Tissue and species differences in bile salt-dependent neutral cholesteryl ester hydrolase activity and gene expression.

Zolfaghari, Reza; Harrison, Earl H.; Han, Jang H.; Rutter, William J.; Fisher, Edward A.

doi:10.1161/01.atv.12.3.295

Cited by 26 publications

(13 citation statements)

References 23 publications

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“…Species differences in tissue expression of the bile salt-stimulated cholesterol esterase gene have been reported previously (44). While the pancreas of all species examined to date were capable of cholesterol esterase biosynthesis, the bile salt-stimulated pancreatic type cholesterol esterase mRNA was present only in rabbit intestine and not the intestine of rat, human, or mouse (41,44).…”

Section: Expression Of Cholesteryl Ester Hydrolytic Enzymes In Mousementioning

confidence: 70%

“…While the pancreas of all species examined to date were capable of cholesterol esterase biosynthesis, the bile salt-stimulated pancreatic type cholesterol esterase mRNA was present only in rabbit intestine and not the intestine of rat, human, or mouse (41,44). Cholesterol esterase mRNA was reported to be present in some but not all rat liver tested (41,44), and was absent in the rat hepatoma Fu5AH cells (15). However, the cholesterol esterase mRNA was detectable in the HepG2 human hepatoma cells (Ref.…”

Section: Expression Of Cholesteryl Ester Hydrolytic Enzymes In Mousementioning

confidence: 99%

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Modified Low Density Lipoprotein Enhances the Secretion of Bile Salt-stimulated Cholesterol Esterase by Human Monocyte-Macrophages

Hui

1997

Journal of Biological Chemistry

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Reverse transcriptase-polymerase chain reaction was used to study the biosynthesis of two different cholesteryl ester hydrolases by human and mouse macrophages. Oligonucleotide primers for bile salt-stimulated cholesterol esterase yielded positive reactions with RNA isolated from human peripheral blood monocytes, monocyte-derived macrophages, the human monocytic THP-1 cells, and phorbol ester-induced THP-1 macrophages. In contrast, oligonucleotide primers for hormone-sensitive lipase yielded positive reactions only with RNA isolated from non-differentiated human THP-1 monocytic cells and peripheral blood monocytes, but not those obtained from differentiated THP-1 macrophages or monocyte-derived macrophages. Thus, while human monocytes were capable of synthesizing both enzymes, human macrophages synthesized only bile salt-stimulated cholesterol esterase and not the hormone-sensitive lipase. The synthesis of bile salt-stimulated cholesterol esterase by human macrophages was confirmed by detection of bile salt-stimulated cholesteryl ester hydrolytic activity in conditioned media of differentiated THP-1 cells and human peripheral blood monocyte-derived macrophages. Moreover, incubating human macrophages with oxidized low density lipoprotein (LDL) or acetylated LDL increased bile salt-stimulated cholesterol esterase activity in the conditioned media of these cells. These results with human macrophages were contrasted with results of studies with mouse macrophages, which showed the presence of hormone-sensitive lipase mRNA but not the bile salt-stimulated cholesterol esterase mRNA. Taken together, these results demonstrated species-specific differences in expression of cholesteryl ester hydrolytic enzymes in macrophages. The expression of bile salt-stimulated cholesterol esterase by human macrophages, in a process inducible by modified LDL, suggests a role of this protein in atherogenesis.A major characteristic of atherosclerosis is the accumulation of lipid-laden foam cells in the arterial wall. The foam cells are derived mainly from macrophages that have endocytosed modified lipoproteins through the scavenger receptor-mediated pathways (1). The cytoplasmic lipid droplets are mostly cholesteryl esters, which exist in a dynamic equilibrium with unesterified cholesterol and undergo continues hydrolysis and re-esterification (1). In the presence of exogenous cholesterol acceptors such as high density lipoproteins, the equilibrium favors cholesteryl ester hydrolysis with a net efflux of cholesterol from cells. In such circumstances, very little amount of cholesterol is stored in the macrophages. However, in the absence of extracellular cholesterol acceptors, or when acceptor concentration is low, equilibrium of the cholesteryl ester cycle favors esterification and cholesteryl esters accumulate in the cytosol.Cholesteryl ester can also accumulate in macrophages due to different levels of the esterification and de-esterification enzymes. Macrophages with high neutral cholesteryl ester hydrolytic activity were shown to accu...

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Section: Expression Of Cholesteryl Ester Hydrolytic Enzymes In Mousementioning

confidence: 70%

Section: Expression Of Cholesteryl Ester Hydrolytic Enzymes In Mousementioning

confidence: 99%

Modified Low Density Lipoprotein Enhances the Secretion of Bile Salt-stimulated Cholesterol Esterase by Human Monocyte-Macrophages

Hui

1997

Journal of Biological Chemistry

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“…Conversely, as one early study has shown, for certain hydrolases there is little correlation between mRNA levels and lipolytic activity. 46 It remains to be determined how epoxycholesterol decreases CE hydrolysis in lipid-loaded macrophages. We do know that this occurs independently of LXR activation, because the simultaneous treatment of lipid-loaded THP-1 cells with epoxycholesterol and an LXR antagonist does not increase cholesterol efflux, and the addition of an LXR synthetic agonist in conjunction with epoxycholesterol fails to rescue the efflux defect (supplemental Figure II) macrophages via transcriptional downregulation of CEH or HSL, the possibility of altered posttranslational regulation of these enzymes remains to be investigated, as well as the contribution of other candidate enzymes for CE hydrolysis in these macrophages.…”

mentioning

confidence: 99%

Epoxycholesterol Impairs Cholesteryl Ester Hydrolysis in Macrophage Foam Cells, Resulting in Decreased Cholesterol Efflux

Ouimet

Wang

Cadotte

et al. 2008

ATVB

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Objective-Strategies to inhibit or reverse cholesterol accumulation in macrophages have been shown to be atheroprotective. Notably, the administration of LXR agonists upregulates key players in the reverse cholesterol transport pathway, including the ABCA1 and ABCG1 transporters. However, the effects of natural LXR activators, oxysterols, on lipid-laden macrophages remains elusive. Methods and Results-We assessed the ability of 2 oxysterols, 22(R)-hydroxycholesterol (22-OH) and 24(S), 25-epoxycholesterol (epoxycholesterol), to promote cholesterol efflux to apoA-I from LDL-and modified LDL-labeled and loaded macrophages and thus rescue the phenotype associated with the accumulation of cellular cholesterol in these cells. In macrophages labeled with LDL-derived cholesterol, epoxycholesterol treatment enhances ABCA1-mediated cholesterol efflux. In contrast, in AcLDL-loaded macrophages, epoxycholesterol treatment decreases cholesterol efflux to apoA-I, despite a dramatic increase in the expression of ABCA1 in response to epoxycholesterol treatment. We show that the decreased efflux is attributable to impaired cholesterol mobilization from lipid droplets, resulting from decreased cholesteryl ester hydrolase activity. W hereas low density lipoprotein (LDL) endocytosis is a regulated process, the uptake of modified LDL via macrophage scavenger receptors 1 or via macropinocytosis 2 lacks feedback inhibition by intracellular cholesterol accumulation. The internalization of modified LDL, such as oxidized LDL (OxLDL), acetylated LDL (AcLDL), or aggregated LDL (AgLDL), leads to the formation of foam cells, 3,4 which are a major component of atherosclerotic lesions. Conclusion-EpoxycholesterolThe liver X receptors (LXRs) ␣ and ␤, members of the nuclear receptor family of transcription factors, are key regulators of whole body lipid homeostasis. LXR-␤ is expressed ubiquitously whereas LXR-␣ is predominantly expressed in tissues important in lipid metabolism including liver, adipose tissue, and macrophages. 5,6 The naturally occurring oxysterols 22(R)-hydroxycholesterol (22-HC) and 24(S),25-epoxycholesterol (epoxycholesterol) are endogenous LXR ligands and have been shown to be potent physiological activators of both LXRs. 7,8 LXRs function by forming an obligate heterodimer with the retinoid X receptor (RXR), and this complex drives LXR-dependent transactivation of multiple genes involved in cellular cholesterol homeostasis, including ABCA1, ABCG1, and apoE in the lipid efflux pathway, which normally prevent cholesterol accumulation as intracellular lipid droplets. 9 Given that ABCA1-mediated cholesterol efflux to lipidpoor apolipoprotein A-I (apoA-I) is the preferred efflux pathway of the macrophage foam cell, 10 we sought to promote this pathway in cholesterol-loaded cells using 22-HC and epoxycholesterol. Oxysterols have been shown to be beneficial for enhancing cholesterol efflux 6,11-13 and preventing foam cell formation, 14 but it is not established whether they are similarly effective when macrophages become cholestero...

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“…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 (16,17). Furthermore, there seem to be differences with respect to the tissue-specific expression among different species (18). This might be explained by differences that have taken place during the evolution of the CEL gene locus.…”

mentioning

confidence: 99%

Transcriptional Regulation of the Human Carboxyl Ester Lipase Gene in Exocrine Pancreas

Lidberg¹,

Kannius-Janson

Nilsson

et al. 1998

Journal of Biological Chemistry

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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 ciselements. 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 tissuespecific 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.

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Tissue and species differences in bile salt-dependent neutral cholesteryl ester hydrolase activity and gene expression.

Cited by 26 publications

References 23 publications

Modified Low Density Lipoprotein Enhances the Secretion of Bile Salt-stimulated Cholesterol Esterase by Human Monocyte-Macrophages

Modified Low Density Lipoprotein Enhances the Secretion of Bile Salt-stimulated Cholesterol Esterase by Human Monocyte-Macrophages

Epoxycholesterol Impairs Cholesteryl Ester Hydrolysis in Macrophage Foam Cells, Resulting in Decreased Cholesterol Efflux

Transcriptional Regulation of the Human Carboxyl Ester Lipase Gene in Exocrine Pancreas

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