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• W2002059213 abstract "The human carboxyl ester lipase (CEL) is an important enzyme for the intestinal absorption of dietary lipids. The gene is highly expressed in exocrine pancreas and in the mammary gland during pregnancy and lactation. In this paper, we have focused on its transcriptional regulation in exocrine pancreas. Reporter gene analysis in cell cultures reveals that a high level of tissue-specific expression is established by the proximal 839 base pairs of the 5′-flanking region. This is due to a strong enhancer, located at −672 to −637. Transfections in mammary gland-derived cells reveal that the enhancer is pancreas-specific and does not contribute to the mammary gland expression. This indicates that the expression of the CEL gene in the mammary gland and pancreas, respectively, is due to two different regulatory systems. Further characterizations of the enhancer reveal that it is composed of two closely located cis-elements. The proximal element mediates a positive effect, whereas the distal element exerts a silencing effect on the positive proximal element. The functional enhancer complex is composed of ubiquitously expressed factors, since similar interactions are achieved with nuclear extracts from cells derived from other tissues. However, no enhancer activity is achieved in such cells. Hence, the net enhancer activity is the result of a tissue-specific balance between factors interacting with the two elements. Since none of the described cis-elements show any clear homology to known cis-elements, we propose that the interacting complex is composed of yet unidentified transcription factors. The human carboxyl ester lipase (CEL) is an important enzyme for the intestinal absorption of dietary lipids. The gene is highly expressed in exocrine pancreas and in the mammary gland during pregnancy and lactation. In this paper, we have focused on its transcriptional regulation in exocrine pancreas. Reporter gene analysis in cell cultures reveals that a high level of tissue-specific expression is established by the proximal 839 base pairs of the 5′-flanking region. This is due to a strong enhancer, located at −672 to −637. Transfections in mammary gland-derived cells reveal that the enhancer is pancreas-specific and does not contribute to the mammary gland expression. This indicates that the expression of the CEL gene in the mammary gland and pancreas, respectively, is due to two different regulatory systems. Further characterizations of the enhancer reveal that it is composed of two closely located cis-elements. The proximal element mediates a positive effect, whereas the distal element exerts a silencing effect on the positive proximal element. The functional enhancer complex is composed of ubiquitously expressed factors, since similar interactions are achieved with nuclear extracts from cells derived from other tissues. However, no enhancer activity is achieved in such cells. Hence, the net enhancer activity is the result of a tissue-specific balance between factors interacting with the two elements. Since none of the described cis-elements show any clear homology to known cis-elements, we propose that the interacting complex is composed of yet unidentified transcription factors. carboxyl ester lipase pancreas transcription factor 1 nucleotide(s) restriction enzyme chloramphenicol acetyltransferase electrophoretic mobility shift assay base pair(s) estrogen response element wild type. The need for fat is of special importance for infants, since malabsorption would influence both growth and development (1Crawford M.A. Hassam A.G. Stevens P.A. Prog. Lipid Res. 1981; 20: 31-40Crossref PubMed Scopus (123) Google Scholar). To secure the requirement, several different lipolytical enzymes, secreted from the pancreas, contribute to the digestion of dietary fat. One of the important enzymes is carboxyl ester lipase (CEL),1 since it, because of its broad substrate specificity, is believed to be the main enzyme for the hydrolysis of fat-soluble vitamin esters, monoglycerides, and cholesterol esters (2Fredrikzon B. Hernell O. Bläckberg L. Olivecrona T. Pediatr. Res. 1978; 12: 1048-1052Crossref PubMed Scopus (111) Google Scholar, 3Howles P.N. Carter C.P. Hui D.Y. J. Biol. Chem. 1996; 271: 7196-7202Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). CEL is synthesized in the acinar cells of exocrine pancreas, secreted with the pancreatic juice, and activated in the intestinal lumen by bile salts (for reviews, see Refs. 4Wang C.S. Hartsuck J.A. Biochim. Biophys. Acta. 1993; 1166: 1-19Crossref PubMed Scopus (133) Google Scholar and 5Hui D.Y. Biochim. Biophys. Acta. 1996; 1303: 1-14Crossref PubMed Scopus (61) Google Scholar). CEL seems to be a very old enzyme. A pancreatic expression has been found in all vertebrates analyzed so far (6Gjellesvik D.R. Lombardo D. Walther B.T. Biochim. Biophys. Acta. 1992; 1124: 123-134Crossref PubMed Scopus (209) Google Scholar, 7Gjellesvik D.R. Lorens J.B. Male R. Eur. J. Biochem. 1994; 226: 603-612Crossref PubMed Scopus (53) Google Scholar). In fact, in the pancreas of leopard sharks, CEL is the only lipolytic enzyme for hydrolyzing dietary lipids (8Patton J.S. Warner T.G. Benson A.A. Biochim. Biophys. Acta. 1977; 486: 322-330Crossref PubMed Scopus (73) Google Scholar), which suggests that CEL, because of its broad substrate specificity, might even have been one of the first lipolytic enzymes expressed in the pancreas. The importance of CEL for intestinal absorption of dietary lipids is strongly supported by the fact that in mammals it is also synthesized in lactating mammary gland, secreted into the milk, and activated in the intestine (9Hernell O. Olivecrona T. J. Lipid Res. 1974; 15: 367-374Abstract Full Text PDF PubMed Google Scholar, 10Freed L.M. York C.M. Hamosh M. Sturman J.A. Hamosh P. Biochim. Biophys. Acta. 1986; 878: 209-215Crossref PubMed Scopus (43) Google Scholar). Since the capacity of human infants to digest milk lipids is poor during the first months, due to poorly developed pancreatic function (11Hernell O. Bläckberg L. J. Pediatr. Gastroenterol. Nutr. 1983; 2 Suppl. 1: 242-247Crossref Scopus (13) Google Scholar), the presence of CEL in milk seems to secure fat absorption. After cloning of the CEL cDNA and gene, respectively, we and other groups could show that there is only one gene responsible for the expression in the two tissues (12Nilsson J. Bläckberg L. Carlsson P. Enerbäck S. Hernell O. Bjursell G. Eur. J. Biochem. 1990; 192: 543-550Crossref PubMed Scopus (119) Google Scholar, 13Baba T. Downs D. Jackson K.W. Tang J. Wang C.S. Biochemistry. 1991; 30: 500-510Crossref PubMed Scopus (92) Google Scholar, 14Hui D.Y. Kissel J.A. FEBS Lett. 1990; 276: 131-134Crossref PubMed Scopus (54) Google Scholar, 15Lidberg U. Nilsson J. Strömberg K. Stenman G. Sahlin P. Enerbäck S. Bjursell G. Genomics. 1992; 13: 630-640Crossref PubMed Scopus (52) Google Scholar). Neither the enzyme nor the gene shows any homology to the classical lipases or their corresponding genes; instead, homologies are found to esterases, such as acetylcholine esterase (12Nilsson J. Bläckberg L. Carlsson P. Enerbäck S. Hernell O. Bjursell G. Eur. J. Biochem. 1990; 192: 543-550Crossref PubMed Scopus (119) Google Scholar), which might indicate that the CEL gene has evolved as a separate lipase/esterase gene.Besides the predominant CEL gene expression in mammary gland and pancreas of humans it has recently been shown that small but significant levels of expression could be detected in other tissues, such as macrophages and liver and endothelial cells. The function of this expression is still unknown, but it has been suggested that CEL interacts with cholesterol esters and oxidized lipoproteins and thereby modulates the progression of atherosclerosis (16Li F. Hui D.Y. J. Biol. Chem. 1997; 272: 28666-28671Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 17Li F. Hui D.Y. Biochem. J. 1998; 329: 675-679Crossref PubMed Scopus (48) Google Scholar). Furthermore, there seem to be differences with respect to the tissue-specific expression among different species (18Zolfaghari R. Harrison E.H. Han J.H. Rutter W.J. Fisher E.A. Arterioscler. Thromb. 1992; 12: 295-301Crossref PubMed Scopus (21) Google Scholar). This might be explained by differences that have taken place during the evolution of the CEL gene locus. For example, in humans, the CEL gene has been duplicated, and the original CEL gene, the mouse homologue, has become a pseudogene (19Madeyski K. Lidberg U. Bjursell G. Nilsson J. Mamm. Genome. 1998; 9: 334-338Crossref PubMed Scopus (15) Google Scholar).The digestive enzymes have been in focus for a long time. As proposed by Pavlov in the early 1900s (20Pavlov I.P. The Work of the Digestive Glands. (English translation from Russian by W. H. Thompson). Griffin, London1910Google Scholar) and first shown by Grossman et al. (21Grossman M.I. Greengard H. Ivy A.C. Am. J. Physiol. 1943; 138: 676-682Crossref Google Scholar), the variations in levels between different secreted digestive enzymes are controlled by changes in the levels of circulating hormones in response to food composition (22Scheele G.A. Kern H.F. Schultz S.G. Forte J.G. Rauner B.B. Handbook of Physiology. III. American Physiological Society, Bethesda, MD1989: 477-498Google Scholar). This response is fast and dependent on translational regulation and increased secretion of stored enzymes (23Wicker C. Puigserver A. Scheele G. Eur. J. Biochem. 1984; 139: 381-387Crossref PubMed Scopus (63) Google Scholar, 24Schick J. Kern H. Scheele G. J. Cell Biol. 1984; 99: 1569-1574Crossref PubMed Scopus (116) Google Scholar). Changes in mRNA levels can only be induced following prolonged stimulation by nutrients (22Scheele G.A. Kern H.F. Schultz S.G. Forte J.G. Rauner B.B. Handbook of Physiology. III. American Physiological Society, Bethesda, MD1989: 477-498Google Scholar). The regulation of the CEL gene activity in pancreas has been studied by Huang and Hui (25Huang Y. Hui D.Y. J. Biol. Chem. 1991; 266: 6720-6725Abstract Full Text PDF PubMed Google Scholar), who have shown that the pancreatic cell line AR4-2J constitutively expresses CEL and that this protein expression can be induced by cholecystokinin and secretin without any changes in mRNA level. Further investigations have indicated that Ca2+ and protein kinase C are part of the signal mechanism by which the acinar cells are induced to secret CEL (26Brodt-Eppley J. Hui D.Y. Biochem. J. 1995; 306: 605-608Crossref PubMed Scopus (6) Google Scholar). The same group was also able to show that a high fat/high cholesterol diet exhibited increased CEL mRNA levels in rats (27Brodt-Eppley J. Hui D.Y. J. Lipid Res. 1994; 35: 27-35Abstract Full Text PDF PubMed Google Scholar) and that cationizied low density lipoprotein can induce a 2-fold increase in the CEL mRNA level in AR4-2J cells (28Huang Y. Hui D.Y. Biochim. Biophys. Acta. 1994; 1214: 317-322Crossref PubMed Scopus (10) Google Scholar). A similar induction by prolonged cholesterol treatment has recently also been shown to occur in rabbits (29Lopez-Candales A. Grosjlos J. Sasser T. Buddhiraju C. Scherrer D. Lange L.G. Kumar V.B. Biochem. Cell Biol. 1996; 74: 257-264Crossref PubMed Scopus (10) Google Scholar). The ability to respond to cholesterol has been shown for several other genes such as the low density lipoprotein receptor gene (30Wang X. Sato R. Brown M.S. Hua X. Goldstein J.L. Cell. 1994; 77: 53-62Abstract Full Text PDF PubMed Scopus (851) Google Scholar) and the cholesteryl ester transfer protein gene (31Oliveira H.C.F. Chouinard R.A. Agellon L.B. Bruce C. Ma L.M. Walsh A. Breslow J.L. Tall A.R. J. Biol. Chem. 1996; 271: 31831-31838Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). However, no response element has yet been reported to mediate cholesterol induction of gene activation. Hence, studies of the CEL gene may also provide important insight into cholesterol-induced gene activation.During the last decade, the tissue-specific regulation of genes expressed in exocrine pancreas has been extensively studied, and the transcriptional regulation has been characterized to some extent. Most work has concerned genes encoding proteases and amylases, in which the pancreatic transcription factor 1 (PTF-1) seems to play a major role (32Kruse F. Rose S.D. Swift G.H. Hammer R.E. MacDonald R.J. Mol. Cell. Biol. 1995; 15: 4385-4394Crossref PubMed Scopus (35) Google Scholar, 33Cockell M. Stevenson B.J. Strubin M. Hagenbuchle O. Wellauer P.K. Mol. Cell. Biol. 1989; 9: 2464-2476Crossref PubMed Scopus (116) Google Scholar). Almost nothing is known about the transcriptional regulation of the corresponding lipase genes. Recently, some reports have indicated that the amount and type of fat can modulate the rate of transcription of pancreatic lipase (34Wicker C. Puigserver A. Biochem. Biophys. Res. Commun. 1990; 166: 358-364Crossref PubMed Scopus (20) Google Scholar, 35Ricketts J. Brannon P.M. J. Nutr. 1994; 124: 1166-1171Crossref PubMed Scopus (42) Google Scholar). Furthermore, PTF-1 seems to be involved in the regulation of the pancreatic colipase gene (36Fukuoka S. Zhang D.E. Taniguchi Y. Scheele G.A. J. Biol. Chem. 1993; 268: 11312-11320Abstract Full Text PDF PubMed Google Scholar,37Sims H.F. Lowe M.E. Biochemistry. 1992; 31: 7120-7125Crossref PubMed Scopus (13) Google Scholar).The high expression level in two different tissues, constitutively in pancreas and induced during lactation in the mammary gland, makes the CEL gene an interesting system for studying tissue-specific regulation. In this first report, we have, by using reporter gene analysis of promoter constructs in the rat pancreatic cell line AR4-2J, analyzed the basic structure of the transcriptional regulatory machinery responsible for the expression of the human CEL gene.DISCUSSIONThe elements responsible for the tissue-specific expression of genes expressed in exocrine pancreas are mainly located within the first few hundred bp of the 5-flanking region (33Cockell M. Stevenson B.J. Strubin M. Hagenbuchle O. Wellauer P.K. Mol. Cell. Biol. 1989; 9: 2464-2476Crossref PubMed Scopus (116) Google Scholar, 46Boulet A.M. Erwin C.R. Rutter W.J. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 3599-3603Crossref PubMed Scopus (70) Google Scholar). The expression of such genes is the effect of a cooperative interaction between several elements as described previously and exemplified by the elastase I gene enhancer (32Kruse F. Rose S.D. Swift G.H. Hammer R.E. MacDonald R.J. Mol. Cell. Biol. 1995; 15: 4385-4394Crossref PubMed Scopus (35) Google Scholar). For this gene, it has been shown that PTF-1, which binds to the A element, is the critical key in directing the expression to the acinar cells (47Roux E. Strubin M. Hagenbuchle O. Wellauer P.K. Genes Dev. 1989; 3: 1613-1624Crossref PubMed Scopus (58) Google Scholar). The activity is further enhanced by other elements such as the B and C elements, respectively.Although expression of the CEL gene in the pancreas is highly restricted to exocrine tissue, it seems to be regulated in a different manner. The main response element in the CEL gene promoter is located approximately 650 bp upstream from the transcription initiation site. This element is an absolute requirement for activity as well as for maintenance of the tissue specificity of the promoter. Although the high activity of the largest construct, CEL4740Luc, is the combined effect of several regions, as shown in Fig. 1 by the stepwise increase in activity, its activity is almost abolished if the main element is deleted (Fig. 2 A). Despite the fact that PTF-1 does not seem to be involved in this activation, this element is acting as a pancreas-specific enhancer as demonstrated by transfection of the chimeric CEL/SV40 construct (Fig. 3). In contrast, and as shown by transfection of HC11 cells, the enhancer does not contribute to the high CEL expression seen in lactating mammary gland. Hence, the dominating dual expression pattern of the CEL gene, mammary gland, and pancreas, respectively, is due to two different regulatory systems.Tissue- or cell-specific regulation of transcription, especially of genes with highly restricted expression, often involves cooperative interactions between several regulatory elements (32Kruse F. Rose S.D. Swift G.H. Hammer R.E. MacDonald R.J. Mol. Cell. Biol. 1995; 15: 4385-4394Crossref PubMed Scopus (35) Google Scholar, 48Cockell M. Stolarczyk D. Frutiger S. Hughes G.J. Hagenbuchle O. Wellauer P.K. Mol. Cell. Biol. 1995; 15: 1933-1941Crossref PubMed Google Scholar, 49Sanchez H.B. Yieh L. Osborne T.F. J. Biol. Chem. 1995; 270: 1161-1169Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar, 50Simonet W.S. Bucay N. Lauer S.J. Taylor J.M. J. Biol. Chem. 1993; 268: 8221-8229Abstract Full Text PDF PubMed Google Scholar). Such interactions between enhancer elements and their cognate promoters have also been described (51Crenshaw E.B.D. Kalla K. Simmons D.M. Swanson L.W. Rosenfeld M.G. Genes Dev. 1989; 3: 959-972Crossref PubMed Scopus (127) Google Scholar, 52Pinkert C.A. Ornitz D.M. Brinster R.L. Palmiter R.D. Genes Dev. 1987; 1: 268-276Crossref PubMed Scopus (294) Google Scholar). Sequence analysis has shown that the proximal part of the CEL gene promoter has been conserved during evolution and is highly similar between human and rat (15Lidberg U. Nilsson J. Strömberg K. Stenman G. Sahlin P. Enerbäck S. Bjursell G. Genomics. 1992; 13: 630-640Crossref PubMed Scopus (52) Google Scholar). Although the CEL enhancer itself seems to be able to establish tissue-specific expression, the abolished promoter activity following the deletion of the −317 to −63 region, as shown in Fig. 2 B, indicates the presence of other important elements. As shown in Fig. 1, this region is not in itself sufficient to activate the expression of the human CEL gene in AR4-2J cells. Hence, the results obtained in this study may be consistent with described models of cell-specific gene regulation involving cooperative interactions. However, a further deletion of most of the proximal promoter region, −631 to −63 (Fig. 2 B), resulted in a restoration of the promoter activity (which again indicates the importance of the element located at −650), suggesting that a negative regulatory element is located in the region −631 to −318. As a consequence, the deletion construct CEL1640Δ631/322Luc, in which this region has been deleted, should then give rise to an increased activity; instead, the observed activity is reduced. Moreover, the insertion of an unrelated DNA fragment of identical length as the fragment deleted above into the CEL1640Δ631/63Luc results in a similar reduction of the promoter activity. Taken together, a more likely explanation is that the restored promoter activity observed by the elongation of the deletion −63/−317 up to −631, is the result of moving the enhancer closer to the core promoter. This might also indicate that the effect of the enhancer in the CEL gene promoter is not absolutely position-independent at short distances to the core promoter.The enhancer seems to be built up by two subelements, enhansons: a distal negative element and a proximal positive element. As demonstrated in Fig. 5 B, each trans-acting factor is capable of binding DNA by itself. Enhancers composed of both positive and negative elements often mechanistically involve competition for DNA binding. Overlapping response elements will prevent simultaneous DNA interaction, as seen in the δ1-crystallin gene enhancer (53Kamachi Y. Kondoh H. Mol. Cell. Biol. 1993; 13: 5206-5215Crossref PubMed Google Scholar). Alternatively, too close location of the response elements might result in steric hindrance, as seen for YY1 and the MGF site in the rat β-casein gene promoter (54Meier V.S. Groner B. Mol. Cell. Biol. 1994; 14: 128-137Crossref PubMed Google Scholar). As shown in Fig. 5 B, this seems not to be the case for the CEL gene enhancer, since EMSA with GO26, containing both the response elements, results in a large complex. This complex seems to be composed of both factors, since it can be competed by oligonucleotides containing a single positive or negative element, respectively. A cooperative interaction like that seen for the sterol regulatory element-binding protein 1 factors in the low density lipoprotein receptor gene promoter (49Sanchez H.B. Yieh L. Osborne T.F. J. Biol. Chem. 1995; 270: 1161-1169Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar) cannot be excluded, although it seems less likely, since a similar amount of cold oligonucleotide was required for competition as for the single elements. However, as has been shown in Figs. 4 and 6 E, respectively, deletion or mutation of the negative element results in a highly increased promoter activity. On the other hand, the negative factor fails to influence the basal promoter activity when the positive element is deleted or mutated. This indicates that the negatively acting factor seems to influence the promoter activity by modulating the activity of the positively acting factor, which is similar to the hierarchical model suggested for the main positive element in the apolipoprotein B gene promoter (40Carlsson P. Bjursell G. Gene (Amst.). 1989; 77: 113-121Crossref PubMed Scopus (27) Google Scholar).As shown in Fig. 6 A and 7 A, the factors that bind to the enhancer seem to be ubiquitously expressed, since all studied cell types contain nuclear proteins capable of binding to the unique enhancer elements in the CEL gene promoter. Furthermore, GO26, covering the entire enhancer, revealed similar but weaker band patterns with nuclear extract from other cells (data not shown). The ubiquity of factors giving rise to mobility shifts, but not of enhancer activity, may be explained in several ways. The binding to these specific DNA sequences, respectively, could represent the interaction of several distinct nuclear proteins or heteropolymers of nuclear proteins. The cell-specific differences in the subunit composition of a multimeric binding protein may then account for the difference in activity, as is seen in the case of the NF-κB family (55La Rosa F.A. Pierce J.W. Sonenshein G.E. Mol. Cell. Biol. 1994; 14: 1039-1044Crossref PubMed Google Scholar, 56Miyamoto S. Schmitt M.J. Verma I.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 5056-5060Crossref PubMed Scopus (103) Google Scholar). An alternative could be the existence of cell-specific differences in the phosphorylation state, as is seen in interferon-regulated genes and lactation associated genes (57Burdon T.G. Demmer J. Clark A.J. Watson C.J. FEBS Lett. 1994; 350: 177-182Crossref PubMed Scopus (51) Google Scholar, 58Pine R. Canova A. Schindler C. EMBO J. 1994; 13: 158-167Crossref PubMed Scopus (339) Google Scholar). Also small differences in the balance between a positive and a negative factor may strongly influence the activation potential as seen for the CCAAT/enhancer-binding protein β isoforms ratio in the mammary gland (59Raught B. Liao W.S. Rosen J.M. Mol. Endocrinol. 1995; 9: 1223-1232PubMed Google Scholar). The difficulties in comparing the amount of a transcription factor in different nuclear extracts are obvious. Nevertheless, it seems to us that the factor binding to the positive element is significantly more highly expressed in cells derived from exocrine pancreas. This suggests that the net enhancer activity might be the result of a tissue-specific balance between the positively and negatively acting factors.Sequence analysis of the functional enhancer reveals no homology to the A, B, or C elements, respectively, in the elastase I gene promoter. Nor does a comparison to other known transcription factor binding sites show any clear homology; however, a comparison of respective subelements to previously reported cis-elements reveals some homologies, which mainly constitute half-sites. However, none of the oligonucleotides containing the corresponding cis-element tested in EMSA (ERE, AP-2, PTF-1) were able to compete with the interactions achieved by GO22 (negative subelement) or GO13 (positive subelement), respectively. The subelement mediating the positive effect contains a spaced palindrome motif that might indicate the binding of a homodimer. When the sequences of the subelements were compared with other promoter sequences, it was found that the subelement mediating the negative effect is present in the promoters of several other lipolytical genes, but none of them is yet connected to any functional activity. Hence, it is possible that the functional enhancer complex might be composed of not yet described transcription factors with new unique DNA binding specificities. Alternatively, it might be composed of common subfactors organized in a unique tissue-specific enhancer structure, as suggested by Tjian and Maniatis (60Tjian R. Maniatis T. Cell. 1994; 77: 5-8Abstract Full Text PDF PubMed Scopus (953) Google Scholar).An attractive hypothesis is that the enhancer element in the CEL gene promoter in some way might be connected with the observed cholesterol induction. The lack of sequence homology for the enhancer element to any known response elements might support this hypothesis. Also, the inactivity of the pancreatic enhancer element in mammary gland is in agreement with this hypothesis, since other factors/hormones are believed to induce milk protein gene expression. However, the reported up-regulation of the CEL gene by cholesterol is a process both too slow and too limited to be studied by transient transfection in the highly CEL expressing AR4-2J cells and will await stably transfected cell lines or more truly transgenes. Hence, analysis of the CEL gene regulation might contribute to the understanding of cholesterol-induced gene activation.In conclusion, the data presented here demonstrate that the expression of the human CEL gene in exocrine pancreas, but not in the lactating mammary gland, is due to a strong pancreas-specific enhancer. This suggests that the tissue-specific expression of the CEL gene is due to different regulatory systems. Also, in contrast to other studied genes expressed in exocrine pancreas, the PTF-1 does not seem to play a major role in the regulation of the CEL gene. Instead, yet unidentified factors interact with the unique enhancer elements. Although these factors are ubiquitously expressed, the functional enhancer complex seems to be organized in a tissue-specific structure. Hence, further characterization of the enhancer complex will provide additional insights into the regulation of exocrine pancreas-specific genes. The need for fat is of special importance for infants, since malabsorption would influence both growth and development (1Crawford M.A. Hassam A.G. Stevens P.A. Prog. Lipid Res. 1981; 20: 31-40Crossref PubMed Scopus (123) Google Scholar). To secure the requirement, several different lipolytical enzymes, secreted from the pancreas, contribute to the digestion of dietary fat. One of the important enzymes is carboxyl ester lipase (CEL),1 since it, because of its broad substrate specificity, is believed to be the main enzyme for the hydrolysis of fat-soluble vitamin esters, monoglycerides, and cholesterol esters (2Fredrikzon B. Hernell O. Bläckberg L. Olivecrona T. Pediatr. Res. 1978; 12: 1048-1052Crossref PubMed Scopus (111) Google Scholar, 3Howles P.N. Carter C.P. Hui D.Y. J. Biol. Chem. 1996; 271: 7196-7202Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). CEL is synthesized in the acinar cells of exocrine pancreas, secreted with the pancreatic juice, and activated in the intestinal lumen by bile salts (for reviews, see Refs. 4Wang C.S. Hartsuck J.A. Biochim. Biophys. Acta. 1993; 1166: 1-19Crossref PubMed Scopus (133) Google Scholar and 5Hui D.Y. Biochim. Biophys. Acta. 1996; 1303: 1-14Crossref PubMed Scopus (61) Google Scholar). CEL seems to be a very old enzyme. A pancreatic expression has been found in all vertebrates analyzed so far (6Gjellesvik D.R. Lombardo D. Walther B.T. Biochim. Biophys. Acta. 1992; 1124: 123-134Crossref PubMed Scopus (209) Google Scholar, 7Gjellesvik D.R. Lorens J.B. Male R. Eur. J. Biochem. 1994; 226: 603-612Crossref PubMed Scopus (53) Google Scholar). In fact, in the pancreas of leopard sharks, CEL is the only lipolytic enzyme for hydrolyzing dietary lipids (8Patton J.S. Warner T.G. Benson A.A. Biochim. Biophys. Acta. 1977; 486: 322-330Crossref PubMed Scopus (73) Google Scholar), which suggests that CEL, because of its broad substrate specificity, might even have been one of the first lipolytic enzymes expressed in the pancreas. The importance of CEL for intestinal absorption of dietary lipids is strongly supported by the fact that in mammals it is also synthesized in lactating mammary gland, secreted into the milk, and activated in the intestine (9Hernell O. Olivecrona T. J. Lipid Res. 1974; 15: 367-374Abstract Full Text PDF PubMed Google Scholar, 10Freed L.M. York C.M. Hamosh M. Sturman J.A. Hamosh P. Biochim. Biophys. Acta. 1986; 878: 209-215Crossref PubMed Scopus (43) Google Scholar). Since the capacity of human infants to digest milk lipids is poor during the first months, due to poorly developed pancreatic function (11Hernell O. Bläckberg L. J. Pediatr. Gastroenterol. Nutr. 1983; 2 Suppl. 1: 242-247Crossref Scopus (13) Google Scholar), the presence of CEL in milk seems to secure fat absorption. After cloning of the CEL cDNA and gene, respectively, we and other groups could show that there is only one gene responsible for the expression in the two tissues (12Nilsson J. Bläckberg L. Carlsson P. Enerbäck S. Hernell O. Bjursell G. Eur. J. Biochem. 1990; 192: 543-550Crossref PubMed Scopus (119) Google Scholar, 13Baba T. Downs D. Jackson K.W. Tang J. Wang C.S. Biochemistry. 1991; 30: 500-510Crossref PubMed Scopus (92) Google Scholar, 14Hui D.Y. Kissel J.A. FEBS Lett." @default.
• W2002059213 created "2016-06-24" @default.
• W2002059213 creator A5028363615 @default.
• W2002059213 creator A5048791993 @default.
• W2002059213 creator A5067000982 @default.
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• W2002059213 date "1998-11-01" @default.
• W2002059213 modified "2023-10-13" @default.
• W2002059213 title "Transcriptional Regulation of the Human Carboxyl Ester Lipase Gene in Exocrine Pancreas" @default.
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