Neutral cholesterol ester hydrolase 1 explained

Neutral cholesterol ester hydrolase 1 (NCEH) also known as arylacetamide deacetylase-like 1 (AADACL1) or KIAA1363 is an enzyme that in humans is encoded by the NCEH1 gene.^[1]

NCEH is an enzyme located in the endoplasmic reticulum. NCEH hydrolyzes 2-acetyl monoalkylglycerol ether, as part of an enzymatic pathway regulating the levels of platelet activating factor and lysophospholipids that may be involved in cancer development.^{[2] [3]}

Function

The enzymatic reaction catalyzed by NCEH is:^[2]

• 2-acetyl monoalkylglycerol ether → monoalkylglycerol ether

Monoalkylglycerol ethers (MAGEs) can then be converted to lysophospholipids alkyl-lysophosphatidic acid (alkyl-LPA) and alkyl-lysophosphatidylcholine (alkyl-LPC).

Controversial studies by one group also implicate the protein in the hydrolysis of cholesterol esters.^[4] However, loss of the protein in mice selectively reduces 2-acetyl monoalkylglycerol ether activity throughout the body.^[3]

Clinical significance

Evidence suggests a role for NCEH in cancer. Cancer cell lines contain unusually high levels of the protein.^[5] Reduction of the amount of NCEH1 in cancer cells reduces tumor migration and growth in mice and addition of alkyl-LPA restores these processes.^[2]

NCEH can break down organophosphates like the pesticide metabolite chlorpyrifos oxon.^[6] Conversely, enzymatic activity can be inhibited by organophosphates.^[7]

Structure

NCEH is a serine hydrolase that contains an N-terminal transmembrane domain, a central catalytic domain and a lipid-binding domain at its C-terminus.^[8] The protein exists in three isoforms that result from differences in mRNA splicing. Transcripts encode a protein for isoform a of 448, b of 440 and c of 275 amino acids long.

See also

• Autotaxin
• phosphatidic acid
• Lysophospholipid receptor
• LPA signaling

Further reading

• Herman AG, Stockwell BR . Enzyme annotation with chemical tools . Chemistry & Biology . 13 . 10 . 1013–1014 . Oct 2006 . 17052604 . 10.1016/j.chembiol.2006.10.002 . free .
• Chiang KP, Niessen S, Saghatelian A, Cravatt BF . An enzyme that regulates ether lipid signaling pathways in cancer annotated by multidimensional profiling . Chemistry & Biology . 13 . 10 . 1041–1050 . Oct 2006 . 17052608 . 10.1016/j.chembiol.2006.08.008 . free .
• Okazaki H, Igarashi M, Nishi M, Sekiya M, Tajima M, Takase S, Takanashi M, Ohta K, Tamura Y, Okazaki S, Yahagi N, Ohashi K, Amemiya-Kudo M, Nakagawa Y, Nagai R, Kadowaki T, Osuga J, Ishibashi S . Identification of neutral cholesterol ester hydrolase, a key enzyme removing cholesterol from macrophages . The Journal of Biological Chemistry . 283 . 48 . 33357–33364 . Nov 2008 . 18782767 . 2662263 . 10.1074/jbc.M802686200 . free .
• Yilmaz S, Boffito M, Collot-Teixeira S, De Lorenzo F, Waters L, Fletcher C, Back D, Pozniak A, Gazzard B, McGregor JL . Investigation of low-dose ritonavir on human peripheral blood mononuclear cells using gene expression whole genome microarrays . Genomics . 96 . 1 . 57–65 . Jul 2010 . 20353815 . 10.1016/j.ygeno.2010.03.011 . free .
• Igarashi M, Osuga J, Uozaki H, Sekiya M, Nagashima S, Takahashi M, Takase S, Takanashi M, Li Y, Ohta K, Kumagai M, Nishi M, Hosokawa M, Fledelius C, Jacobsen P, Yagyu H, Fukayama M, Nagai R, Kadowaki T, Ohashi K, Ishibashi S . The critical role of neutral cholesterol ester hydrolase 1 in cholesterol removal from human macrophages . Circulation Research . 107 . 11 . 1387–1395 . Nov 2010 . 20947831 . 10.1161/CIRCRESAHA.110.226613 . free .

Notes and References

1. Web site: Entrez Gene: Neutral cholesterol ester hydrolase 1.
2. Chiang KP, Niessen S, Saghatelian A, Cravatt BF . An enzyme that regulates ether lipid signaling pathways in cancer annotated by multidimensional profiling . Chemistry & Biology . 13 . 10 . 1041–50 . Oct 2006 . 17052608 . 10.1016/j.chembiol.2006.08.008 . free .
3. Buchebner M, Pfeifer T, Rathke N, Chandak PG, Lass A, Schreiber R, Kratzer A, Zimmermann R, Sattler W, Koefeler H, Fröhlich E, Kostner GM, Birner-Gruenberger R, Chiang KP, Haemmerle G, Zechner R, Levak-Frank S, Cravatt B, Kratky D . Cholesteryl ester hydrolase activity is abolished in HSL-/- macrophages but unchanged in macrophages lacking KIAA1363 . Journal of Lipid Research . 51 . 10 . 2896–908 . Oct 2010 . 20625037 . 2936755 . 10.1194/jlr.M004259 . free .
4. Igarashi M, Osuga J, Uozaki H, Sekiya M, Nagashima S, Takahashi M, Takase S, Takanashi M, Li Y, Ohta K, Kumagai M, Nishi M, Hosokawa M, Fledelius C, Jacobsen P, Yagyu H, Fukayama M, Nagai R, Kadowaki T, Ohashi K, Ishibashi S . The critical role of neutral cholesterol ester hydrolase 1 in cholesterol removal from human macrophages . Circulation Research . 107 . 11 . 1387–95 . Nov 2010 . 20947831 . 10.1161/CIRCRESAHA.110.226613 . free .
5. Jessani N, Liu Y, Humphrey M, Cravatt BF . Enzyme activity profiles of the secreted and membrane proteome that depict cancer cell invasiveness . Proceedings of the National Academy of Sciences of the United States of America . 99 . 16 . 10335–40 . Aug 2002 . 12149457 . 124915 . 10.1073/pnas.162187599 . free . 2002PNAS...9910335J .
6. Nomura DK, Leung D, Chiang KP, Quistad GB, Cravatt BF, Casida JE . A brain detoxifying enzyme for organophosphorus nerve poisons . Proceedings of the National Academy of Sciences of the United States of America . 102 . 17 . 6195–200 . Apr 2005 . 15840715 . 1087944 . 10.1073/pnas.0501915102 . free . 2005PNAS..102.6195N .
7. Quistad GB, Liang SN, Fisher KJ, Nomura DK, Casida JE . Each lipase has a unique sensitivity profile for organophosphorus inhibitors . Toxicological Sciences . 91 . 1 . 166–72 . May 2006 . 16449251 . 10.1093/toxsci/kfj124 . free .
8. Okazaki H, Igarashi M, Nishi M, Sekiya M, Tajima M, Takase S, Takanashi M, Ohta K, Tamura Y, Okazaki S, Yahagi N, Ohashi K, Amemiya-Kudo M, Nakagawa Y, Nagai R, Kadowaki T, Osuga J, Ishibashi S . Identification of neutral cholesterol ester hydrolase, a key enzyme removing cholesterol from macrophages . The Journal of Biological Chemistry . 283 . 48 . 33357–64 . Nov 2008 . 18782767 . 2662263 . 10.1074/jbc.M802686200 . free .