Pancreatic lipase family explained

Triglyceride lipases are a family of lipolytic enzymes that hydrolyse ester linkages of triglycerides.^[1] Lipases are widely distributed in animals, plants and prokaryotes.

At least three tissue-specific isozymes exist in higher vertebrates, pancreatic, hepatic and gastric/lingual. These lipases are closely related to each other and to lipoprotein lipase, which hydrolyses triglycerides of chylomicrons and very low density lipoproteins (VLDL).^[2]

The most conserved region in all these proteins is centred on a serine residue which has been shown^[3] to participate, with a histidine and an aspartic acid residue, in a charge relay system. Such a region is also present in lipases of prokaryotic origin and in lecithin-cholesterol acyltransferase (LCAT),^[4] which catalyzes fatty acid transfer between phosphatidylcholine and cholesterol.

Human pancreatic lipase

Pancreatic lipase, also known as pancreatic triacylglycerol lipase or steapsin, is an enzyme secreted from the pancreas. As the primary lipase enzyme that hydrolyzes (breaks down) dietary fat molecules in the human digestive system, it is one of the main digestive enzymes, converting triglyceride substrates like 1 found in ingested oils to monoglycerides 3 and free fatty acids 2a and 2b.^[5]

Bile salts secreted from the liver and stored in gallbladder are released into the duodenum, where they coat and emulsify large fat droplets into smaller droplets, thus increasing the overall surface area of the fat, which allows the lipase to break apart the fat more effectively. The resulting monomers (2 free fatty acids and one 2-monoacylglycerol) are then moved by way of peristalsis along the small intestine to be absorbed into the lymphatic system by a specialized vessel called a lacteal.

Unlike some pancreatic enzymes that are activated by proteolytic cleavage (e.g., trypsinogen), pancreatic lipase is secreted in its final form. However, it becomes efficient only in the presence of colipase in the duodenum.

In humans, pancreatic lipase is encoded by the PNLIP gene.^[6] ^[7]

Human proteins containing this domain

LIPC
LIPG
LIPH
LIPI
LPL
PLA1A
PNLIP
PNLIPRP1
PNLIPRP2
PNLIPRP3

Diagnostic importance

Pancreatic lipase is secreted into the duodenum through the duct system of the pancreas. Its concentration in serum is normally very low. Under extreme disruption of pancreatic function, such as pancreatitis or pancreatic adenocarcinoma, the pancreas may begin to autolyse and release pancreatic enzymes including pancreatic lipase into serum. Thus, through measurement of serum concentration of pancreatic lipase, acute pancreatitis can be diagnosed.^[8]

Inhibitors

Lipase inhibitors such as orlistat can be used as a treatment for obesity.^[9]

One peptide selected by phage display was found to inhibit pancreatic lipase.^[10]

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Ranaldi S, Belle V, Woudstra M, Rodriguez J, Guigliarelli B, Sturgis J, Carriere F, Fournel A . Lid opening and unfolding in human pancreatic lipase at low pH revealed by site-directed spin labeling EPR and FTIR spectroscopy . Biochemistry . 48 . 3 . 630–8 . 2009 . 19113953 . 10.1021/bi801250s .
Grupe A, Li Y, Rowland C, Nowotny P, Hinrichs AL, Smemo S, Kauwe JS, Maxwell TJ, Cherny S, Doil L, Tacey K, van Luchene R, Myers A, Wavrant-De Vrièze F, Kaleem M, Hollingworth P, Jehu L, Foy C, Archer N, Hamilton G, Holmans P, Morris CM, Catanese J, Sninsky J, White TJ, Powell J, Hardy J, O'Donovan M, Lovestone S, Jones L, Morris JC, Thal L, Owen M, Williams J, Goate A . A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease . Am. J. Hum. Genet. . 78 . 1 . 78–88 . 2006 . 16385451 . 1380225 . 10.1086/498851 .
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van Tilbeurgh H, Egloff MP, Martinez C, Rugani N, Verger R, Cambillau C . Interfacial activation of the lipase-procolipase complex by mixed micelles revealed by X-ray crystallography . Nature . 362 . 6423 . 814–20 . 1993 . 8479519 . 10.1038/362814a0 . 1993Natur.362..814V . 4305832 .
Lessinger JM, Arzoglou P, Ramos P, Visvikis A, Parashou S, Calam D, Profilis C, Férard G . Preparation and characterization of reference materials for human pancreatic lipase: BCR 693 (from human pancreatic juice) and BCR 694 (recombinant) . Clin. Chem. Lab. Med. . 41 . 2 . 169–76 . 2003 . 12667003 . 10.1515/CCLM.2003.028 . 28593258 .
Colin DY, Deprez-Beauclair P, Allouche M, Brasseur R, Kerfelec B . Exploring the active site cavity of human pancreatic lipase . Biochem. Biophys. Res. Commun. . 370 . 3 . 394–8 . 2008 . 18353248 . 10.1016/j.bbrc.2008.03.043 .
Ramos P, Coste T, Piémont E, Lessinger JM, Bousquet JA, Chapus C, Kerfelec B, Férard G, Mély Y . Time-resolved fluorescence allows selective monitoring of Trp30 environmental changes in the seven-Trp-containing human pancreatic lipase . Biochemistry . 42 . 43 . 12488–96 . 2003 . 14580194 . 10.1021/bi034900e .
Yang Y, Lowe ME . Human pancreatic triglyceride lipase expressed in yeast cells: purification and characterization . Protein Expr. Purif. . 13 . 1 . 36–40 . 1998 . 9631512 . 10.1006/prep.1998.0874 .
Sims HF, Jennens ML, Lowe ME . The human pancreatic lipase-encoding gene: structure and conservation of an Alu sequence in the lipase gene family . Gene . 131 . 2 . 281–5 . 1993 . 8406023 . 10.1016/0378-1119(93)90307-O .
Grandval P, De Caro A, De Caro J, Sias B, Carrière F, Verger R, Laugier R . Critical evaluation of a specific ELISA and two enzymatic assays of pancreatic lipases in human sera . Pancreatology . 4 . 6 . 495–503; discussion 503–4 . 2004 . 15316225 . 10.1159/000080246 . 39583651 .
Belle V, Fournel A, Woudstra M, Ranaldi S, Prieri F, Thomé V, Currault J, Verger R, Guigliarelli B, Carrière F . Probing the opening of the pancreatic lipase lid using site-directed spin labeling and EPR spectroscopy . Biochemistry . 46 . 8 . 2205–14 . 2007 . 17269661 . 10.1021/bi0616089 .
Lowe ME . Structure and function of pancreatic lipase and colipase . Annu. Rev. Nutr. . 17 . 141–58 . 1997 . 9240923 . 10.1146/annurev.nutr.17.1.141 .
Bourbon-Freie A, Dub RE, Xiao X, Lowe ME . Trp-107 and trp-253 account for the increased steady state fluorescence that accompanies the conformational change in human pancreatic triglyceride lipase induced by tetrahydrolipstatin and bile salt . J. Biol. Chem. . 284 . 21 . 14157–64 . 2009 . 19346257 . 2682864 . 10.1074/jbc.M901154200 . free .
Ranaldi S, Belle V, Woudstra M, Bourgeas R, Guigliarelli B, Roche P, Vezin H, Carrière F, Fournel A . Amplitude of pancreatic lipase lid opening in solution and identification of spin label conformational subensembles by combining continuous wave and pulsed EPR spectroscopy and molecular dynamics . Biochemistry . 49 . 10 . 2140–9 . 2010 . 20136147 . 10.1021/bi901918f .

Notes and References

Chapus C, Rovery M, Sarda L, Verger R . Minireview on pancreatic lipase and colipase . Biochimie . 70 . 9 . 1223–1234 . 1988 . 3147715 . 10.1016/0300-9084(88)90188-5.
Persson B, Bengtsson-Olivecrona G, Enerback S, Olivecrona T, Jornvall H . Structural features of lipoprotein lipase. Lipase family relationships, binding interactions, non-equivalence of lipase cofactors, vitellogenin similarities and functional subdivision of lipoprotein lipase . Eur. J. Biochem. . 179 . 1 . 39–45 . 1989 . 2917565 . 10.1111/j.1432-1033.1989.tb14518.x. free .
Blow D . Enzymology. More of the catalytic triad . Nature . 343 . 6260 . 694–695 . 1990 . 2304545 . 10.1038/343694a0. 1990Natur.343..694B . 4281247 .
McLean J, Fielding C, Drayna D, Dieplinger H, Baer B, Kohr W, Henzel W, Lawn R . Cloning and expression of human lecithin-cholesterol acyltransferase cDNA . Proc. Natl. Acad. Sci. U.S.A. . 83 . 8 . 2335–2339 . 1986 . 3458198 . 10.1073/pnas.83.8.2335 . 323291. 1986PNAS...83.2335M . free .
Peter Nuhn: Naturstoffchemie, S. Hirzel Wissenschaftliche Verlagsgesellschaft, Stuttgart, 2. Auflage, 1990, S. 308−309, .
Davis RC, Diep A, Hunziker W, Klisak I, Mohandas T, Schotz MC, Sparkes RS, Lusis AJ . Assignment of human pancreatic lipase gene (PNLIP) to chromosome 10q24-q26 . Genomics . 11 . 4 . 1164–6 . December 1991 . 1783385 . 10.1016/0888-7543(91)90048-J .
Web site: Entrez Gene: pancreatic lipase.
Koop H . Serum levels of pancreatic enzymes and their clinical significance . Clin Gastroenterol . 13 . 3 . 739–61 . September 1984 . 10.1016/S0300-5089(21)00756-2 . 6207965 .
Web site: US orlistat label. FDA. 18 April 2018. August 2015. For label updates see FDA index page for NDA 020766
10.1194/jlr.M500048-JLR200. 15863836. Peptide inhibitor of pancreatic lipase selected by phage display using different elution strategies. Journal of Lipid Research. 46. 7. 1512–1516. 2005. Lunder. M.. Bratkovič. T.. Kreft. S.. Štrukelj. B.. free.