Lipases are water-soluble enzymes that hydrolyze ester bonds of water-insoluble substrates, such as triglycerides, into diglycerides, monoglycerides, and fatty acids (Figure 1). Lipases belong to a superfamily of enzymes that share a characteristic α/β-hydrolase fold surrounding the catalytic triad where hydrolysis takes place.1,2 The α/β-hydrolase fold is generally composed of 8 β-strands connected by α-helices.1 Other enzymes of this superfamily include peroxidases, proteases, esterases, and hydrolases.
Lipases are ubiquitous in nature and are present in humans, animals, insects, plants, fungi, and microorganisms. Many lipases are phylogenetically related.3 The pancreatic lipase gene family is one of the best-characterized lipase gene families and consists of 7 mammalian subfamilies (i.e., pancreatic lipase, pancreatic lipase related proteins 1 and 2, hepatic lipase, lipoprotein lipase, endothelial lipase, and phosphatidylserine phospholipase A1) and an ever-expanding number of subfamilies of invertebrate lipases (Figure 2).3,5 Other mammalian lipases that play important roles in lipid digestion include carboxyl ester lipase and gastric lipase.6,7
This Currents in One Health article provides an overview of endogenous lipases important for the digestion and metabolism of dietary lipids in veterinary species. Using pancreatic lipase as a model, we will introduce the general structure and function of digestive lipases. Subsequently, we will look at selected subfamilies of the pancreatic lipase gene family, as well as carboxyl ester lipase and gastric lipase, focusing specifically on their distribution in various important species and their enzymatic functions. Although most enzymes have their preferred substrate(s), much overlap may occur across the plethora of digestive lipases. Measurement of specific lipases is also of diagnostic use in clinical patients. Veterinary medicine is leading the way in the use of immunological assays that specifically quantify pancreatic lipase for the diagnosis of pancreatitis. This may have been driven by more challenging access to the advanced imaging modalities that are routinely used in humans with suspected pancreatitis and are considered far more sensitive and specific than is the case for dogs and cats. The principles behind these assays do, however, have translational significance and could be of value in humans unable to undergo advanced imaging for a variety of reasons. Additionally, utilization of such assays may reduce diagnostic cost.
Dr. Lim and Dr. Steiner are employed by Texas A&M University and are affiliated with the Gastrointestinal (GI) Laboratory, which offers measurement of serum pancreatic lipase (PLI using the Spec fPL/cPL) concentration for diagnostic purposes on a fee-for-service basis. Dr. Steiner also acts as a paid consultant for IDEXX Laboratories, which also offers PLI testing using the Spec fPL/cPL on a fee-for-service basis and also manufactures the Snap cPL/fPL. Dr. Cridge has published research funded by Abaxis, Inc and has also published in collaboration with authors from the GI Laboratory. None of the authors has any other financial or personal relationships that could inappropriately influence or bias the content of this manuscript.
Belle V, Fournel A, Woudstra M, et al. Probing the opening of the pancreatic lipase lid using site-directed spin labeling and EPR spectroscopy. Biochemistry. 2007;46:2205–2214.
Kumar S, Stecher G, Li M, Knyaz C, Tamura K. MEGA X: molecular evolutionary genetics analysis across computing platforms. Mol Biol Evol. 2018;35:1547–1549.
Kirchgessner TG, Chuat JC, Heinzmann C, et al. Organization of the human lipoprotein lipase gene and evolution of the lipase gene family. Proc Natl Acad Sci U S A. 1989;86:9647–9651.
Hui DY, Howles PN. Carboxyl ester lipase: structure-function relationship and physiological role in lipoprotein metabolism and atherosclerosis. J Lipid Res. 2002;43:2017–2030.
Canaan S, Roussel A, Verger R, Cambillau C. Gastric lipase: crystal structure and activity. Biochim Biophys Acta. 1999;1441:197–204.
Moreau H, Gargouri Y, Lecat D, Junien JL, Verger R. Screening of preduodenal lipases in several mammals. Biochim Biophys Acta. 1988;959:247–252.
Knospe C, Plendl J. Histochemical demonstration of lipase activity in the gastric mucosa of the cat. Anat Histol Embryol. 1997;26:303–304.
Bakala N'Goma JC, Amara S, Dridi K, Jannin V, Carriere F. Understanding the lipid-digestion processes in the GI tract before designing lipid-based drug-delivery systems. Ther Deliv. 2012;3:105–124.
Giller T, Buchwald P, Blum-Kaelin D, Hunziker W. Two novel human pancreatic lipase related proteins, hPLRP1 and hPLRP2. Differences in colipase dependence and in lipase activity. J Biol Chem. 1992;267:16509–16516.
Sato T, Aoki J, Nagai Y, et al. Serine phospholipid-specific phospholipase A that is secreted from activated platelets–a new member of the lipase family. J Biol Chem. 1997;272:2192–2198.
Rader DJ, Jaye M. Endothelial lipase: a new member of the triglyceride lipase gene family. Curr Opin Lipidol. 2000;11:141–147.
van Groningen JJ, Egmond MR, Bloemers HP, Swart GW. nmd, a novel gene differentially expressed in human melanoma cell lines, encodes a new atypical member of the enzyme family of lipases. FEBS Lett. 1997;404:82–86.
van Tilbeurgh H, Sarda L, Verger R, Cambillau C. Structure of the pancreatic lipase-procolipase complex. Nature. 1992;359:159–162.
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. 1993;362:814–820.
Carriere F, Withers-Martinez C, van Tilberugh H, Roussel A, Cambillau C, Verger R. Structural basis for the substrate selectivity of pancreatic lipases and some related proteins. Biochim Biophys Acta. 1998;1376:417–432.
De Caro J, Eydoux C, Cherif S, et al. Occurrence of pancreatic lipase-related protein-2 in various species and its relationship with herbivore diet. Comp Biochem Physiol B Biochem Mol Biol. 2008;150:1–9.
Steiner JM, Berridge BR, Wojcieszyn J, Williams DA. Cellular immunolocalization of gastric and pancreatic lipase in various tissues obtained from dogs. Am J Vet Res. 2002;63:722–727.
Crenon I, Foglizzo E, Kerfelec B, et al. Pancreatic lipase-related protein type I: a specialized lipase or an inactive enzyme. Protein Eng. 1998;11:135–142.
De Caro J, Carrière F, Barboni P, Giller T, Verger R, De Caro A. Pancreatic lipase-related protein 1 (PLRP1) is present in the pancreatic juice of several species. Biochim Biophys Acta. 1998;1387:331–341.
Payne RM, Sims HF, Jennens ML, Lowe ME. Rat pancreatic lipase and two related proteins: enzymatic properties and mRNA expression during development. Am J Physiol. 1994;266:G914–921.
Crenon I, Jayne S, Kerfelec B, Hermoso J, Pignol D, Chapus C. Pancreatic lipase-related protein type 1: a double mutation restores a significant lipase activity. Biochem Biophys Res Commun. 1998;246:513–517.
Hecker N, Sharma V, Hiller M. Convergent gene losses illuminate metabolic and physiological changes in herbivores and carnivores. Proc Natl Acad Sci U S A. 2019;116:3036–3041.
Lowe ME, Kaplan MH, Jackson-Grusby L, D'Agostino D, Grusby MJ. Decreased neonatal dietary fat absorption and T cell cytotoxicity in pancreatic lipase-related protein 2-deficient mice. J Biol Chem. 1998;273:31215–31221.
Li X, Lindquist S, Lowe M, Noppa L, Hernell O. Bile salt-stimulated lipase and pancreatic lipase-related protein 2 are the dominating lipases in neonatal fat digestion in mice and rats. Pediatr Res. 2007;62:537–541.
Sias B, Ferrato F, Pellicer-Rubio MT, et al. Cloning and seasonal secretion of the pancreatic lipase-related protein 2 present in goat seminal plasma. Biochim Biophys Acta. 2005;1686:169–180.
Eydoux C, Aloulou A, De Caro J, et al. Human pancreatic lipase-related protein 2: tissular localization along the digestive tract and quantification in pancreatic juice using a specific ELISA. Biochim Biophys Acta. 2006;1760:1497–1504.
Record M, Amara S, Subra C, et al. Bis (monoacylglycero) phosphate interfacial properties and lipolysis by pancreatic lipase-related protein 2, an enzyme present in THP-1 human monocytes. Biochim Biophys Acta. 2011;1811:419–430.
Gilleron M, Lepore M, Layre E, et al. Lysosomal lipases PLRP2 and LPLA2 process mycobacterial multi-acylated lipids and generate T cell stimulatory antigens. Cell Chem Biol. 2016;23:1147–1156.
Chatterjee C, Sparks DL. Hepatic lipase, high density lipoproteins, and hypertriglyceridemia. Am J Pathol. 2011;178:1429–1433.
Merkel M, Eckel RH, Goldberg IJ. Lipoprotein lipase: genetics, lipid uptake, and regulation. J Lipid Res. 2002;43:1997–2006.
Perret B, Mabile L, Martinez L, Terce F, Barbaras R, Collet X. Hepatic lipase: structure/function relationship, synthesis, and regulation. J Lipid Res. 2002;43:1163–1169.
Kimura N, Kikumori A, Kawase D, et al. Species differences in lipoprotein lipase and hepatic lipase activities: comparative studies of animal models of lifestyle-related diseases. Exp Anim. 2019;68:267–275.
Beisson F, Tiss A, Riviere C, Verger R. Methods for lipase detection and assay: a critical review. Eur J Lipid Sci Tech. 2000;102:133–153.
Lim SY, Xenoulis PG, Stavroulaki EM, et al. The 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6’-methylresorufin) ester (DGGR) lipase assay in cats and dogs is not specific for pancreatic lipase. Vet Clin Pathol. 2020;49:607–613.
Jaye M, Lynch KJ, Krawiec T, et al. A novel endothelial-derived lipase that modulates HDL metabolism. Nat Genet. 1999;21:424–428.
Hirata K, Dichek HL, Cioffi JA, et al. Cloning of a unique lipase from endothelial cells extends the lipase gene family. J Biol Chem. 1999;274:14170–14175.
Aoki J, Nagai Y, Hosono H, Inoue K, Arai H. Structure and function of phosphatidylserine-specific phospholipase A1. Biochim Biophys Acta. 2002;1582:26–32.
Moreau H, Laugier R, Gargouri Y, Ferrato F, Verger R. Human preduodenal lipase is entirely of gastric fundic origin. Gastroenterology. 1988;95:1221–1226.
Carriere F, Grandval P, Renou C, et al. Quantitative study of digestive enzyme secretion and gastrointestinal lipolysis in chronic pancreatitis. Clin Gastroenterol Hepatol. 2005;3:28–38.