering C.P. Carey M.C. Sphingomyelins of rat liver: biliary enrichment with molecular species containing 16:0 fatty acids as compared to canalicular-enriched plasma membranes.J. Membr. Biol. 1999; 167: 165-171Google Scholar). The brush border of the mucosal cells is rich in sphingolipids and is an additional source of endogenous SM. In dog and human chyle chylomicrons, SM accounts for ∼5% and 7%, respectively, of the total polar lipids (26Zilversmit D.B. The surface coat of chylomicrons: lipid chemistry.J. Lipid Res. 1968; 9: 180-186Google Scholar, 27Schlierf C. Falor W.H. Wood P.D. Lee Y.L. Kinsell L.W. Composition of human chyle chylomicrons following single fat feedings.Am. J. Clin. Nutr. 1969; 22: 79-86Google Scholar). Therefore, the question was early raised whether dietary SM could be absorbed intact and contribute to the chylomicron and plasma SM pools. Studies on lymphatic duct-cannulated rats that were fed [3H]sphingosine- or [14C]stearic acid-labeled SM, however, showed that little or no labeled SM was absorbed intact into the chyle (28Nilsson A. Metabolism of sphingomyelin in the intestinal tract of the rat.Biochim. Biophys. Acta. 1968; 164: 575-584Google Scholar). SM was sequentially hydrolyzed to ceramide and then to sphingosine and free fatty acids (29Nilsson A. The presence of sphingomyelin- and ceramide-cleaving enzymes in the small intestinal tract.Biochim. Biophys. Acta. 1969; 176: 339-347Google Scholar). Similarly, after feeding [3H]palmitoyl-sphingosine, no evidence was obtained for the incorporation of intact dietary ceramide into chyle lipoproteins either as ceramide or as SM, but the [3H]palmitic acid appears primarily in chyle TG. A small amount of radioactive ceramide was found in intestinal tissue, but it was not confirmed whether it was located intracellularly as a result of a slow absorption of intact long-chain ceramide or just associated to the mucosal surface. In contrast to SM and ceramide, free sphingosine is well absorbed and rapidly metabolized in the mucosal cells. Most of the absorbed sphingosine is converted to palmitic acid and incorporated into chylomicrons. The key enzymes in this reaction [i.e., sphingosine kinase (30Fukuda Y. Kihara A. Igarashi Y. Distribution of sphingosine kinase activity in mouse tissues: contribution of SPHK1.Biochem. Biophys. Res. Commun. 2003; 309: 155-160Google Scholar), sphingosine-1-phosphate lyase, and the palmitaldehyde oxidase] are all found at high levels in the intestinal mucosa (31van Veldhoven P.P. Mannaerts G.P. Sphingosine-phosphate lyase.Adv. Lipid Res. 1993; 26: 69-98Google Scholar). A smaller portion of the sphingoid bases are reincorporated into mucosal ceramide and more complex sphingolipids (28Nilsson A. Metabolism of sphingomyelin in the intestinal tract of the rat.Biochim. Biophys. Acta. 1968; 164: 575-584Google Scholar, 32Schmelz E.M. Crall K.J. Larocque R. Dillehay D.L. Merrill Jr., A.H. Uptake and metabolism of sphingolipids in isolated intestinal loops of mice.J. Nutr. 1994; 124: 702-712Google Scholar), and some of this newly formed ceramide appears as chyle ceramide rather than chyle SM (28Nilsson A. Metabolism of sphingomyelin in the intestinal tract of the rat.Biochim. Biophys. Acta. 1968; 164: 575-584Google Scholar). The pathways for the metabolism of dietary SM in the gut are summarized in Fig. 1. The initial step in the digestion of dietary SM in the gut is catalyzed by intestinal alkaline sphingomyelinase (SMase), which is present in all species examined except guinea pig (33Duan R.D. Hertervig E. Nyberg L. Hauge T. Sternby B. Lillienau J. Farooqi A. Nilsson A. Distribution of alkaline sphingomyelinase activity in human beings and animals. Tissue and species differences.Dig. Dis. Sci. 1996; 41: 1801-1806Google Scholar) and is also found in human bile (34Duan R.D. Nilsson A. Purification of a newly identified alkaline sphingomyelinase in human bile and effects of bile salts and phosphatidylcholine on enzyme activity.Hepatology. 1997; 26: 823-830Scopus (40) Google Scholar). Its longitudinal distribution shows a maximum in the jejunum. Recently, the enzyme was purified (35Cheng Y. Nilsson A. Tomquist E. Duan R.D. Purification, characterization, and expression of rat intestinal alkaline sphingomyelinase.J. Lipid Res. 2002; 43: 316-324Google Scholar, 36Duan R.D. Cheng Y. Hansen G. Hertervig E. Liu J.J. Syk I. Sjostrom H. Nilsson A. Purification, localization, and expression of human intestinal alkaline sphingomyelinase.J. Lipid Res. 2003; 44: 1241-1250Google Scholar) and cloned from both human and rat and found to lack homology to known neutral and acid SMases but to be related to the nucleotide-phosphodiesterase family (37Duan R.D. Bergman T. Xu N. Wu J. Cheng Y. Duan J. Nelander S. Palmberg C. Nilsson A. Identification of human intestinal alkaline sphingomyelinase as a novel ecto-enzyme related to the nucleotide phosphodiesterase family.J. Biol. Chem. 2003; 278: 38528-38536Google Scholar, 38Wu J. Cheng Y. Palmberg C. Bergman T. Nilsson A. Duan R.D. Cloning of alkaline sphingomyelinase from rat intestinal mucosa and adjusting of the hypothetical protein XP_221184 in GenBank.Biochim. Biophys. Acta. 2005; 1687: 94-102Google Scholar). However, it does not hydrolyze nucleotides like other nucleotide-phosphodiesterases but only choline phospholipids, preferring SM. The enzyme is strictly bile salt-dependent, taurocholate and taurochenodeoxycholate being the most effective stimulators. It is resistant to pancreatic proteases and can be released from the mucosa by bile salts and by tryptic digestion of a C-terminal peptide that anchors the enzyme to the brush border (39Wu J. Liu F. Nilsson A. Duan R.D. Pancreatic trypsin cleaves intestinal alkaline sphingomyelinase from mucosa and enhances the sphingomyelinase activity.Am. J. Physiol. Gastrointest. Liver Physiol. 2004; 287: G967-G973Google Scholar). Ceramide formed by alkaline SMase is further hydrolyzed by intestinal neutral ceramidase, which was recently purified from rat intestinal mucosa and characterized (40Olsson M. Duan R.D. Ohlsson L. Nilsson A. Rat intestinal ceramidase: purification, properties, and physiological relevance.Am. J. Physiol. Gastrointest. Liver Physiol. 2004; 287: G929-G937Google Scholar). The enzyme is identical to or highly homologous to the neutral ceramidase identified previously in the apical membrane of renal tubular cells (41Mitsutake S. Tani M. Okino N. Mori K. Ichinose S. Omori A. Iida H. Nakamura T. Ito M. Purification, characterization, molecular cloning, and subcellular distribution of neutral ceramidase of rat kidney.J. Biol. Chem. 2001; 276: 26249-26259Google Scholar) and the one shown by Choi et al. (42Choi M.S. Anderson M.A. Zhang Z. Zimonjic D.B. Popescu N. Mukherjee A.B. Neutral ceramidase gene: role in regulating ceramide-induced apoptosis.Gene. 2003; 315: 113-122Google Scholar) to be expressed at a high level in the gut and located at the brush border. Although the bile salt-stimulated lipase (BSSL) present in human milk and in pancreatic juice was shown to hydrolyze ceramide (43Nyberg L. Farooqi A. Blackberg L. Duan R.D. Nilsson A. Hernell O. Digestion of ceramide by human milk bile salt-stimulated lipase.J. Pediatr. Gastroenterol. Nutr. 1998; 27: 560-567Google Scholar), the mucosal ceramidase is probably more important for the digestion of ceramide formed from dietary SM than is BSSL (44Duan R.D. Cheng Y. Yang L. Ohlsson L. Nilsson A. Evidence for specific ceramidase present in the intestinal contents of rats and humans.Lipids. 2001; 36: 807-812Google Scholar). The neutral ceramidase has a longitudinal distribution that coincides with the main site of ceramide digestion (i.e., the middle and lower small intestine), where the ceramidase activity is not decreased in BSSL−/− mice (45Kirby R.J. Zheng S. Tso P. Howles P.N. Hui D.Y. Bile salt-stimulated carboxyl ester lipase influences lipoprotein assembly and secretion in intestine: a process mediated via ceramide hydrolysis.J. Biol. Chem. 2002; 277: 4104-4109Google Scholar). The level of BSSL is highest in the upper part of the intestine, where the action of BSSL on ceramide is expected to be inhibited by the presence of glycerolipids (43Nyberg L. Farooqi A. Blackberg L. Duan R.D. Nilsson A. Hernell O. Digestion of ceramide by human milk bile salt-stimulated lipase.J. Pediatr. Gastroenterol. Nutr. 1998; 27: 560-567Google Scholar). The course of SM digestion and thus the exposure of distal small intestine and colon to SM and its metabolites can be influenced by multiple factors, such as the amount of SM given, the presence of bile salts and other lipids, and the levels of the enzymes involved in SM digestion. Early studies indicated an extended course and a limited capacity of SM digestion. The recovery of SM [14C]stearic acid in chyle was lower than is generally obtained for glycerolipid fatty acids, and ∼25% of the sphingosine part appeared in feces, mainly as ceramide (28Nilsson A. Metabolism of sphingomyelin in the intestinal tract of the rat.Biochim. Biophys. Acta. 1968; 164: 575-584Google Scholar). This proportion, however, did not increase when the given dose was increased from 1 to 25 mg. Nyberg et al. (46Nyberg L. Duan R.D. Axelsson J. Nilsson Å. Localization and capacity of sphingomyelin digestion in the rat intestinal tract.J. Nutr. Biochem. 1997; 8: 112-118Google Scholar) fed 0.2 to 32 μmol of milk SM together with [3H]sphinganine-labeled dihydrosphingomyelin and analyzed the tissue and the content of four different levels of small intestine after 1–8 h as well as feces collected during 24 h. Increasing the dose increased the proportion and amount of undigested SM in the lower half of the gut, decreased the reincorporation of fatty acids in gut and liver tissue, and increased the output of SM and ceramide in feces. In a human study, Hertervig (47Hertervig E. Alkaline Sphingomyelinase, a Potential Inhibitor in Colorectal Carcinogenesis.PhD Dissertation. University of Lund, Lund, Sweden2000Google Scholar) found that feeding a dose of 250 mg of milk SM in a standardized meal significantly increased the output of both ceramide and intact SM in ileostomy content in humans, indicating an incomplete digestion and absorption of SM. Although the factors that are rate-limiting for the digestion of SM and ceramide are not fully understood, some relevant observations have been made. When radiolabeled SM was sonicated together with cholesterol or sitosterol and given orally to rats, the digestion of SM was delayed and colonic exposure was increased (48Nyberg L. Duan R. Nilsson A. A mutual inhibitory effect on absorption of sphingomyelin and cholesterol.J. Nutr. Biochem. 2000; 11: 244-249Google Scholar). Studies in vitro using purified alkaline SMase showed that the presence of either polar or nonpolar glycerolipids, or sterols, but not of free fatty acids, inhibited SM hydrolysis by purified alkaline SMase (49Liu J.J. Nilsson A. Duan R.D. In vitro effects of fat, FA, and cholesterol on sphingomyelin hydrolysis induced by rat intestinal alkaline sphingomyelinase.Lipids. 2002; 37: 469-474Google Scholar). The higher alkaline SMase in jejunum and ileum than in duodenum as well as the presence of higher concentrations of dietary glycerolipids in the upper part may thus favor the location of SM digestion primarily to the middle and lower small intestine. The regulation of alkaline SMase and ceramidase expression has not been studied extensively. Data from some studies in our laboratory indicate that expression of alkaline SMase and ceramidase can be affected by dietary factors and drugs. It was found that alkaline SMase was increased by psyllium and ursodeoxycholic acid (50Duan R.D. Cheng Y. Tauschel H.D. Nilsson A. Effects of ursodeoxycholate and other bile salts on levels of rat intestinal alkaline sphingomyelinase: a potential implication in tumorigenesis.Dig. Dis. Sci. 1998; 43: 26-32Google Scholar, 51Cheng Y. 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Because SM accounts for almost 40% of the polar lipids in human and cow milk, it is important to know whether the neonate can utilize the different components of the SM molecule and whether metabolites formed during the digestion of milk SM may influence normal gut function, maturation, and differentiation. This question has not been thoroughly investigated. Both alkaline SMase and neutral ceramidase, however, were early found to be present in human meconium (29Nilsson A. The presence of sphingomyelin- and ceramide-cleaving enzymes in the small intestinal tract.Biochim. Biophys. Acta. 1969; 176: 339-347Google Scholar), and studies on fetal and neonatal rats showed that alkaline SMase was promptly expressed soon before birth and the levels kept increasing to a plateau at 4 weeks after birth (53Lillienau J. Cheng Y. Nilsson A. Duan R.D. Development of intestinal alkaline sphingomyelinase in rat fetus and newborn rat.Lipids. 2003; 38: 545-549Google Scholar). Three week old suckling pigs had high levels of alkaline SMase in jejunum and ileum (54Nyberg L. Digestion and Absorption of Sphingomyelin from Milk.PhD Dissertation. Lund University, Lund, Sweden1998Google Scholar). The enzymes that digest SM are thus expressed when suckling starts. Acid SMase was shown to be secreted in milk (43Nyberg L. Farooqi A. Blackberg L. Duan R.D. Nilsson A. Hernell O. Digestion of ceramide by human milk bile salt-stimulated lipase.J. Pediatr. Gastroenterol. Nutr. 1998; 27: 560-567Google Scholar). Gastric and duodenal intubation studies of 11 suckling newborns, however, indicated that digestion of milk SM in stomach and upper duodenum is negligible, whereas three jejunal samples and two ileal samples obtained from babies undergoing surgery indicated ceramide formation in these regions of the gut (54Nyberg L. Digestion and Absorption of Sphingomyelin from Milk.PhD Dissertation. Lund University, Lund, Sweden1998Google Scholar). The transfer of nervonic acid, which occurs specifically in sphingolipids, to tissues of newborn rats from mother's milk supports the notion that milk SM is indeed digested and the fatty acids absorbed (55Bettger W.J. DiMichelle-Ranalli E. Dillingham B. Blackadar C.B. Nervonic acid is transferred from the maternal diet to milk and tissues of suckling rat pups.J. Nutr. Biochem. 2003; 14: 160-165Google Scholar). During the period from birth to weanling, there is a continuous change in the lipid composition of both the brush border and the basolateral membrane of the gut epithelium. Whereas the brush border increases its cholesterol and SM content during suckling, there is a progressive decrease in the SM/PC ratio in the basolateral membrane (56Schwarz S.M. Hostetler B. Ling S. Mone M. Watkins J.B. Intestinal membrane lipid composition and fluidity during development in the rat.Am. J. Physiol. 1985; 248: G200-G207Google Scholar, 57Schwarz S.M. Bostwick H.E. Danziger M.D. Newman L.J. Medow M.S. Ontogeny of basolateral membrane lipid composition and fluidity in small intestine.Am. J. Physiol. 1989; 257: G138-G144Google Scholar). The physiological relevance of these changes and whether the supply of SM in milk contributes to these changes are unknown. Because of the extended and slow digestion, SM may influence the course of the digestion and absorption of other lipids by physical effects in the gut lumen or via biological effects of the metabolites. It is known that the rate of hydrolysis of emulsified TG by pancreatic colipase-dependent lipase may be inhibited by the presence of phospholipids on the polar surface. A previous study by Borgström (58Borgström B. Importance of phospholipids, pancreatic phospholipase A2, and fatty acid for the digestion of dietary fat: in vitro experiments with the porcine enzymes.Gastroenterology. 1980; 78: 954-962Abstract Full Text PDF Google Scholar) showed that simultaneous treatment of TG emulsion by phospholipase A2 significantly shortened the lag time of TG hydrolysis by pancreatic lipase. Patton and Carey (59Patton J.S. Carey M.C. Inhibition of human pancreatic lipase-colipase activity by mixed bile salt-phospholipid micelles.Am. J. Physiol. 1981; 241: G328-G336Google Scholar) found that bile salt phospholipid micelles, including SM-bile salt micelles, could displace colipase from gum arabic emulsified substrate and inhibit the lipolysis of TG. Therefore, it is possible that the presence of SM and the slow hydrolysis of SM extend the course of TG hydrolysis, which has been demonstrated in vitro. SM has been shown to inhibit cholesterol absorption both in vivo and in CaCo2 cell cultures. When equimolar amounts of cholesterol and SM were fed orally to rats as sonicated dispersions, only 10% of the radioactive cholesterol was absorbed, as estimated by the dual isotope method (48Nyberg L. Duan R. Nilsson A. A mutual inhibitory effect on absorption of sphingomyelin and cholesterol.J. Nutr. Biochem. 2000; 11: 244-249Google Scholar). The inhibitory effect was mutual in the sense that cholesterol and plant sterols also decreased the digestion and absorption of SM (48Nyberg L. Duan R. Nilsson A. A mutual inhibitory effect on absorption of sphingomyelin and cholesterol.J. Nutr. Biochem. 2000; 11: 244-249Google Scholar). Incorporation of cholesterol into SM-PC vesicles was shown to have profound effects on detergent-induced phase transitions, indicating a physicochemical cause of the absorption inhibition (60Moschetta A. Frederik P.M. Portincasa P. vanBerge-Henegouwen G.P. van Erpecum K.J. Incorporation of cholesterol in sphingomyelin- phosphatidylcholine vesicles has profound effects on detergent-induced phase transitions.J. Lipid Res. 2002; 43: 1046-1053Google Scholar). In support of this possibility, Eckhardt et al. (61Eckhardt E.R. Wang D.Q. Donovan J.M. Carey M.C. Dietary sphingomyelin suppresses intestinal cholesterol absorption by decreasing thermodynamic activity of cholesterol monomers.Gastroenterology. 2002; 122: 948-956Google Scholar) correlated the effect of SM on the partitioning of cholesterol from bile salt solutions to polymerized silicone to an inhibitory effect of SM on cholesterol uptake in vivo and in differentiated CaCo2 cells. When cholesterol absorption was studied in lymphatic duct-cannulated rats, both egg SM and milk SM decreased cholesterol absorption, milk SM being most effective (62Noh S.K. Koo S.I. Egg sphingomyelin lowers the lymphatic absorption of cholesterol and alpha-tocopherol in rats.J. Nutr. 2003; 133: 3571-3576Google Scholar, 63Noh S.K. Koo S.I. Milk sphingomyelin is more effective than egg sphingomyelin in inhibiting intestinal absorption of cholesterol and fat in rats.J. Nutr. 2004; 134: 2611-2616Google Scholar). Interestingly, the lymphatic output of SM decreased rather than increased during SM feeding. Whether this reflects a decreased incorporation of SM into chylomicrons secondary to the decreased cholesterol absorption is unknown. Studies by Kirby et al. (45Kirby R.J. Zheng S. Tso P. Howles P.N. Hui D.Y. Bile salt-stimulated carboxyl ester lipase influences lipoprotein assembly and secretion in intestine: a process mediated via ceramide hydrolysis.J. Biol. Chem. 2002; 277: 4104-4109Google Scholar) and by Field and colleagues (64Chen H. Born E. Mathur S.N. Johlin Jr., F.C. Field F.J. Sphingomyelin content of intestinal cell membranes regulates cholesterol absorption. Evidence for pancreatic and intestinal cell sphingomyelinase activity.Biochem. J. 1992; 286: 771-777Google Scholar, 65Field F.J. Chen H. Born E. Dixon B. Mathur S. Release of ceramide after membrane sphingomyelin hydrolysis decreases the basolateral secretion of triacylglycerol and apolipoprotein B in cultured human intestinal cells.J. Clin. Invest. 1993; 92: 2609-2619Google Scholar) showed an increased uptake of cholesterol by CaCo2 cells after hydrolysis of SM or ceramide. Recently, sphingosine was shown to decrease cholesterol absorption in CaCo2 cells and to downregulate the Niemann-Pick-Like Protein 1, which has been implicated as a key protein in cholesterol absorption and a target for the cholesterol absorption inhibitor ezetimibe (66Garmy N. Taieb N. Yahi N. Fantini J. Interaction of cholesterol with sphingosine: physicochemical characterization and impact on intestinal absorption.J. Lipid Res. 2005; 46: 36-45Google Scholar). Not only the physical interaction of SM in gut lumen but also regulatory influences of the metabolites may thus influence cholesterol absorption and lipoprotein composition. The conclusion is that dietary SM may influence cholesterol absorption and lipoprotein metabolism in the gut by several mechanisms. The important questions of whether SM may influence the absorption of endogenous cholesterol and postprandial lipoprotein metabolism in humans have not been answered. Because ceramide and sphingosine are well-known regulators of cell growth, differentiation, and apoptosis, the questions have been asked whether the metabolites formed from dietary SM may influence the cell cycle of the gut epithelium under normal and tumorigenic conditions, and whether sphingolipid metabolites regulate normal proliferation and differentiation in the crypt cell progenitor compartment and cell fate along the crypt villous axis. Choi et al. (42Choi M.S. Anderson M.A. Zhang Z. Zimonjic D.B. Popescu N. Mukherjee A.B. Neutral ceramidase gene: role in regulating ceramide-induced apoptosis.Gene. 2003; 315: 113-122Google Scholar) found increased apoptosis in absorptive villous cells after feeding a short-chain ceramide, if ceramidase was blocked, and suggested that the brush border ceramidase is needed to protect absorptive cells from the apoptotic effect of absorbed ceramide. Whether this can be applied to long-chain ceramides that are expected to be less effectively absorbed than the short-chain ceramide is not known. SM in the milk may have important roles in the mucosal development of intestine in the newborn. Milk replacement formulas regularly contain far less SM than does mother's milk. Motouri et al. (67Motouri M. Matsuyama H. Yamamura J. Tanaka M. Aoe S. Iwanaga T. Kawakami H. Milk sphingomyelin accelerates enzymatic and morphological maturation of the intestine in artificially reared rats.J. Pediatr. Gastroenterol. Nutr. 2003; 36: 241-247Google Scholar) fed SM-enriched milk formulas or an equivalent amount of PC to suckling rat pups and found lower lactase levels, a larger Auerbach nerve plexus, and restriction of vacuolated epithelial cells to the villous tip in the SM group. More extensive studies in this area, including examination of the intestinal immune system, are needed. As reviewed by Schmelz (68Schmelz E.M. Sphingolipids in the chemoprevention of colon cancer.Front. Biosci. 2004; 9: 2632-2639Google Scholar) and by Duan (69Duan R.D. Anticancer compounds and sphingolipid metabolism in the colon.In Vivo. 2005; 19: 293-300Google Scholar), several pieces of evidence indicate that sphingolipid metabolism may mediate anticarcinogenic mechanisms in the colon. Feeding sphingolipids to animals treated with the chemical carcinogen dimethylhydrazine or to MIN mice, an animal model for human familial adenomatous polyposis, showed an inhibitory effect on both the initiation and propagation of colon tumors. Studies on colon cancer HT9 cells showed that sphingosine induced apoptosis and the inhibition of proliferation by interacting with the β-catenin system (70Schmelz E.M. Roberts P.C. Kustin E.M. Lemonnier L.A. Sullards M.C. Dillehay D.L. Merrill Jr., A.H. Modulation of intracellular beta-catenin localization and intestinal tumorigenesis in vivo and in vitro by sphingolipids.Cancer Res. 2001; 61: 6723-6729Google Scholar). Antitumor effects of SM in the gut may thus be exerted by increasing the exposure of the gut to its degradation products ceramide and/or sphingosine. Although alkaline SMase is expressed at the highest level in the middle and lower small intestine (71Duan R.D. Nilsson A. Sphingolipid hydrolyzing enzymes in the gastrointestinal tract.Methods Enzymol. 2000; 311: 276-286Google Scholar), it is found also in the colon mucosa. The enzyme activity was low in many colon tumors, in mucosa from familial adenomatous polyposis patients (72Hertervig E. Nilsson A. Nyberg L. Duan R.D. Alkaline sphingomyelinase activity is decreased in human colorectal carcinoma.Cancer. 1997; 79: 448-453Google Scholar, 73Hertervig E. Nilsson A. Bjork J. Hultkrantz R. Duan R.D. Familial adenomatous polyposis is associated with a marked decrease in alkaline sphingomyelinase activity: a key factor to the unrestrained cell proliferation?.Br. J. Cancer. 1999; 81: 232-236Google Scholar), and in stools of colorectal cancer patients (74Di Marzio L. Di Leo A. Cinque B. Fanini D. Agnifili A. Berloco P. Linsalata M. Lorusso D. Barone M. De Simone C. et al.Detection of alkaline sphingomyelinase activity in human stool: proposed role as a new diagnostic and prognostic marker of colorectal cancer.Cancer Epidemiol. Biomarkers Prev. 2005; 14: 856-862Google Scholar). Purified alkaline SMase was shown to inhibit the proliferation of colon cancer HT29 cells (75Hertervig E. Nilsson A. Cheng Y. Duan R.D. Purified intestinal alkaline sphingomyelinase inhibits proliferation without inducing apoptosis in HT-29 colon carcinoma cells.J. Cancer Res. Clin. Oncol. 2003; 129: 577-582Google Scholar). Recently, we found that this cell line has an inactivating mutation in the alkaline SMase gene (76Wu J. Cheng Y. Nilsson A. Duan R.D. Identification of one exon deletion of intestinal alkaline sphingomyelinase in colon cancer HT-29 cells and a differentiation-related expression of the wild-type enzyme in Caco-2 cells.Carcinogenesis. 2004; 25: 1327-1333Google Scholar). Under normal conditions, notably substantial amounts of alkaline SMase and intestinal ceramidase reach the colon in the intestinal content. These enzymes may protect the colonic mucosa from tumorigenesis by generating ceramide and sphingosine in the colon. SM is present in bile, where it accounts for a small minority of the total phospholipids in most species examined (24Alvaro D. Cantafora A. Attili A.F. Ginanni Corradini S. De Luca C. Minervini G. Di Biase A. Angelico M. Relationships between bile salts hydrophilicity and phospholipid composition in bile of various animal species.Comp. Biochem. Physiol. B. 1986; 83: 551-554Google Scholar). There is convincing evidence that phospholipids in bile prevent cytotoxicity induced by bile salts (77Elferink R.P. Groen A.K. The mechanism of biliary lipid secretion and its defects.Gastroenterol. Clin. North Am. 1999; 28 (vi): 59-74Google Scholar). Although SM accounts for a small part of the bile phospholipids, it may contribute to this effect (78Moschetta A. vanBerge-Henegouwen G.P. Portincasa P. Palasciano G. Groen A.K. van Erpecum K.J. Sphingomyelin exhibits greatly enhanced protection compared with egg yolk phosphatidylcholine against detergent bile salts.J. Lipid Res. 2000; 41: 916-924Google Scholar), particularly in the lower small intestine, where some undigested SM persists but where most other lipids but not the bile salts have been absorbed. SM was also found to prevent deoxycholate-induced apoptosis and hyperproliferation in CaCo2 cells. This provides an alternative mechanism by which SM may have anticarcinogenic effects in colon (79Moschetta A. Portincasa P. van Erpecum K.J. Debellis L. Vanberge-Henegouwen G.P. Palasciano G. Sphingomyelin protects against apoptosis and hyperproliferation induced by deoxycholate: potential implications for colon cancer.Dig. Dis. Sci. 2003; 48: 1094-1101Google Scholar). SM digestion is an extended process with limited capacity and is catalyzed primarily by alkaline SMase and neutral ceramidase, which are in part released into and act in the gut lumen. The generated sphingosine is well absorbed and effectively metabolized in the mucosal cells. SM and its metabolites in the gut may inhibit TG hydrolysis and cholesterol absorption and affect cell proliferation and maturation. The slow and extended digestion of SM makes it possible to increase the exposure of the whole gut to SM and its metabolites by dietary means. However, many questions regarding the biological effects or the mechanism of the effects remain to be solved, such as the factors limiting ceramide assimilation and the effects on cell growth and differentiation in both the neonate and the adult. It is still not known whether SM has a significant effect on postprandial lipoproteins in humans.
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