Hydrolysis of Retinyl Esters by Pancreatic Triglyceride Lipase

Bennekum, van; Fisher, Edward A.; Blaner, WS; Eh, Harrison

doi:10.1021/bi9927235

Cited by 60 publications

(41 citation statements)

References 16 publications

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“…This selectivity of trihydroxylated bile salt for TAG hydrolytic activity in PTL Ϫ/Ϫ pancreas is consistent with the trihdroxy-but not dihydroxy-bile salt dependence of CEL (6), thus implying that CEL may have a previously unrecognized role as a supplementary enzyme for TAG digestion in vivo. Likewise, significant colipase-dependent retinyl ester hydrolytic activity was demonstrated in pancreatic extracts from both CEL ϩ/ϩ and CEL Ϫ/Ϫ mice (7). This colipase dependence suggests that PTL may also serve as a retinyl ester hydrolase in the digestive tract.…”

mentioning

confidence: 85%

Carboxyl Ester Lipase Deficiency Exacerbates Dietary Lipid Absorption Abnormalities and Resistance to Diet-induced Obesity in Pancreatic Triglyceride Lipase Knockout Mice

Gilham¹,

Labonté²,

Rojas

et al. 2007

Journal of Biological Chemistry

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Despite the fundamental importance that digestion, absorption, and subsequent trafficking of dietary fat, fat soluble vitamins, and cholesterol play in health and disease, details of the molecular events involved in these processes remain poorly described. Dietary lipids, such as triacylglycerol (TAG), 4 phospholipids, cholesteryl esters, and retinyl esters must be cleaved by intestinal hydrolases before absorption. Thus, lipid hydrolases derived from the pancreas are central in the digestion and absorption of these dietary components. The most abundant lipolytic enzymes secreted by the pancreas include pancreatic triglyceride lipase (PTL) and carboxyl ester lipase (CEL, formerly named cholesterol esterase). The principal enzyme involved in the hydrolysis of dietary TAG, thereby mediating its absorption, has generally been accepted as PTL. In contrast, the major role of CEL in the digestive tract is generally ascribed to digestion of cholesteryl esters and retinyl esters before their absorption.Recent studies with genetically modified mouse models designed to critically examine the role of pancreatic lipolytic enzymes in lipid digestion and transport revealed some unexpected findings. First, TAG absorption was altered very little, but free cholesterol absorption was reduced substantially in PTL Ϫ/Ϫ mice (1). Second, whereas CEL Ϫ/Ϫ mice displayed dramatically reduced cholesteryl ester hydrolysis and absorption as expected (2), retinyl ester digestion and absorption were similar between CEL ϩ/ϩ and CEL Ϫ/Ϫ mice (3). The decrease in cholesterol absorption observed in the PTL Ϫ/Ϫ mice was attributed to PTL deficiency delaying dietary fat absorption to the distal small intestine (ileum) where intestinal cholesterol uptake is less efficient (4, 5). However, the nearly normal absorption of TAG and retinyl esters in PTL Ϫ/Ϫ and CEL Ϫ/Ϫ mice suggested that more than one enzyme participates in the digestion of these lipids in vivo. In vitro studies examining lipolytic activities in pancreatic extracts from PTL Ϫ/Ϫ and CEL Ϫ/Ϫ mice provided insights to the identity of enzymes responsible for TAG and retinyl ester hydrolysis. In these studies pancreatic extracts from PTL Ϫ/Ϫ mice were shown to contain robust TAG hydrolytic activity, albeit at lower levels than those observed in pancreatic extracts from wild type mice. Importantly, the TAG hydrolytic activity in PTL Ϫ/Ϫ pancreas was dependent on the presence of taurocholate, whereas taurodeoxycholate was found to be ineffective (1). This selectivity of trihydroxylated bile salt for TAG hydrolytic activity in PTL Ϫ/Ϫ pancreas is consistent with the trihdroxy-but not dihydroxy-bile salt dependence of CEL (6), thus * This work was supported by National Institutes of Health Grant DK067416.The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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mentioning

confidence: 85%

Carboxyl Ester Lipase Deficiency Exacerbates Dietary Lipid Absorption Abnormalities and Resistance to Diet-induced Obesity in Pancreatic Triglyceride Lipase Knockout Mice

Gilham¹,

Labonté²,

Rojas

et al. 2007

Journal of Biological Chemistry

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“…Since tetrahydrolipstatin inhibits PTL as well as CEL, these results did not conclusively demonstrate the participation of CEL in vitamin absorption. In fact, earlier studies suggested that the PTL has retinyl ester hydrolytic activity (106). A third enzyme with the potential to contribute to vitamin A ester digestion and absorption is the intestinal phospholipase B. Rigtrup and Ong demonstrated that both CEL and phospholipase B are potent retinyl ester hydrolases and can be distinguished by their location either proximally or distally in the intestine, respectively (59,60).…”

Section: Vitamin Absorptionmentioning

confidence: 99%

Carboxyl ester lipase

Hui

Howles

2002

Journal of Lipid Research

193

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Carboxyl ester lipase (CEL), previously named cholesterol esterase or bile salt-stimulated (or dependent) lipase, is a lipolytic enzyme capable of hydrolyzing cholesteryl esters, tri-, di-, and mono-acylglycerols, phospholipids, lysophospholipids, and ceramide. The active site catalytic triad of serine-histidine-aspartate is centrally located within the enzyme structure and is partially covered by a surface loop. The carboxyl terminus of the protein regulates enzymatic activity by forming hydrogen bonds with the surface loop to partially shield the active site. Bile salt binding to the loop domain frees the active site for accessibility by water-insoluble substrates. CEL is synthesized primarily in the pancreas and lactating mammary gland, but the enzyme is also expressed in liver, macrophages, and in the vessel wall. In the gastrointestinal tract, CEL serves as a compensatory protein to other lipolytic enzymes for complete digestion and absorption of lipid nutrients. Importantly, CEL also participates in chylomicron assembly and secretion, in a mechanism mediated through its ceramide hydrolytic activity. Cell culture studies suggest a role for CEL in lipoprotein metabolism and oxidized LDL-induced atherosclerosis. Thus, this enzyme, which has a wide substrate reactivity and diffuse anatomic distribution, may have multiple functions in lipid and lipoprotein metabolism, and atherosclerosis. Carboxyl ester lipase (CEL), previously named pancreatic cholesterol esterase and also known as bile salt-stimulated (or -dependent) lipase, is a nonspecific lipolytic enzyme capable of hydrolyzing cholesteryl esters, tri-, di-, and mono-acylglycerols, phospholipids, lysophospholipids, and ceramide (1-3). The hydrolysis of water-insoluble carboxyl esters with long chain fatty acyl groups by CEL requires its activation by bile salt. However, CEL hydrolysis of water-soluble substrates such as carboxyl esters with short chain fatty acids or lysophospholipids does not have an absolute dependence on bile salt activation. The CEL protein is synthesized primarily in the pancreatic acinar cells and lactating mammary glands of higher mammals. Small amounts of CEL are found in other tissues, particularly the liver, macrophages, endothelial cells, and eosinophils (4-10). Extensive research has been performed in recent years on the structure-function relationship of this protein as well as its physiological role in lipid metabolism. A significant body of work has also been devoted to studying CEL processing and transport in pancreatic acinar cells. The latter topic was reviewed recently (11) and will be discussed only briefly in this article when appropriate. This article will present an updated review on the structure-function studies of CEL as well as an in-depth discussion on the current understanding of its role in lipid metabolism. PROTEIN STRUCTURE-FUNCTION RELATIONSHIP Active siteThe nucleotide sequence of CEL from various species shows that it is a highly conserved protein belonging to the ␣ / ␤ hydrolase family. The carb...

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“…Amino acid sequence alignments for previously reported human (Homo sapiens) PTL [56], PLR1 [61], PLR2 [6] and PLR3 [9] and mouse PTL [42,62], PLR1 [61] and PLR2 [26,42] sequences are shown in Figure 2 (also see 1). The amino acid sequence for the human PLR1 subunit contained 467 residues while the mouse PLR1 sequence contained 473 amino acids, due to an extended C-terminus sequence.…”

Section: Alignments Of Vertebrate Ptl-like Amino Acid Sequencesmentioning

confidence: 98%

“…These overall features are readily observed for the predicted frog PTL and PLR1 three-dimensional structures. Table 1 and Supplementary Table 1 summarize the predicted locations for vertebrate PTL-like genes based upon BLAT interrogations of genomes using the reported sequences for human PTL, PLR1, PLR2 and PLR3 [6,9,56,61] and the predicted sequences for other vertebrate PTL-like proteins and the UC Santa Cruz Genome Browser [49]. The mammalian PTL-like genes were predominantly transcribed on the positive strand and located in the following gene order: PLR3-PTL-PLR1-PLR2 for human (see Supplementary Figure 2), orangutan and rhesus genomes; and PTL-PLR1-PLR2 for other mammalian genomes, including mouse, rat, dog, pig, rabbit, opossum and platypus genomes (Table 1 and Supplementary Table 1).…”

Section: Secondary and Tertiary Structures For Vertebrate Ptl-like LImentioning

confidence: 99%

Bioinformatics and Evolution of Vertebrate Pancreatic Lipase and Related Proteins and Genes

Holmes¹,

Cox²

2012

JDMGP

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Background: Pancreatic lipase (PTL) functions in the presence of colipase in the hydrolysis of emulsified fats in the small intestine following secretion from the pancreas. Pancreatic lipase related protein 1 (PLR1) is also found in pancreatic secretions and may perform a regulatory role in lipolysis; PLR2 catalyses pancreatic triglyceride and galactolipase reactions while PLR3 may serve a related but unknown lipase function. Comparative PTL, PLR1, PLR2 and PLR3 amino acid sequences and structures and gene locations and sequences were examined using data from several vertebrate genome projects. Methods:Sequence alignments and conserved predicted secondary and tertiary structures were studied and key amino acid residues and domains identified based on previous reports on human and pig PTL. Comparative analyses of vertebrate PTL-like genes were conducted using the UC Santa Cruz Genome Browser. Phylogeny studies investigated the evolution of these vertebrate PTL-like genes.Data: Human and mouse PTL sequences shared 78% identities but only 64-68% identities with human and mouse PLR1 and PLR2 sequences. Several vertebrate PTL and PTL-like protein domains were predicted using bioinformatics including an N-signal peptide; N-glycosylation site(s); an α/β hydrolase fold region containing a catalytic triad; a 'lid' region for the active site; a 'hinge' separating the lipase and PLAT regions; and a C-terminal PLAT region. Eutherian mammalian PLR1 sequences retained residues (196Val/198Ala) responsible for the loss of triacylglycerol lipase activity whereas lower vertebrate PLR1 sequences retained the 'active' lipase residues. In contrast, mammalian PTL, PLR2 and PLR3 sequences exhibited lipase 'active' residues (196Ala/198Pro); chicken and frog PLR1 sequences retained the lipase 'active' residues; and opossum and platypus PLR1 sequences exhibited 196Ala/Ser198 and 196Ser/198Pro residues. A phylogenetic tree analysis provided evidence for four distinct vertebrate PTL-like gene families. Conclusions:Pancreatic lipase (PTL) and related genes and proteins (PLR1 and PLR2) are present in all vertebrate genomes examined whereas PLR3 is found only in primate genomes. The 'inactive' form of vertebrate PLR1 is restricted to eutherian mammals. Vertebrate PTL-like genes apparently originated in a vertebrate ancestor following gene duplication events of an ancestral PTL-like ancestral gene. Two separate lines of PTL-like gene evolution are proposed in lower vertebrates (PTL/PLR1 and PLR2), with a further gene duplication event (PLR2/PLR3) for primate genomes.

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Hydrolysis of Retinyl Esters by Pancreatic Triglyceride Lipase

Cited by 60 publications

References 16 publications

Carboxyl Ester Lipase Deficiency Exacerbates Dietary Lipid Absorption Abnormalities and Resistance to Diet-induced Obesity in Pancreatic Triglyceride Lipase Knockout Mice

Carboxyl Ester Lipase Deficiency Exacerbates Dietary Lipid Absorption Abnormalities and Resistance to Diet-induced Obesity in Pancreatic Triglyceride Lipase Knockout Mice

Carboxyl ester lipase

Bioinformatics and Evolution of Vertebrate Pancreatic Lipase and Related Proteins and Genes

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