The triglyceride lipases of the pancreas Published, JLR Papers in Press, October 1, 2002. DOI 10.1194/jlr.R200012-JLR200

Pancreatic triglyceride lipase (PTL) and its protein cofactor, colipase, are required for efficient dietary triglyceride digestion. In addition to PTL, pancreatic acinar cells synthesize two pancreatic lipase related proteins (PLRP1 and PLRP2), which have a high degree of sequence and structural homology with PTL. PLRP1 has no known activity. PTL and PLRP2 differ in substrate specificity, behavior in bile salts and dependence on colipase. Each protein has a globular amino-terminal (N-terminal) domain, which contains the catalytic site for PTL and PLRP2, and a β-sandwich carboxyl-terminal (C-terminal) domain, which includes the predominant colipase-binding site for PTL. Inactive and active conformations of PTL have been described. They differ in the position of a surface loop, the lid domain, and of the β5-loop. In the inactive conformation, the lid covers the active site and, upon activation by bile salt micelles and colipase or by lipid-water interfaces, the lid moves dramatically to open and configure the active site. After the lid movement, PTL and colipase create a large hydrophobic plateau that can interact with the lipid-water interface. A hydrophobic surface loop in the C-terminal domain, the β5′ loop, may also contribute to the interfacial-binding domain of the PTL-colipase complex.

[1]  D. Pignol,et al.  Pancreatic lipase-related protein type 1: a double mutation restores a significant lipase activity. , 1998, Biochemical and biophysical research communications.

[2]  M. Lowe,et al.  Rat GP-3 is a pancreatic lipase with kinetic properties that differ from colipase-dependent pancreatic lipase. , 1995, Journal of lipid research.

[3]  H. van Tilbeurgh,et al.  The 2.46 A resolution structure of the pancreatic lipase-colipase complex inhibited by a C11 alkyl phosphonate. , 1994, Biochemistry.

[4]  C. Figarella,et al.  Human pancreatic lipase: a glycoprotein. , 1977, Biochimica et biophysica acta.

[5]  A. Nilsson,et al.  Hydrolysis of galactolipids by human pancreatic lipolytic enzymes and duodenal contents. , 1995, Journal of lipid research.

[6]  H. Tilbeurgh,et al.  Crystallographic study of the structure of colipase and of the interaction with pancreatic lipase , 1995, Protein science : a publication of the Protein Society.

[7]  J. Kastelein,et al.  Mutation of Tryptophan Residues in Lipoprotein Lipase , 1997, The Journal of Biological Chemistry.

[8]  R. Verger,et al.  Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans. , 1993, Gastroenterology.

[9]  R. Verger,et al.  Human pancreatic lipase: colipase dependence and interfacial binding of lid domain mutants. , 1999, Biochemistry.

[10]  E. Lebenthal,et al.  Development of functional responses in human exocrine pancreas. , 1980, Pediatrics.

[11]  H. Tilbeurgh,et al.  Interfacial activation of the lipase–procolipase complex by mixed micelles revealed by X-ray crystallography , 1993, Nature.

[12]  G. J. Fernando-Warnakulasuriya,et al.  Studies on fat digestion, absorption, and transport in the suckling rat. II. Triacylglycerols: molecular species, stereospecific analysis, and specificity of hydrolysis by lingual lipase. , 1981, Journal of lipid research.

[13]  D. Figarella-Branger,et al.  Developmental gene expression of trypsinogen and lipase in human fetal pancreas. , 1997, Journal of pediatric gastroenterology and nutrition.

[14]  Bengt Borgström Digestion and absorption of fat. , 1962, Gastroenterology.

[15]  R. Verger,et al.  Structure and Activity of Rat Pancreatic Lipase-related Protein 2* , 1998, The Journal of Biological Chemistry.

[16]  P. Savary The action of pure pig pancreatic lipase upon esters of long-chain fatty acids and short-chain primary alcohols. , 1971, Biochimica et biophysica acta.

[17]  R. Verger,et al.  A conformational transition between an open and closed form of human pancreatic lipase revealed by a monoclonal antibody. , 2000, Biochimica et biophysica acta.

[18]  G. Bengtsson-Olivecrona,et al.  Chymotryptic cleavage of lipoprotein lipase. Identification of cleavage sites and functional studies of the truncated molecule. , 1993, European journal of biochemistry.

[19]  R. Verger,et al.  Effect of bile lipids on the adsorption and activity of pancreatic lipase on triacylglycerol emulsions. , 1980, Biochimica et biophysica acta.

[20]  M. Lowe,et al.  Colipase Residues Glu64 and Arg65 Are Essential for Normal Lipase-mediated Fat Digestion in the Presence of Bile Salt Micelles* , 2001, The Journal of Biological Chemistry.

[21]  H. van Tilbeurgh,et al.  Colipase: structure and interaction with pancreatic lipase. , 1999, Biochimica et biophysica acta.

[22]  M. Lowe,et al.  The open lid mediates pancreatic lipase function. , 2000, Journal of lipid research.

[23]  P. Desnuelle [Pancreatic lipase]. , 1971, Biochimie.

[24]  M. Kaplan,et al.  Decreased Neonatal Dietary Fat Absorption and T Cell Cytotoxicity in Pancreatic Lipase-related Protein 2-Deficient Mice* , 1998, The Journal of Biological Chemistry.

[25]  Y. Nakamaru,et al.  Elicitation of the brain microsomal (Mg2+ + Ca2+)-activated ATPase by digitonin treatment. , 1968, Biochimica et biophysica acta.

[26]  D. Pignol,et al.  Ion Pairing between Lipase and Colipase Plays a Critical Role in Catalysis* , 1998, The Journal of Biological Chemistry.

[27]  H. Greene,et al.  Isolated congenital lipase-colipase deficiency. , 1984, Gastroenterology.

[28]  D. Saunders,et al.  Fat absorption in bile fistula man. A morphological and biochemical study. , 1971, Gastroenterology.

[29]  C Cambillau,et al.  Horse pancreatic lipase. The crystal structure refined at 2.3 A resolution. , 1994, Journal of molecular biology.

[30]  L. Thim,et al.  Pancreatic lipase structure-function relationships by domain exchange. , 1997, Biochemistry.

[31]  Joel L. Sussman,et al.  The α/β hydrolase fold , 1992 .

[32]  B H Robinson,et al.  Interfacial membrane docking of cytosolic phospholipase A2 C2 domain using electrostatic potential-modulated spin relaxation magnetic resonance. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[33]  O. Hernell,et al.  Physical-chemical behavior of dietary and biliary lipids during intestinal digestion and absorption. 2. Phase analysis and aggregation states of luminal lipids during duodenal fat digestion in healthy adult human beings. , 1990, Biochemistry.

[34]  L. Thim,et al.  A structural domain (the lid) found in pancreatic lipases is absent in the guinea pig (phospho)lipase. , 1993, Biochemistry.

[35]  M. Lowe,et al.  Rat pancreatic lipase and two related proteins: enzymatic properties and mRNA expression during development. , 1994, The American journal of physiology.

[36]  M. Lowe,et al.  A surface loop covering the active site of human pancreatic lipase influences interfacial activation and lipid binding. , 1994, The Journal of biological chemistry.

[37]  R. Verger,et al.  The specific activities of human digestive lipases measured from the in vivo and in vitro lipolysis of test meals. , 2000, Gastroenterology.

[38]  L. Ayvazian,et al.  The Lipase C-terminal Domain , 2001, The Journal of Biological Chemistry.

[39]  H. Tilbeurgh,et al.  Structure of the pancreatic lipase–procolipase complex , 1992, Nature.

[40]  S. Jayne,et al.  High expression in adult horse of PLRP2 displaying a low phospholipase activity. , 2002, Biochimica et biophysica acta.

[41]  B. Borgström,et al.  Isolated co-lipase deficiency in two brothers. , 1982, Gut.

[42]  M. Lowe The catalytic site residues and interfacial binding of human pancreatic lipase. , 1992, The Journal of biological chemistry.

[43]  R. Verger ‘Interfacial activation’ of lipases: facts and artifacts , 1997 .

[44]  A. Kuksis,et al.  Lipolysis of menhaden oil triacylglycerols and the corresponding fatty acid alkyl esters by pancreatic lipase in vitro: a reexamination. , 1990, Journal of lipid research.

[45]  R. Verger,et al.  Inhibition of lipase adsorption at interfaces. Role of bile salt micelles and colipase. , 1978, Biochemistry.

[46]  M. Lowe New pancreatic lipases: gene expression, protein secretion, and the newborn. , 1997, Methods in enzymology.

[47]  D. Pignol,et al.  Lipase Activation by Nonionic Detergents , 1996, The Journal of Biological Chemistry.

[48]  D. Lairon,et al.  Physicochemical characteristics of emulsions during fat digestion in human stomach and duodenum. , 1996, The American journal of physiology.

[49]  E. Harrison,et al.  Hydrolysis of retinyl esters by pancreatic triglyceride lipase. , 2000, Biochemistry.

[50]  P. Andrews,et al.  Identification and cloning of GP-3 from rat pancreatic acinar zymogen granules as a glycosylated membrane-associated lipase. , 1993, The Journal of biological chemistry.

[51]  F. Winkler,et al.  Large spectral changes accompany the conformational transition of human pancreatic lipase induced by acylation with the inhibitor tetrahydrolipstatin. , 1992, European journal of biochemistry.

[52]  H. Brockman Kinetic behavior of the pancreatic lipase-colipase-lipid system. , 2000, Biochimie.

[53]  M. Lowe,et al.  Properties and function of pancreatic lipase related protein 2. , 2000, Biochimie.

[54]  R. Verger,et al.  Pancreatic lipase-related protein 2 but not classical pancreatic lipase hydrolyzes galactolipids. , 1996, Biochimica et biophysica acta.

[55]  D. Figarella-Branger,et al.  Immunohistochemical study of secretory proteins in the developing human exocrine pancreas. , 1992, Differentiation; research in biological diversity.

[56]  H. Chahinian,et al.  The beta 5' loop of the pancreatic lipase C2-like domain plays a critical role in the lipase-lipid interactions. , 2002, Biochemistry.

[57]  M. Billeter,et al.  MOLMOL: a program for display and analysis of macromolecular structures. , 1996, Journal of molecular graphics.

[58]  M. Lowe Mutation of the catalytic site Asp177 to Glu177 in human pancreatic lipase produces an active lipase with increased sensitivity to proteases. , 1996, Biochimica et biophysica acta.

[59]  B. Robinson,et al.  Angiotensin-converting enzyme inhibitors regulate the Na(+)-K+ pump via effects on angiotensin metabolism. , 1996, The American journal of physiology.

[60]  R. Verger,et al.  Reactivation of the totally inactive pancreatic lipase RP1 by structure‐predicted point mutations , 1998, Proteins.

[61]  B. Borgstrom Digestion and absorption of fat. , 1962, Gastroenterology.

[62]  M. Lowe Colipase Stabilizes the Lid Domain of Pancreatic Triglyceride Lipase* , 1997, The Journal of Biological Chemistry.

[63]  R. Verger,et al.  Possible roles of bile lipids and colipase in lipase adsorption. , 1978, Biochemistry.

[64]  F. Winkler,et al.  Structure of human pancreatic lipase , 1990, Nature.

[65]  Roger L. Williams,et al.  Mapping the Phospholipid-binding Surface and Translocation Determinants of the C2 Domain from Cytosolic Phospholipase A2 * , 1999, The Journal of Biological Chemistry.

[66]  J. Bluestone,et al.  Cloning of an interleukin-4 inducible gene from cytotoxic T lymphocytes and its identification as a lipase , 1990, Cell.

[67]  M. Hayden,et al.  Mapping of the epitope on lipoprotein lipase recognized by a monoclonal antibody (5D2) which inhibits lipase activity. , 1992, Biochimica et biophysica acta.

[68]  L. Muglia,et al.  Decreased Postnatal Survival and Altered Body Weight Regulation in Procolipase-deficient Mice* , 2002, The Journal of Biological Chemistry.

[69]  D. Pignol,et al.  Pancreatic lipase-related protein type I: a specialized lipase or an inactive enzyme. , 1998, Protein engineering.

[70]  G. Zoppi,et al.  Exocrine Pancreas Function in Premature and Full Term Neonates , 1972, Pediatric Research.

[71]  H. Brockerhoff Substrate specificity of pancreatic lipase. Influence of the structure of fatty acids on the reactivity of esters. , 1970, Biochimica et biophysica acta.

[72]  D. Pignol,et al.  Critical Role of Micelles in Pancreatic Lipase Activation Revealed by Small Angle Neutron Scattering* , 2000, The Journal of Biological Chemistry.

[73]  C. Figarella,et al.  Congenital pancreatic lipase deficiency. , 1980, The Journal of pediatrics.

[74]  P. Buchwald,et al.  Two novel human pancreatic lipase related proteins, hPLRP1 and hPLRP2. Differences in colipase dependence and in lipase activity. , 1992, The Journal of biological chemistry.

[75]  H. Brockerhoff Substrate specificity of pancreatic lipase. , 1968, Biochimica et biophysica acta.

[76]  R. Verger,et al.  Evidence for a pancreatic lipase subfamily with new kinetic properties. , 1994, Biochemistry.

[77]  S. Penel,et al.  Neutron crystallographic evidence of lipase–colipase complex activation by a micelle , 1997, The EMBO journal.

[78]  M. Lowe,et al.  C-terminal domain of human pancreatic lipase is required for stability and maximal activity but not colipase reactivation. , 1995, Journal of lipid research.