Retinyl ester hydrolase

Mercier, M., G. Pascal, and V. Azais-Braesco. 1990. Retinyl ester hydrolase and Vitamin A status in rats treated with 3,3, 4,4 -tetrachlorobiphenyl. Biochim. Biophys. Acta 1047 70-76. 

The overall metabolism of vitamin A in the body is regulated by esterases. Dietary retinyl esters are hydrolyzed enzymatically in the intestinal lumen, and free retinol enters the enterocyte, where it is re-esterified. The resulting esters are then packed into chylomicrons delivered via the lymphatic system to the liver, where they are again hydrolyzed and re-esterified for storage. Prior to mobilization from the liver, the retinyl esters are hydrolyzed, and free retinol is complexed with the retinol-binding protein for secretion from the liver [101]. Different esterases are involved in this sequence. Hydrolysis of dietary retinyl esters in the lumen is catalyzed by pancreatic sterol esterase (steryl-ester acylhydrolase, cholesterol esterase, EC 3.1.1.13) [102], A bile salt independent retinyl-palmitate esterase (EC 3.1.1.21) located in the liver cell plasma hydrolyzes retinyl esters delivered to the liver by chylomicrons. Another neutral retinyl ester hydrolase has been found in the nuclear and cytosolic fractions of liver homogenates. This enzyme is stimulated by bile salts and has properties nearly identical to those observed for... 

As extrahepatic demand dictates, retinyl esters stored in the stellate cells of the liver are mobilized (18).This process involves de-ester-ification by the action several retinyl ester hydrolases, rebinding to RBP, and transport to... 

Fig. 1. The structures of key retinoids and their precursors. Fish convert retinyl esters (e.g. retinyl palmitate (RP)) and carotenoids (e.g. /3-carotene) to retinol in the gut lumen prior to intestinal absorption. Retinyl esters (e.g. RP) stored in the liver are synthesized from retinol by lecithin retinol acyltransferase (LRAT) and acyl CoAiretinol acyltransferase (ARAT). The retinyl esters are mobilized through their conversion to retinol by retinyl ester hydrolase (REH), which is then transported in the circulation to various sites in the body. Retinol is further metabolized within specific tissues to retinal by alcohol dehydrogenases (ADH) or short-chain dehydrogenase/reductase. Retinal is converted to the two major biologically active forms of retinoic acid (RA) (all-trans and 9-cis RA). Retinaldehyde dehydrogenase 2 (Raldh2) synthesizes all-trans RA from all-trans precursors and 9-cis RA form 9-cis precursors.

Dietary retinyl esters, retinol, and provitamin A carotenoids are dispersed and emulsified in the stomach during the gastric phase of lipid digestion. They then enter the lumen of the duodenum where extensive hydrolysis of retinyl esters takes place. In infants, the bile salt-stimulated lipase in human milk may play a role in retinyl ester hydrolysis in the duodenum (Fredrikzon et al., 1978). The major retinyl ester hydrolase activity that acts in the intestines is, however, derived from the pancreas. 

Depletion of plasma retinol and/or intracellular retinol metabolism results in compensatory elevation of intracellular retinol through mobilization of retinyl ester (RE). Mechanisms appear to include inhibition of LRAT and stimulation of RE hydrolysis by apo-CRBP [6-8]. Observation and partial purification of membrane-associated, bile salt-independent retinyl ester hydrolase (REH) provided insight into intracellular RE hydrolysis. This REH lacks activity for cholesterol esters, has reduced activity for triacylglycerol, and distributes widely in retinoid target tissues [9-11]. To date, two probable physiologically significant, bile salt-mdependent... 

Harrison EH, Gad M (1989) Hydrolysis of retinyl palmitate by enzymes of rat pancreas and liver differentiation of bile salt-dependent and bile salt-independent, neutral retinyl ester hydrolases in rat i ct.J Biol Chem 264 17 142-17 147... 

Gad MZ, Harrison EH (1991) Neutral and acid retinyl ester hydrolases associated with rat liver microsomes relationships to microsomal cholesteryl ester hydrolases. J Lipid Res 32 685-694... 

Sun G, Alexon SEH, Harrison EH (1997) Purifieation and characterization of a neutral, bile salt-independent retinyl ester hydrolase from rat liver microsomes relationship to rat carboxylesterase ES-2.Chem 272 24 488-24 493... 

It is likely that the ll-cis retinol is stored as the ester and therefore it would be expected that an 1 l-cis retinyl ester hydrolase would be present in the RPE. 1 l-cis Retinyl esters have been shown to be present in the RPE, particularly in the dark [68]. Mata et al. [69] have observed an 1 l-cis ester hydrolase. This enzyme has been colocalized with 1 l-cis retinyl esters in the plasma membrane of the RPE [70]. Interestingly, these results suggest a compartmentalization of the retinoid esters, as the site of synthesis of these esters is in the endoplasmic reticulum utilizing the enzyme lecithimretinol acyltransferase (LRAT) [71]. 

Mata NL, Villazana ET, Tsin AT (1998) Colocalization of 1 l-cis retinyl esters and retinyl ester hydrolase activ-... 

Figure 4 Model of atRA biogeneration in mammals. REH, retinyl ester hydrolase (e.g., ES4 and ES10) TTR, transthyretin RAR-RXR, the heterodimer of retinoic acid receptors with retinoid X receptors atRCHO, all-frans-relinal atROH, all-frans-retinol CRBP(I), cellular retinol binding protein, type I LRAT, lecithin retinol acyltransferase SRBP, semm retinol binding protein. CRBP(I), CRABP(I), and CRABP(II) have been placed in the same cell for simplicity. This does not necessarily occur in vivo.

Dietary retinyl esters must be hydrolyzed in the lumen of the small intestine before retinol is absorbed, while carotenoids must be absorbed into the intestinal mucosa before being cleaved intracel-lularly. Several enzymes with retinyl ester hydrolase (REH) activity are present in pancreatic juice or on the brush border of duodenal and jujenal enterocytes (Figure 3). Retinol and carotenoids must be solubilized in the lumen in mixed micelles composed of bile acids and products of lipid digestion prior to their uptake into enterocytes. These processes require the release of an adequate amount of bile... 

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