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Lipases and Carboxylesterases: Possible Roles in the Hepatic Utilization of Vitamin A^{1 ,2}

Human Nutrition Research Center, U.S. Department of Agriculture, Agricultural Research Service, Beltsville, MD 20705

	ABSTRACT

TOP ABSTRACT INTRODUCTION Hepatic retinyl ester hydrolases Bile salt-independent retinyl... Carboxylesterases Other retinyl ester hydrolases... Summary and proposed model... REFERENCES

 
The formation and hydrolysis of retinyl esters are key processes in the metabolism of the fat-soluble micronutrient vitamin A. Long-chain acyl esters of retinol are the major chemical form of vitamin A (retinoid) stored in the body. Although retinyl esters are found in a variety of tissues and cell types, most of the total body retinoid is accounted for by the retinyl esters stored in the liver. Thus, these esters represent the major endogenous source of retinoid that can be delivered to peripheral tissues for conversion to biologically active forms. This paper summarizes the current state of our knowledge about the identity, function and regulation of the hepatic enzymes that are potentially involved in catalyzing the hydrolysis of retinyl esters. These enzymes include several known and characterized lipases and carboxylesterases.

KEY WORDS: • retinoids • retinol • retinol esters • hydrolases • liver

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Hepatic retinyl ester hydrolases Bile salt-independent retinyl... Carboxylesterases Other retinyl ester hydrolases... Summary and proposed model... REFERENCES

 
The formation and hydrolysis of retinyl esters are key processes in the metabolism of the fat-soluble micronutrient vitamin A. Vitamin A is essential for the growth and general health of higher animals, including humans. The vitamin is required for vision, reproduction, and the development and maintenance of differentiated tissues. The vitamin’s role in vision is fulfilled by its metabolic conversion to 11-cis retinaldehyde, which functions as the active chromophore in rhodopsin (Saari 1994 , Wald 1968 ). Its role in differentiation and development is likely fulfilled by its conversion to either all-trans or 9-cis retinoid acid, both of which interact with a number of nuclear receptors [of the retinoic acid receptor (RAR)³ or retinoid X receptor (RXR) families] that function as hormone-activated trans-activating factors in the regulation of gene expression (Evans 1996 ). The role of retinoic acid in gene expression is likely the basis of the profound role of retinoids in preventing or reversing certain neoplasms (Moon et al. 1994 ).

Long-chain acyl esters of retinol are the major chemical form of vitamin A (retinoid) stored in the body. Although retinyl esters are found in a variety of tissues and cell types, most of the total body retinoid is accounted for by the retinyl esters stored in the liver. These esters represent the major endogenous source of retinoid that can be delivered to peripheral tissues for conversion to biologically active forms. This paper summarizes briefly current knowledge about the hepatic enzymes that are potentially involved in catalyzing the hydrolysis of retinyl esters. A more complete review of this topic was recently published (Harrison 1998 ).

	Hepatic retinyl ester hydrolases

TOP ABSTRACT INTRODUCTION Hepatic retinyl ester hydrolases Bile salt-independent retinyl... Carboxylesterases Other retinyl ester hydrolases... Summary and proposed model... REFERENCES

 
Bile salt–dependent retinyl ester hydrolase and carboxylester lipase.

Much recent work on the hepatic, bile salt–dependent retinyl ester hydrolase (BSDREH) has focused on the possibility that most or all of this activity is due to the bile salt–activated carboxylester lipase (CEL), an enzyme that has been purified from the pancreata and milks of several mammalian species (Wang and Hartsuck 1993 ). The basis for initially considering this possibility was the fact that, like the BSDREH of rat liver, the bile salt–activated carboxylester lipase required millimolar concentrations of trihydroxy bile salts for activity in bulk-phase assay systems and showed a broad substrate range including cholesteryl esters and retinyl esters (Erlanson and Borgstrom 1968 , Fredrikzon et al. 1978 , Gallo 1981 , Lombarbo and Guy 1980 ). Experiments in the author’s laboratory demonstrated the very close similarity in enzymatic properties between purified rat pancreatic carboxylester lipase and the bile salt-dependent lipid ester hydrolase activities of rat liver cytosol for the hydrolysis of both cholesteryl esters and retinyl esters (Harrison 1988 , Harrison and Gad 1989 ). Moreover, monospecific antipancreatic hydrolase immunoglobulin G specifically and completely inhibited both the bile salt–dependent cholesteryl ester and retinyl ester hydrolase activities of rat liver cytosol (Harrison 1988 , Harrison and Gad 1989 ).

Further support for the suggestion that the bile salt–dependent liver hydrolase is highly related to the pancreatic enzyme came from the work of Hui, Brockman and their colleagues. These investigators isolated a bile salt–stimulated cholesteryl ester hydrolase from rat liver cytosol using chromatography on DEAE-sepharose, gel filtration and an immunoaffinity column of antiporcine pancreatic cholesterol esterase (Camulli et al. 1989 ). On the basis of N-terminal sequence analysis and reaction with antipancreatic enzyme antibodies, they concluded that the liver and pancreatic enzymes are identical. Finally, recent analysis of the nucleotide sequence of the cDNA for the hepatic enzyme also indicates that it is identical to the pancreatic enzyme (Chen et al. 1997 , Kissel et al. 1989 ).

Much of the early work on the hepatic, bile salt–dependent carboxylester lipase was motivated by the search for an intracellular enzyme in rat liver that might be involved in the mobilization of stored retinyl esters. However, there is now evidence suggesting that the hepatic enzyme (like that of the pancreas and breast) is largely secreted from the tissue that makes it. Thus, both rat hepatoma cells and intact rat livers secrete more enzyme than they retain in the cell (Winkler et al. 1992 ). Consistent with the idea that the enzyme is secreted by the liver is the demonstration of enzyme activity in rat serum (Harrison 1988 ). Thus, the hepatic carboxylester lipase may function as a retinyl ester hydrolase to hydrolyze chylomicron remnant retinyl esters after the enzyme is secreted into the space of Disse.

To test this hypothesis, we recently investigated uptake and hydrolysis of chylomicron-retinyl esters by rat hepatoma (McArdle-RH7777) cells stably transfected with a rat CEL cDNA and also studied tissue uptake of chlomicron-retinyl esters in CEL-deficient mice generated by targeted disruption of the CEL gene (van Bennekum et al. 1999b ). CEL-transfected cells secreted active enzyme into the medium. However, both control and CEL-transfected cells accumulated exogenously added chylomicron- or chylomicron remnant–derived retinyl esters in equal amounts. Serum clearance of intravenously injected chylomicron-retinyl esters and cholesteryl ester was not different between wild-type and CEL-deficient mice. Also, the uptake of the two compounds by the liver and other tissues did not differ. These data indicate that the lack of CEL expression does not affect the uptake of dietary chylomicron-retinyl esters by the liver or other tissues. Moreover, the percentage of retinol formed in the liver after chylomicron-retinyl esters uptake, the level of retinol and retinol-binding protein in serum and retinoid levels in various tissues did not differ, indicating that CEL deficiency does not affect hepatic retinoid metabolism and retinoid distribution throughout the body. Surprisingly, in both pancreas and liver of wild-type, heterozygous and homozygous CEL-deficient mice, the levels of bile salt–dependent retinyl ester hydrolase (REH) activity were similar. This indicates that an REH enzyme activity, active in the presence of bile salt and distinct from CEL, is present in the mouse pancreas and liver, compatible with results from our other recent studies showing that the intestinal processing and absorption of retinyl esters were unimpaired in CEL-deficient mice (Weng et al. 1999 ).

	Bile salt–independent retinyl ester hydrolases

TOP ABSTRACT INTRODUCTION Hepatic retinyl ester hydrolases Bile salt-independent retinyl... Carboxylesterases Other retinyl ester hydrolases... Summary and proposed model... REFERENCES

 
Most early studies of the hydrolysis of retinyl esters in liver and other tissues focused on the bile salt–dependent hydrolase described above. More recently, reports have documented the existence of bile salt–independent retinyl ester hydrolases that are distinct from the bile salt–dependent hydrolase (Boerman and Napoli, 1991 , Gad and Harrison 1991 , Harrison and Gad, 1989 , Harrison and Napoli 1990 , Harrison et al. 1995 , Napoli et al. 1989 ).

Harrison and Gad (1989) showed that rat liver homogenates contain a neutral, bile salt–independent REH activity that differs from the BSDREH (i.e., carboxylester lipase) as follows: 1) its absolute activity does not vary widely among individual rats; 2) it is not inhibited by antibodies to pancreatic carboxylester lipase; and 3) it is localized in the microsomal fraction of liver homogenates, with almost no activity in the soluble fraction. Subfractionation of microsomes demonstrated that the enzyme activity is enriched specifically in plasma membranes and/or endosomes. This localization would allow the enzyme to play a role in the initial hydrolysis of retinyl esters delivered to liver in association with chylomicron remnants.

The potential specificity and importance of the bile salt–independent, neutral REH activity in retinoid metabolism is also indicated by the evidence presented by Boerman and Napoli (1991) that the reaction is specifically activated by apo-cellular retinol-binding protein (apo-CRBP). In these elegant studies, it was demonstrated that the hydrolysis of endogenous retinyl esters in rat liver microsomes was stimulated by apo-CRBP in a concentration-dependent and saturable fashion. The lack of inhibition of the apo-CRBP–stimulated hydrolysis by antipancreatic cholesterol esterase demonstrated that the reaction under study was, in fact, the bile salt–independent REH. Moreover, the concentrations of apo-CRBP used in this study were close to the concentrations of the binding protein found in rat liver cytosol (Harrison et al. 1987 ). Thus, apo-CRBP may be an important regulator of retinyl ester hydrolysis in vivo.

Other studies (Gad and Harrison, 1991 ) have demonstrated that the microsomal, neutral, bile salt–independent REH is distinct from microsomal cholesteryl esterases. Activities against the two ester substrates were markedly differentially sensitive to heat inactivation, protease treatments and active site-directed inhibitors. This same study demonstrated that rat liver plasma membrane/endosome fractions also contain bile salt–independent REH activity, active at acid pH. The acid REH was shown to be distinct from the neutral activity on the basis of their differential sensitivity to n-alkyl carbamates and diethylphosphates. The available evidence suggests that chylomicron retinyl esters delivered to the liver are initially associated with endosomes but are not transferred to lysosomes (Blomhoff et al. 1985 , Harrison et al. 1995 ). Thus, the presence of neutral and acid REH in plasma membranes and endosomes could allow for the efficient hydrolysis of retinyl esters newly delivered to the liver.

More recent studies were directed at asking whether the neutral and acid, bile salt–independent retinyl ester hydrolases, associated with plasma membrane and endosome fractions of rat liver homogenates, are involved in hepatic retinyl ester metabolism (Harrison et al. 1995 ). Toward this end, chylomicrons containing tritium-labeled retinyl esters were injected intravenously into rats to study the initial metabolism of retinyl esters during and after uptake into the liver. At various times after chylomicron injection, plasma was obtained, and the liver was homogenized and subjected to analytical subcellular fractionation. Labeled retinyl esters were rapidly cleared from plasma (half-time ~ 10 min) and appeared in the liver. Within the liver, label first appeared in plasma membrane/endosomal fractions that were also enriched in both neutral and acid, bile salt–independent retinyl ester hydrolase activities. At no time were the labeled esters significantly associated with fractions enriched in lysosomes. Rather, it appeared that the labeled esters were hydrolyzed and/or transferred to fractions enriched in endoplasmic reticulum. These studies demonstrated the colocalization of newly delivered retinyl esters and bile salt–independent retinyl ester hydrolase enzyme activities, thus suggesting a probable role for these enzymes in the initial hepatic metabolism of chylomicron retinyl esters. This conclusion was supported further by the observation that plasma membrane/endosomal fractions were active in catalyzing the hydrolysis of chylomicron remnant retinyl esters in vitro.

Analysis of the cellular distribution of the membrane-bound, bile salt–independent REH in hepatocytes and nonparenchymal cell fractions of rat liver revealed that for each of the enzyme activities, there was no preferential enrichment in either cell fraction (Matsuura et al. 1997 ). Thus, these enzymes are clearly present in hepatocytes, the cell type that is almost exclusively involved in chylomicron uptake in liver. In this same study cited above (Matsuura et al. 1997 ), it was also demonstrated that the activities of the neutral and acid, bile salt–independent REH were unaffected by vitamin A (retinoid) status.

	Carboxylesterases

TOP ABSTRACT INTRODUCTION Hepatic retinyl ester hydrolases Bile salt-independent retinyl... Carboxylesterases Other retinyl ester hydrolases... Summary and proposed model... REFERENCES

 
Although the older biochemical literature refers to >30 rat liver carboxylesterases, it is now appreciated that almost all of these enzyme activities are manifestations of the gene products of five major loci in linkage group V (Mentlein et al. 1987 ). These esterases (ES) are referred to as ES-2 (also called serum esterase), ES-3 (also called the pI 5.6 esterase), ES-4 (also called the pI 6.2/6.4 esterase or microsomal hydrolase), ES-10 (also called the pI 6.0/6.1 esterase) and ES-15 (also called the pI 5.0/5.2 esterase). All of these enzymes have polypeptide monomer molecular weights of 58–65 kDa and all function catalytically as the monomer, except for esterase ES-10, which exists as a homotrimer in the native state (Mentlein et al. 1987 ). All of these enzymes function as carboxylesterases (on a wide variety of oxyester substrates), whereas the microsomal hydrolase, ES-4, also functions as a thioesterase and catalyzes the hydrolysis of long-chain acyl-CoA (Alexson et al. 1993 , Mentlein et al. 1987 ).

Mentlein and Heymann (1987) studied the hydrolysis of retinyl palmitate by four purified rat liver microsomal carboxylesterases, ES-3, ES-10 and esterases of pIs 6.2 and 6.4 (isozymic forms of a single protein coded by the ES-4 locus). The latter enzyme (ES-4) hydrolyzed retinyl palmitate that was comixed with various emulsifiers. Emulsification with 0.1 mmol/L bovine serum albumin, 10 mmol/L taurocholate or 0.2% Triton X-100 all supported hydrolysis, with the last-mentioned giving the highest rates (two times higher than the others). Thus, this assay is not measuring the BSDREH, but rather a neutral bile salt–independent REH. ES-10 showed lower activity with some substrate forms. ES-3 was inactive under any of the assay conditions employed.

Recently, a neutral, bile salt–independent retinyl ester hydrolase was purified from a rat liver microsomal fraction (Sun et al. 1997 ). The purification procedure involved detergent extraction, DEAE-Sepharose ion exchange, Phenyl-Sepharose hydrophobic interaction, Sephadex G-100 and Sephacryl S-200 gel filtration chromatographies and SDS-PAGE. The isolated enzyme has an apparent molecular mass of ~66 kDa under denaturing conditions on SDS-PAGE. Analysis of the amino acid sequences of four peptides isolated after proteolytic digestion revealed that the enzyme is highly homologous with other rat liver carboxylesterases. In particular, the sequences of the four peptides of the neutral REH (60 amino acids total) were identical to those of a rat serum carboxylesterase (ES-2) expressed in the liver (Alexson et al. 1994 ). Antibodies against ES-2 also reacted with the purified neutral REH, which showed a substrate preference for retinyl palmitate over triolein and did not catalyze the hydrolysis of cholesteryl oleate. With retinyl palmitate as substrate, the enzyme had a pH optimum of 7 and showed apparent saturation kinetics, with half-maximal activity achieved at substrate concentrations (K_m) of ~70 µmol/L. In the same study, evidence was presented, demonstrating that a nearly homogeneous preparation of ES-10 also functioned as a neutral bile salt–independent REH. Thus, it appears that three known carboxylesterases (viz., ES-2, ES-4 and ES-10) can function effectively as REHs in vitro.

	Other retinyl ester hydrolases in liver: lipoprotein lipase and hepatic lipase

TOP ABSTRACT INTRODUCTION Hepatic retinyl ester hydrolases Bile salt-independent retinyl... Carboxylesterases Other retinyl ester hydrolases... Summary and proposed model... REFERENCES

 
It is thought that the first step in the hepatic metabolism of chylomicron remnants is their "sequestration" in the space of Disse by the binding of apolipoprotein E to heparin sulfate proteoglycans on the cell surface (Mahley and Hussain 1991 ). It is also now appreciated that secreted lipases, namely, lipoprotein lipase (LPL) and hepatic lipase (HL), are also found in the space of Disse. Both of these lipases can potentiate the cellular uptake of cholesteryl ester from chylomicron remnants or other lipoproteins by mechanisms that may involve anchoring the lipoprotein to the cell surface and/or hydrolysis of the esters themselves (Borensztajn et al. 1988 , Ji et al. 1994 , Olivecrona and Bengtsson-Olivecrona 1990 , Rumsey et al. 1992 , Sultan et al. 1990 ).

Recent work by Blaner et al. (1994) strongly suggests that LPL can catalyze the hydrolysis of retinyl esters in both chylomicrons and artificial emulsions. Moreover, through this stimulation of hydrolysis, the enzyme facilitated retinoid uptake by cultured adipocytes. More recent work also suggests that the level of expression of LPL influences tissue uptake of chylomicron retinyl esters in intact animals (van Bennekum et al. 1999a ).

	Summary and proposed model of the roles of various retinyl ester hydrolases in hepatic retinyl ester metabolism

TOP ABSTRACT INTRODUCTION Hepatic retinyl ester hydrolases Bile salt-independent retinyl... Carboxylesterases Other retinyl ester hydrolases... Summary and proposed model... REFERENCES

 
Figure 1 outlines a possible pathway for the hepatic metabolism of retinyl esters that is consistent with the available experimental data and that emphasizes the possible role of various REHs. It is now thought that the first step in the hepatic metabolism of chylomicron remnants is their "sequestration" in the space of Disse by the binding of apolipoprotein E to heparin sulfate proteoglycans on the cell surface (Mahley and Hussain 1991 ). While in the space of Disse, some of the neutral lipid ester may be hydrolyzed by secreted lipases such as HL and LPL. Because the serum carboxylesterase ES-2 (Alexson et al. 1994 ) is also secreted by the liver, it is possible that this enzyme may play some role in the metabolism of remnants in the space of Disse, although there is no evidence to date that supports this possibility directly.

View larger version (27K): [in this window] [in a new window]   Figure 1. Proposed scheme for the involvement of lipases and carboxylesterases in the hydrolysis of retinyl esters (RE) during the uptake and mobilization of vitamin A in liver. Chylomicron remnants containing RE are first sequestered in the sinusoidal space of Disse outside of hepatocytes. Carboxylester lipase (CEL), hepatic lipase (HL) and carboxylesterase ES-2 (ES-2) are all secreted by the liver and could occur in the space of Disse along with lipoprotein lipase (LPL) bound to sinusoidal endothelial cells. Current evidence suggests that LPL and HL function to enhance uptake and/or hydrolysis of RE to free retinol (ROH) and that CEL does not. The role of ES-2 has not yet been tested. During endocytosis, the bile salt– independent, neutral retinyl ester hydrolase (NREH) and acid retinyl ester hydrolase (AREH) found in plasma membranes, endosomes and multivesicular bodies (MVB) could continue to hydrolyze RE. The free retinol thus produced is transferred to the endoplasmic reticulum (ER) likely in association with cellular retinol-binding protein (CRBP). In the ER, the ROH can be complexed with plasma retinol-binding protein (RBP) for secretion from the liver, or reesterified by the enzymes lecithin:retinol acyltransferase (LRAT) or acyl-CoA:retinol acyltransferase (ARAT). RE found in the ER or stored in cytoplasmic lipid droplets can also be hydrolyzed enzymatically. The ER localized carboxylesterases ES-10 and ES-4 may play a role in this process. The identity of the hydrolases involved in the hydrolysis of stored RE in stellate cells is not known.

The available evidence suggests that after uptake and hydrolysis of retinyl esters, the unesterified retinol is transferred to the endoplasmic reticulum for further metabolism. The mechanism of this transfer is not known, but it may involve cellular retinol-binding protein (CRBP), if transfer occurs through the cytoplasm. Regardless of the mechanism of transfer to endoplasmic reticulum, it is also clear that, in the steady state, a significant fraction (~one third) of the unesterified retinol is localized there (Harrison et al. 1987 ). So too are the enzymes that can reesterify the retinol for storage in cytoplasmic lipid droplets (LRAT and ARAT) and the binding protein (retinol-binding protein, RBP) necessary for its secretion from the liver. Although it is unclear what enzyme(s) may play a role in the hydrolysis of stored retinyl esters formed in the endoplasmic reticulum, one might speculate that the two carboxylesterases that are known to be localized there and to function in vitro as REH (viz., ES-4 and ES-10) are good potential candidates. However, it is also possible that as yet unrecognized lipases or esterases may be involved.

	FOOTNOTES

 
¹ Presented at the symposium entitled "Mechanistic Aspects of Vitamin and Coenzyme Utilization and Function: A Symposium in Recognition of the Distinguished Career of Donald B. McCormick" as part of the Experimental Biology 99 meeting held April 17–21 in Washington, DC. This symposium was sponsored by the American Society for Nutritional Sciences. The proceedings of this symposium are published as a supplement to The Journal of Nutrition. Guest editors for this supplement publication were Alfred H. Merrill, Jr., Emory University School of Medicine, Atlanta, GA, Barbara Bowman, U.S. Centers for Disease Control and Prevention, Atlanta, GA, and Peter C, Preusch, National Institutes of General Medical Sciences, Bethesda, MD.

² Supported by the National Institutes of Health (grant DK 44498).

³ Abbreviations used: apo-CRBP, apo-cellular retinol-binding protein; BSDREH, bile salt–dependent retinyl ester hydrolase; CEL, carboxylester lipase; ES, esterases; HL, hepatic lipase; LPL, lipoprotein lipase; REH, retinol ester hydrolase.

	REFERENCES

TOP ABSTRACT INTRODUCTION Hepatic retinyl ester hydrolases Bile salt-independent retinyl... Carboxylesterases Other retinyl ester hydrolases... Summary and proposed model... REFERENCES

 

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