ENPP7 explained

Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (E-NPP 7) also known as alkaline sphingomyelin phosphodiesterase (Alk-SMase) or intestinal alkaline sphingomyelinase is an enzyme that in humans is encoded by the ENPP7 gene.[1] [2]

History

ENPP7 is a new name for an old enzyme whose activity was originally identified in 1969 by Nilsson as a type of sphingomyelinase that hydrolyses sphingomyelin to ceramide in the intestinal tract.[3] The enzyme was then purified and characterized by Duan et al. and named alkaline sphingomyelinase (alk-SMase), as the optimal pH of the enzyme was 9.0 and its main substrate is sphingomyelin.[4] [5] Most previous studies used the name of alk-SMase for this protein. The name of ENPP7 was created based on the results of cloning studies which show that alk-SMase shares no structural similarities with either acid or neutral SMase but belongs to the family of ecto nucleotide pyrophosphatase/phosphodiesterase (ENPP).[6] As a new addition to the family it is therefore called ENPP7 or NPP7. A 3D homology model of ENPP7 was recently constructed using the crystal structural of an NPP member in bacteria as a template.[7] [8]

Tissue distribution

Differing from other ENPP members, ENPP7 seems only expressed in the intestinal mucosa in many species and additionally in human liver. In the intestinal tract, ENPP7 activity is low in the duodenum and colon but high in the middle of the jejunum.[9] As an ecto enzyme, ENPP7 is located on the surface of the intestinal mucosa and is released in the lumen by bile salt and pancreatic trypsin.[10] The enzyme expressed in human liver is released in the bile and delivered to the intestine.

The activity of ENPP7 depends specifically on two types of primary bile salts, taurocholate (TC) and taurochenodeoxycholate (TCDC) at critical micelle concentrations.[11] Other detergents, such as CHAPS and Triton X-100 have no stimulatory effects rather inhibitory effects, indicating a biologic interaction between bile salts and the enzyme. Unlike acid and neutral SMases in the intestinal tract that are rapidly inactivated by pancreatic trypsin,[9] alk-SMase is resistant to trypsin digestion.[12] Thus ENPP7 is active in the intestinal lumen and is transported along the intestinal tract. Significant activity can be detected in the faeces.

The substrates of ENPP family vary greatly. Some have activity against nucleotides, some have activity against phospholipid and lysophospholipids.[13] ENPP7 is the only enzyme that has a type of phospholipase C activity against sphingomyelin.

Physiological functions and clinical implications

ENPP7 is the key enzyme in the gut that digests sphingomyelin. Sphingomyelin is a lipid constituent of cell membrane, and a dietary component being particularly abundant in milk, cheese, egg, and meat.[14] Digestion of sphingomyelin mainly occurs in the middle part of the small intestine, where ENPP7 is abundant, indicating a role of the enzyme in sphingomyelin digestion.[15] Recent studies on ENPP7 knockout mice clearly showed that digestion of sphingomyelin and generation of ceramide is severely affected in ENPP7 deficiency mice. ENPP7 is fully developed in the intestine before birth,[16] [17] which gives the infant ability to digest sphingomyelin in the milk.

The daily intake of sphingomyelin for human with Western diet is about 300 mg. Under physiological conditions, only part of the sphingomyelin can be digested and absorbed.[18] The limitation is thought to be caused by several factors that are present in the intestine such as cholesterol, phospholipids, fat and high concentrations of bile salts.[19] It is thus understandable why SM digestion occurs most effectively in the low part of the small intestine, where most fat, phospholipids, and bile salt have been absorbed or up taken. It is also understandable that considerable amount of dietary sphingomyelin is delivered into the colon and excreted in the feces.[15] [20] [21]

ENPP7 may have important roles in preventing tumorigenesis in the intestinal tract, as ceramide, the product of sphingomyelin hydrolysis, can inhibit cell proliferation and stimulate cell differentiation and apoptosis. Animal studies showed that supplement of SM or ceramide in the diet may inhibit the development of colon cancer.[22] Of particular interest is that the activity of ENPP7 is significantly decreased in human colorectal adenoma and carcinoma as well as in the feces of the cancer patients.[23] [24] [25] The decrease is caused by expression of a few mutant forms of ENPP7, which lack exon 4, resulting in total inactivation of the enzyme, as found in human colon and liver cancer cells.[11] [26] [27]

Besides sphingomyelin, ENPP7 can also degrade and inactivate platelet-activating factor (PAF), which is proinflammatory, indicating that ENPP7 may also have antiinflammatory effects.[28] Rectal administration of recombinant ENPP7 has been shown to improve ulcerative colitis in an animal study,[29] and patients with chronic ulcerative colitis are associated with a reduced ENPP7 activity.[30]

ENPP7 may also affect cholesterol absorption. In the intestinal tract cholesterol and sphingomyelin are co-exiting in plasma membrane and in lipid vesicles, liposomes and micelles. The two molecules form a stable complex via van der Waals forces. Cholesterol absorption can be inhibited by supplementation of sphingomyelin in the diet.[31] Milk sphingomyelin seems more potent than egg sphingomyelin, indicating that the inhibition is related to the degree of the saturation and the length of sphingomyelin.[32] Recent studies further showed that formation of ceramide by ENPP7 in the gut enhanced sphingomyelin-induced inhibition of cholesterol,[33] indicating regulatory roles of ENPP7 in cholesterol absorption.

Regulation

The expression of ENPP7 can be modified by dietary factors. High fat diet (53% energy) greatly reduces ENPP7 activities and enzyme protein in the intestinal mucosa by 50%.[34] On the other hand, water-soluble fiber psyllium was shown to increase both the activities and protein of ENPP7 in the colon of mice.[34] Sphingomyelin can also increase the levels of ENPP7 after a long term of administration.[35] Besides, ursodeoxycholic acid and probiotic VSL#3 may stimulate the expression of ENPP7 in the intestine.[36] [37]

Further reading

Notes and References

  1. Duan RD, 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 . 278 . 40 . 38528–36 . Sep 2003 . 12885774 . 10.1074/jbc.M305437200 . free .
  2. Web site: Entrez Gene: ENPP7 ectonucleotide pyrophosphatase/phosphodiesterase 7.
  3. Nilsson A . The presence of sphingomyelin- and ceramide-cleaving enzymes in the small intestinal tract . Biochim. Biophys. Acta . 176 . 2 . 339–47 . March 1969 . 5775951 . 10.1016/0005-2760(69)90192-1.
  4. Cheng Y, Nilsson A, Tömquist E, Duan RD . Purification, characterization, and expression of rat intestinal alkaline sphingomyelinase . J. Lipid Res. . 43 . 2 . 316–24 . February 2002 . 10.1016/S0022-2275(20)30174-7 . 11861674 . free .
  5. Duan RD, Cheng Y, Hansen G, Hertervig E, Liu JJ, Syk I, Sjostrom H, Nilsson A . Purification, localization, and expression of human intestinal alkaline sphingomyelinase . J. Lipid Res. . 44 . 6 . 1241–50 . June 2003 . 12671034 . 10.1194/jlr.M300037-JLR200 . free .
  6. Wu J, Cheng Y, Palmberg C, Bergman T, Nilsson A, Duan RD . Cloning of alkaline sphingomyelinase from rat intestinal mucosa and adjusting of the hypothetical protein XP_221184 in GenBank . Biochim. Biophys. Acta . 1687 . 1–3 . 94–102 . February 2005 . 15708357 . 10.1016/j.bbalip.2004.11.006 .
  7. Duan J, Wu J, Cheng Y, Duan RD . Understanding the molecular activity of alkaline sphingomyelinase (NPP7) by computer modeling . Biochemistry . 49 . 42 . 9096–105 . October 2010 . 20839774 . 10.1021/bi101069u .
  8. Suresh PS, Olubiyi O, Thirunavukkarasu C, Strodel B, Kumar MS . Molecular modeling of human alkaline sphingomyelinase. . Bioinformation . 6 . 2 . 9096–105 . March 2011 . 10.6026/97320630006078. 21544170 . 3082857.
  9. Duan RD, Nyberg L, Nilsson A . Alkaline sphingomyelinase activity in rat gastrointestinal tract: distribution and characteristics . Biochim. Biophys. Acta . 1259 . 1 . 49–55 . October 1995 . 7492615 . 10.1016/0005-2760(95)00137-2.
  10. Duan RD, Cheng Y, Tauschel HD, Nilsson A . Effects of ursodeoxycholate and other bile salts on levels of rat intestinal alkaline sphingomyelinase: a potential implication in tumorigenesis . Dig. Dis. Sci. . 43 . 1 . 26–32 . January 1998 . 9508530 . 10.1023/A:1018807600683. 2473970 .
  11. Duan RD . Alkaline sphingomyelinase: an old enzyme with novel implications . Biochim. Biophys. Acta . 1761 . 3 . 281–91 . March 2006 . 16631405 . 10.1016/j.bbalip.2006.03.007 .
  12. Wu J, Liu F, Nilsson A, Duan RD . Pancreatic trypsin cleaves intestinal alkaline sphingomyelinase from mucosa and enhances the sphingomyelinase activity . Am. J. Physiol. Gastrointest. Liver Physiol. . 287 . 5 . G967–73 . November 2004 . 15205117 . 10.1152/ajpgi.00190.2004 .
  13. Stefan C, Jansen S, Bollen M . NPP-type ectophosphodiesterases: unity in diversity . Trends Biochem. Sci. . 30 . 10 . 542–50 . October 2005 . 16125936 . 10.1016/j.tibs.2005.08.005 .
  14. Duan RD . Sphingomyelin hydrolysis in the gut and clinical implications in colorectal tumorigenesis and other gastrointestinal diseases . Scand. J. Gastroenterol. . 33 . 7 . 673–83 . July 1998 . 9712229 . 10.1080/00365529850171594.
  15. 10.1016/S0955-2863(97)00010-7 . Nyberg L, Nilsson Å, Lundgren P, Duan RD . Localization and capacity of sphingomyelin digestion in the rat intestinal tract . The Journal of Nutritional Biochemistry . 1997 . 8 . 3 . 112–118 . https://archive.today/20130126213355/http://www.jnutbio.com/article/S0955-2863(97)00010-7/abstract . dead . January 26, 2013 .
  16. Duan RD, Cheng Y, Jönsson BA, Ohlsson L, Herbst A, Hellström-Westas L, Nilsson A . Human meconium contains significant amounts of alkaline sphingomyelinase, neutral ceramidase, and sphingolipid metabolites . Pediatr. Res. . 61 . 1 . 61–6 . January 2007 . 17211142 . 10.1203/01.pdr.0000250534.92934.c2 . free .
  17. Lillienau J, Cheng Y, Nilsson A, Duan RD . Development of intestinal alkaline sphingomyelinase in rat fetus and newborn rat . Lipids . 38 . 5 . 545–9 . May 2003 . 12880111 . 10.1007/s11745-003-1340-1. 4026200 .
  18. Book: Nilsson A, Hertervig E, Duan RD . Willem van Nieuwenhuyzen . Bernard F. Szuchaj . Nutrition and Biochemistry of Phospholipids . AOCS Publishing . 2003 . 1-893997-42-1. Digestion and absorption of sphingolipids in food .
  19. Liu JJ, Nilsson A, Duan RD . Effects of phospholipids on sphingomyelin hydrolysis induced by intestinal alkaline sphingomyelinase: an in vitro study . J. Nutr. Biochem. . 11 . 4 . 192–7 . April 2000 . 10827341 . 10.1016/S0955-2863(00)00064-4.
  20. Nilsson A . Metabolism of sphingomyelin in the intestinal tract of the rat . Biochim. Biophys. Acta . 164 . 3 . 575–84 . December 1968 . 5701698 . 10.1016/0005-2760(68)90187-2.
  21. Ohlsson L, Hertervig E, Jönsson BA, Duan RD, Nyberg L, Svernlöv R, Nilsson A . Sphingolipids in human ileostomy content after meals containing milk sphingomyelin . Am. J. Clin. Nutr. . 91 . 3 . 672–8 . March 2010 . 20071649 . 10.3945/ajcn.2009.28311 . free .
  22. Dillehay DL, Webb SK, Schmelz EM, Merrill AH . Dietary sphingomyelin inhibits 1,2-dimethylhydrazine-induced colon cancer in CF1 mice . J. Nutr. . 124 . 5 . 615–20 . May 1994 . 8169652 . 10.1093/jn/124.5.615. free .
  23. Hertervig E, Nilsson A, Nilbert M, Duan RD . Reduction in alkaline sphingomyelinase in colorectal tumorigenesis is not related to the APC gene mutation . Int J Colorectal Dis . 18 . 4 . 309–13 . July 2003 . 12774245 . 10.1007/s00384-002-0471-y . 2133507 .
  24. Hertervig E, Nilsson A, Nyberg L, Duan RD . Alkaline sphingomyelinase activity is decreased in human colorectal carcinoma . Cancer . 79 . 3 . 448–53 . February 1997 . 9028353 . 10.1002/(SICI)1097-0142(19970201)79:3<448::AID-CNCR4>3.0.CO;2-E. 32446993 .
  25. Di Marzio L, Di Leo A, Cinque B, Fanini D, Agnifili A, Berloco P, Linsalata M, Lorusso D, Barone M, De Simone C, Cifone MG . Detection of alkaline sphingomyelinase activity in human stool: proposed role as a new diagnostic and prognostic marker of colorectal cancer . Cancer Epidemiol. Biomarkers Prev. . 14 . 4 . 856–62 . April 2005 . 15824156 . 10.1158/1055-9965.EPI-04-0434 . free .
  26. Cheng Y, Wu J, Hertervig E, Lindgren S, Duan D, Nilsson A, Duan RD . Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis . Br. J. Cancer . 97 . 10 . 1441–8 . November 2007 . 17923876 . 2360232 . 10.1038/sj.bjc.6604013 .
  27. Wu J, Cheng Y, Nilsson A, Duan RD . 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 . 25 . 8 . 1327–33 . August 2004 . 15016655 . 10.1093/carcin/bgh140 . free .
  28. Wu J, Nilsson A, Jönsson BA, Stenstad H, Agace W, Cheng Y, Duan RD . Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity . Biochem. J. . 394 . Pt 1 . 299–308 . February 2006 . 16255717 . 1386028 . 10.1042/BJ20051121 .
  29. Andersson D, Kotarsky K, Wu J, Agace W, Duan RD . Expression of alkaline sphingomyelinase in yeast cells and anti-inflammatory effects of the expressed enzyme in a rat colitis model . Dig. Dis. Sci. . 54 . 7 . 1440–8 . July 2009 . 18989780 . 10.1007/s10620-008-0509-2 . 40115990 .
  30. Sjöqvist U, Hertervig E, Nilsson A, Duan RD, Ost A, Tribukait B, Löfberg R . Chronic colitis is associated with a reduction of mucosal alkaline sphingomyelinase activity . Inflamm. Bowel Dis. . 8 . 4 . 258–63 . July 2002 . 12131609 . 10.1097/00054725-200207000-00004. 23648078 . free .
  31. Nyberg L, Duan RD, Nilsson A . A mutual inhibitory effect on absorption of sphingomyelin and cholesterol . J. Nutr. Biochem. . 11 . 5 . 244–9 . May 2000 . 10876096 . 10.1016/S0955-2863(00)00069-3.
  32. Noh SK, Koo SI . Milk sphingomyelin is more effective than egg sphingomyelin in inhibiting intestinal absorption of cholesterol and fat in rats . J. Nutr. . 134 . 10 . 2611–6 . October 2004 . 15465755 . 10.1093/jn/134.10.2611. free .
  33. Feng D, Ohlsson L, Ling W, Nilsson A, Duan RD . Generating Ceramide from Sphingomyelin by Alkaline Sphingomyelinase in the Gut Enhances Sphingomyelin-Induced Inhibition of Cholesterol Uptake in Caco-2 Cells . Dig. Dis. Sci. . 55. 12. 3377–83. April 2010 . 20393874 . 10.1007/s10620-010-1202-9 . 9945168 .
  34. Cheng Y, Ohlsson L, Duan RD . Psyllium and fat in diets differentially affect the activities and expressions of colonic sphingomyelinases and caspase in mice . Br. J. Nutr. . 91 . 5 . 715–23 . May 2004 . 15137923 . 10.1079/BJN20041107 . free .
  35. Zhang P, Li B, Gao S, Duan RD . Dietary sphingomyelin inhibits colonic tumorigenesis with an up-regulation of alkaline sphingomyelinase expression in ICR mice . Anticancer Res. . 28 . 6A . 3631–5 . 2008 . 19189644 .
  36. Liu F, Cheng Y, Wu J, Tauschel HD, Duan RD . Ursodeoxycholic acid differentially affects three types of sphingomyelinase in human colon cancer Caco 2 cells . Cancer Lett. . 235 . 1 . 141–6 . April 2006 . 16290921 . 10.1016/j.canlet.2005.04.016 .
  37. Soo I, Madsen KL, Tejpar Q, Sydora BC, Sherbaniuk R, Cinque B, Di Marzio L, Cifone MG, Desimone C, Fedorak RN . VSL#3 probiotic upregulates intestinal mucosal alkaline sphingomyelinase and reduces inflammation . Can. J. Gastroenterol. . 22 . 3 . 237–42 . March 2008 . 18354751 . 2662197 . 10.1155/2008/520383. free .

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