Carboxyl Ester Lipase Overexpression in Rat Hepatoma Cells and CEL Deficiency in Mice Have No Impact on Hepatic Uptake or Metabolism of Chylomicron-Retinyl Ester

Bennekum, van; L, Li; Piantedosi, Roseann; Shamir, Raanan; Vogel, Silke; Fisher, Edward A.; Blaner, WS; Eh, Harrison

doi:10.1021/bi981680+

Cited by 45 publications

(35 citation statements)

References 38 publications

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“…One is a bile salt-dependent retinyl ester hydrolase. Most or all of this enzymatic activity in the liver probably arises from the actions of bile salt-activated carboxylester lipase (CEL) ( 53 ). However, since mice lacking CEL display no alteration in retinoid storage, metabolism, or action, this enzyme cannot be the sole physiologically relevant REH ( 53 ).…”

Section: Intestinal Absorptionmentioning

confidence: 99%

Retinol and retinyl esters: biochemistry and physiology

O’Byrne

Blaner

2013

Journal of Lipid Research

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The different retinoid forms present within the body (see Fig. 1 ) are generated by and large through modifi cations to the terminal polar end group of the molecule. Retinol and retinyl esters are the most abundant retinoid forms present in the body. All-trans -retinol is by defi nition vitamin A. When a fatty acyl group is esterifi ed to the hydroxyl terminus of retinol, a storage form of retinol, the retinyl ester, is formed. The most abundant retinyl esters present in the body are those of palmitic acid, oleic acid, stearic acid, and linoleic acid ( 6, 7 ). Although retinyl acetate can be found in supplements to foods and vitamin formulations, only long-chain acyl groups are esterifi ed to retinol by animals. Retinyl esters have no known biological activity aside from retinol storage and for serving as the substrate for the formation of the visual chromophore 11-cis -retinal, which must be formed from all-trans -retinyl ester through linked hydrolysis and isomerization reactions catalyzed by the enzyme RPE65 ( 3,4,8,9 ). Retinol is a transport form and a precursor form, which is enzymatically activated to retinoic acid via a two-step oxidation process. The primary role of retinal is in the eye where 11-cis -retinal is needed for visual pigment formation. In tissues, retinal serves as an intermediate in the synthesis of retinoic acid from retinol ( 6, 7 ). The literature also suggests a direct role for retinal in adipose tissue, where it was shown to inhibit adipogenesis and suppress peroxisome proliferator-activated receptor-␥ (PPAR ␥ ) and retinoid X receptor (RXR) responses in cell culture models and in mouse models fed high-fat diets ( 10 ).Abstract By defi nition, a vitamin is a substance that must be obtained regularly from the diet. Vitamin A must be acquired from the diet, but unlike most vitamins, it can also be stored within the body in relatively high levels. For humans living in developed nations or animals living in present-day vivariums, stored vitamin A concentrations can become relatively high, reaching levels that can protect against the adverse effects of insuffi cient vitamin A dietary intake for six months, or even much longer. The ability to accumulate vitamin A stores lessens the need for routinely consuming vitamin A in the diet, and this provides a selective advantage to the organism. The molecular processes that underlie this selective advantage include effi cient mechanisms to acquire vitamin A from the diet, effi cient and overlapping mechanisms for the transport of vitamin A in the circulation, a specifi c mechanism allowing for vitamin A storage, and a mechanism for mobilizing vitamin A from these stores in response to tissue needs. These processes are considered in this review. Since the identifi cation of fat-soluble A a century ago ( 1 ), retinoids (vitamin A and its natural and synthetic analogs) have been the most extensively studied of the fatsoluble vitamins. This research has identifi ed essential roles for retinoids in many different aspects of mammalian physiology, includ...

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Section: Intestinal Absorptionmentioning

confidence: 99%

Retinol and retinyl esters: biochemistry and physiology

O’Byrne

Blaner

2013

Journal of Lipid Research

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304

250

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“…2, C and D) implicated ES-4 as a lead candidate among this group. Fortunately, a standard model of rat hepatic lipoprotein and lipid metabolism, McA cells (41)(42)(43), has detectable ES-4 mRNA and protein levels, making it a convenient system for performing experiments in which ES-4 levels can be decreased or increased under conditions in which CE content can be easily manipulated.…”

Section: Discussionmentioning

confidence: 99%

Rat Carboxylesterase ES-4 Enzyme Functions as a Major Hepatic Neutral Cholesteryl Ester Hydrolase

Parathath

Doğan

Joaquin

et al. 2011

Journal of Biological Chemistry

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Although esterification of free cholesterol to cholesteryl ester in the liver is known to be catalyzed by the enzyme acyl-coenzyme A:cholesterol acyltransferase, ACAT, the neutral cholesteryl ester hydrolase (nCEH) that catalyzes the reverse reaction has remained elusive. Because cholesterol undergoes continuous cycling between free and esterified forms, the steady-state concentrations in the liver of the two species and their metabolic availability for pathways, such as lipoprotein assembly and bile acid synthesis, depend upon nCEH activity. On the basis of the general characteristics of the family of rat carboxylesterases, we hypothesized that one member, ES-4, was a promising candidate as a hepatic nCEH. Using under-and overexpression approaches, we provide multiple lines of evidence that establish ES-4 as a bona fide endogenous nCEH that can account for the majority of cholesteryl ester hydrolysis in transformed rat hepatic cells and primary rat hepatocytes.Cytosolic cholesterol pools are in a dynamic state of turnover between the free (FC) 2 and esterified forms (CE) (1-3). The identification of the enzyme(s) in the liver that catalyzes the hydrolysis of CE at neutral pH has been elusive. In contrast, the CE that enters cells as part of apoB-containing lipoproteins through receptor-or heparan sulfate proteoglycan-mediated uptake is known to be hydrolyzed by lysosomal acid lipase, with the ensuing FC available to enter various cellular pools. A fraction of the FC trafficked to the endoplasmic reticulum (ER) is esterified by isoforms of acyl-coenzyme A:cholesterol acyltransferase (ACAT). When potentially cytotoxic levels of FC are reached, there is a significant increase in the formation of CE, which is then stored in cytosolic lipid droplets (4, 5).In the liver, CE is a component of very low density lipoproteins (VLDL). The source of CE can be either direct (i.e. synthesized completely in the ER membrane) or indirect through hydrolysis of cytosolic CE and re-esterification of FC by ACAT (6, 7). FC can also become part of VLDL, and, as in all cells, FC resulting from CE hydrolysis can be effluxed to HDL or used in the synthesis of other molecules. In liver, a major fate of FC is its conversion to bile acids and oxysterols. The interconversion between the non-lysosomal cellular pools of FC and CE in the liver is under metabolic regulation, with the key enzymatic components attributed to ACAT and neutral cholesteryl ester hydrolases (nCEHs) (8 -12).The explicit identification of nCEHs in the liver has been elusive. Ghosh and colleagues (13) have recently reported a human macrophage nCEH active in foam cells in atherosclerotic plaques that was related to a previously studied enzyme proposed as a rat hepatic nCEH (14). The latter was cloned from rat liver, and, when overexpressed in COS cells, the lysates exhibited nCEH activity against exogenously provided CE (14). However, whether this candidate operates as a nCEH under physiological conditions in hepatic cells has never been established. Another candidate that...

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“…For instance, bile salt-activated carboxyl ester lipase (CEL) ( 15,16 ) has been demonstrated to hydrolyze RE. However, CEL-defi cient mice generated by targeted disruption of the CEL gene failed to show any effect on RE metabolism in the liver, on serum levels of retinol and RBP4, or on levels of retinoids in various tissues ( 17 ). Two distinct bile salt-independent REHs, one active at neutral ( 18 ), the other at acid pH ( 19 ), have been characterized in rat liver; in addition, three rat liver carboxyl esterases [Es2 ( 20 ), Es4, and Es10 ( 21,22 )] exhibit REH activity in vitro.…”

Section: Preparation Of Cos-7 Cell Lysatesmentioning

confidence: 98%

Esterase 22 and beta-glucuronidase hydrolyze retinoids in mouse liver

Schreiber

Taschler

Wolinski

et al. 2009

Journal of Lipid Research

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This article is available online at http://www.jlr.org retinol is reesterifi ed ( 3-5 ) for the incorporation into chylomicrons and secreted ( 6 ). In the circulation, chylomicrons are depleted from triglycerides by lipoprotein lipase and are thereby transformed to chylomicron remnants ( 7 ). These remnants acquire apolipoprotein E and are then cleared mostly by parenchymal cells of the liver (i.e., hepatocytes) ( 8-10 ). In hepatocytes, REs are hydrolyzed, and unesterifi ed retinol is associated with retinol-binding protein 4 (RBP4) for secretion ( 11,12 ) or transferred to hepatic stellate cells for storage ( 10,13,14 ). These stellate cells store most of the total body vitamin A reserves ( ‫ف‬ 80%) in the form of retinyl palmitate in cytosolic lipid droplets ( 14 ).According to the body's demand, stored retinoids are released from the liver to facilitate a constant supply. In the circulation, the biologically inactive retinol is transported bound to RPB4 and delivered to target tissues. There, retinol is converted into its biologically active metabolites 11-cis retinaldehyde and retinoic acids, which act as h acceptor in the visual cycle and as ligand of nuclear receptors, respectively.The dynamic balance between synthesis and hydrolysis of RE determines the concentration of retinol in the circulation and also the availability of retinol for conversion in active metabolites in various cell types. Retinol is esterifi ed by the action of acyl-CoA:retinol acyltransferase (ARAT) or lecithin:retinol acyltransferase (LRAT) for storage in lipid droplets. Much work has focused on the understanding of how REs are released from lipid droplets and which Abstract Excess dietary vitamin A is esterifi ed with fatty acids and stored in the form of retinyl ester (RE) predominantly in the liver. According to the requirements of the body, liver RE stores are hydrolyzed and retinol is delivered to peripheral tissues. The controlled mobilization of retinol ensures a constant supply of the body with the vitamin. Currently, the enzymes catalyzing liver RE hydrolysis are unknown. In this study, we identifi ed mouse esterase 22 (Es22) as potent RE hydrolase highly expressed in the liver, particularly in hepatocytes. The enzyme is located exclusively at the endoplasmic reticulum (ER), implying that it is not involved in the mobilization of RE present in cytosolic lipid droplets. Nevertheless, cell culture experiments revealed that overexpression of Es22 attenuated the formation of cellular RE stores, presumably by counteracting retinol esterifi cation at the ER. Es22 was previously shown to form a complex with ␤ -glucuronidase (Gus). Our studies revealed that Gus colocalizes with Es22 at the ER but does not affect its RE hydrolase activity. Interestingly, however, Gus was capable of hydrolyzing the naturally occurring vitamin A metabolite retinoyl ␤ -glucuronide. In conclusion, our observations implicate that both Es22 and Gus play a role in liver retinoid metabolism. -Schreiber, R., U. Taschler

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Carboxyl Ester Lipase Overexpression in Rat Hepatoma Cells and CEL Deficiency in Mice Have No Impact on Hepatic Uptake or Metabolism of Chylomicron-Retinyl Ester

Cited by 45 publications

References 38 publications

Retinol and retinyl esters: biochemistry and physiology

Retinol and retinyl esters: biochemistry and physiology

Rat Carboxylesterase ES-4 Enzyme Functions as a Major Hepatic Neutral Cholesteryl Ester Hydrolase

Esterase 22 and beta-glucuronidase hydrolyze retinoids in mouse liver

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