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Articles

Mechanisms Involved in the Intestinal Digestion and Absorption of Dietary Vitamin A^{1 ,2}

Human Nutrition Research Center, U.S. Department of Agriculture, Beltsville MD 20705 and ^* Departments of Anatomy & Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY 11203

³To whom correspondence should be addressed. E-mail: harrisone{at}bhnrc.arsusda.gov.

	ABSTRACT

TOP ABSTRACT INTRODUCTION Hydrolysis of Retinyl Esters... Uptake of Vetinol by... Reesterification and... REFERENCES

 
Dietary retinyl esters are hydrolyzed in the intestine by the pancreatic enzyme, pancreatic triglyceride lipase (PTL), and intestinal brush border enzyme, phospholipase B. Recent work on the carboxylester lipase (CEL) knockout mouse suggests that CEL may not be involved in dietary retinyl ester digestion. The possible roles of the pancreatic lipase-related proteins (PLRP) 1 and 2 and other enzymes require further investigation. Unesterified retinol is taken up by the enterocytes, perhaps involving both diffusion and protein-mediated facilitated transport. Once in the cell, retinol is complexed with cellular retinol-binding protein type 2 (CRBP2) and the complex serves as a substrate for reesterification of the retinol by the enzyme lecithin:retinol acyltransferase (LRAT). Retinol not bound to CRBP2 is esterified by acyl-CoA acyltransferase (ARAT). The retinyl esters are incorporated into chylomicrons, intestinal lipoproteins that transport other dietary lipids such as triglycerides, phospholipids, and cholesterol. Chylomicrons containing newly absorbed retinyl esters are then secreted into the lymph.

KEY WORDS: • retinoids • lipid absorption • pancreatic enzymes • chylomicrons • lipases

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Hydrolysis of Retinyl Esters... Uptake of Vetinol by... Reesterification and... REFERENCES

 
The major sources of vitamin A in the diet are the provitamin A carotenoids in fruits and vegetables and retinyl esters found in foods of animal origin. In humans, carotenoids are either cleaved to generate retinol or absorbed intact. In contrast, retinyl esters are completely hydrolyzed in the intestinal lumen and free retinol is taken up by enterocytes (1 ,2) . This review focuses on the mechanisms involved in the digestion of retinyl esters in the intestinal lumen, the uptake and reesterification of retinol in enterocytes, and the incorporation of the resulting retinyl esters into chylomicrons and secretion of these lipoproteins from the enterocytes.

	Hydrolysis of Retinyl Esters in Intestine.

TOP ABSTRACT INTRODUCTION Hydrolysis of Retinyl Esters... Uptake of Vetinol by... Reesterification and... REFERENCES

 
Carboxylester lipase (CEL)⁴ and pancreatic triglyceride lipase (PTL) effectively hydrolyze retinyl palmitate in vitro. CEL also catalyzes the hydrolysis of cholesteryl esters, triglycerides and lysophospholipids. CEL knockout (CELKO) mice were generated to study the functions of CEL (2 3 4) . CELKO mice absorbed 50% less cholesterol provided as cholesteryl ester compared with wild-type mice. In contrast, CELKO mice absorbed the same amount of retinol, when provided as retinyl ester, as did wild-type mice. On the other hand, neither strain absorbed retinyl hexadecyl ether (2 ,4) . These data suggested that retinyl ester hydrolysis was required for absorption and that CEL was not the enzyme involved (at least in this study in which 100 µg of retinyl esters were delivered in 100 µL of peanut oil). Therefore, one or more other retinyl ester hydrolase (REH) enzymes must be present in the gut lumen or in the enterocyte.

We sought to identify the non-CEL, pancreatic REH activity that was present in CELKO mice, as well as to investigate this activity in wild-type mice and in rats. Several lines of evidence suggest that the activity is due to PTL (5) . First, when pancreatic homogenates of wild-type mice and rats were assayed with different bile salts, cholesteryl ester hydrolase activity was detected only in the presence of trihydroxy bile salts, consistent with previous results (6) . Pancreatic REH activity, however, is not absolutely dependent on trihydroxy bile salts and was detected not only in the presence of trihydroxy bile salts, but also in the presence of dihydroxy bile salts and CHAPS, a bile salt analog, and in the absence of bile salts. Second, when pancreatic homogenates obtained from rats, and wild-type and CELKO mice were used to assay REH activity, a considerable stimulation of the REH activity by colipase was observed, indicating that PTL was contributing to the bile salt-dependent REH activity. Third, when pancreatic homogenates were applied to DEAE-chromatography, the majority of REH activity coeluted with PTL activity. Fourth, the enzymatic characteristics of purified human PTL suggested that retinyl palmitate was a substrate. Hydrolysis of both retinyl esters and triglycerides by the enzyme were completely dependent on the presence of colipase, and other enzymatic properties were similar for both substrates.

Although our data strongly suggest that PTL is a major REH in rat and mouse intestinal lumen, they do not provide final proof. For example, some triglyceride hydrolysis was observed in the absence of colipase in pancreatic homogenates, which may point to the presence of other related enzyme activities such as pancreatic lipase related protein 2 (PLRP2). PLRP2 is 65% identical to PTL and shows activity toward triglycerides in the classical PTL assay (7) . At present, we do not know the percentage contribution of PLRP2 to pancreatic bile salt–dependent REH activity. Also, another pancreatic lipase related protein (PLRP1) has been cloned, which is 68% homologous to PTL, but whose substrate remains unknown (8) . Thus, more than one enzyme may be responsible for the complete hydrolysis of retinyl esters in the intestinal lumen.

In addition to pancreatic bile salt–dependent REH activities, an REH activity intrinsically located in the brush border membrane of enterocytes was shown in rat and human intestines (9 ,10) . This activity was suggested to be due to an intestinal phospholipase B. The authors showed that rat brush border membrane, isolated from rats in which the common pancreatic duct had been ligated for 2 d (thus prohibiting contamination of brush border membrane with enzymes secreted by pancreas such as CEL or PTL), had a greatly decreased hydrolytic activity against short-chain retinyl esters (in the presence of trihydroxy bile salts), and a smaller (30%) decrease in activity against long-chain retinyl esters (such as retinyl palmitate) compared with sham-operated rats. Therefore, they suggested that short-chain REH was due mainly to enzymes of pancreatic origin, whereas the majority (70%) of long-chain REH was intrinsic to the brush border. The remaining 30% of REH activity could be due to PTL because this REH activity was detected in the presence of both trihydroxy and dihydroxy bile salts. It is important to point out that the relative activities observed in vitro may not reflect the relative contributions of the various enzymes in vivo. To determine which of the above-mentioned enzymes is the most critical in intestinal RE digestion and absorption, it will be necessary to perform RE absorption experiments in the appropriate knockout mouse strains and in mice deficient in more than one enzyme. The enzymes potentially involved in hydrolysis of dietary retinyl esters are outlined in Figure 1 .

View larger version (127K): [in this window] [in a new window]   Figure 1. Overview of digestion and absorption of vitamin A. Dietary retinyl esters (RE) are hydrolyzed in the lumen by the pancreatic enzyme, pancreatic triglyceride lipase (PTL), and the intestinal brush border enzyme, phospholipase B (PLB). Recent work on the carboxylester lipase (CEL) knockout mouse suggests that CEL may not be involved in dietary RE digestion. The possible roles of the pancreatic lipase-related proteins (PLRP) 1 and 2 and other enzymes require further investigation. Unesterified retinol (ROH) is taken up by the enterocyte, perhaps facilitated by a yet unidentified retinol transporter (RT). Once in the cell, retinol is complexed with cellular retinol-binding protein type 2 (CRBP2) and the complex serves as a substrate for reesterification of the retinol by the enzyme lecithin:retinol acyltransferase (LRAT). It is possible that "excess" retinol not bound to CRBP2 serves as a substrate for acyl-CoA acyltransferase (ARAT) to form RE that are retained in the cell. The RE are then incorporated into chylomicrons, intestinal lipoproteins containing other dietary lipids such as triglyceride (TG), phospholipid (PL), and cholesterol (Ch) and apolipoprotein B (apoB). Chylomicrons (CM) containing newly absorbed retinyl esters (CMRE) are then secreted into the lymph. Assembly of CM requires apoB and microsomal triglyceride transfer protein (MTP).

	Uptake of Vetinol by Enteroctyes.

TOP ABSTRACT INTRODUCTION Hydrolysis of Retinyl Esters... Uptake of Vetinol by... Reesterification and... REFERENCES

Early studies using intestinal segments also suggested that the unesterified retinol was taken up by protein-mediated facilitated diffusion and passive diffusion mechanisms at physiologic (150 nmol/L) and pharmacologic concentrations (450–2700 nmol/L), respectively (14 ,15) . Recently, some evidence for protein-mediated uptake of retinol has been presented using intestinal segments (16 ,17) . Until now, no protein has been identified and characterized that might be involved in the uptake of retinol (Fig. 1) . However, three different membrane-bound proteins, CD36, membrane-bound fatty acid–binding protein and a fatty acid transport protein that might be involved in fatty acid uptake have been identified [for review, see (18) ]. It is possible that these proteins may play a role in retinol transport. In addition, other proteins may exist for the transport of retinol.

The general perception that retinol is efficiently absorbed and quantitatively transported on chylomicrons may require reevaluation [for review, see (1 ,19) ]. First, the recovery of ingested retinol in lymph varies between 20 and 60% in various studies (1 ,20 ,21) . Second, Hollander (22) showed that 60 and 30% of the absorbed retinol is secreted into lymph and portal circulation, respectively. Furthermore, he showed that secretion of retinol into lymph was modulated by the presence of different concentrations of taurocholate and different fatty acids (22) . Third, oral supplementation of retinol to abetalipoproteinemia patients, who do not assemble and secrete chylomicrons, resulted in partial recovery from symptoms of retinol deficiency (23) . Fourth, cell culture studies showed that free retinol or its metabolized products were transported across the cells independent of the assembly and secretion of lipoproteins (13) . Thus, the majority of the absorbed retinol is secreted into lymph in esterified form. However, a small but significant amount is also secreted into portal circulation, probably as free retinol. The transport of free retinol to the portal circulation is expected to be physiologically important in pathologic conditions that affect the secretion of chylomicrons. Thus, the limited transport of free retinol may be an essential back-up mechanism for the homoeostasis of vitamin A under some conditions.

After cellular uptake, free retinol is probably sequestered by cellular retinol-binding proteins (CRBPs). Two CRBPs, CRBP1 and CRBP2 have been purified and characterized extensively. They have considerable sequence identity and belong to a family of fatty acid–binding proteins. These proteins share considerable structural, genetic and biochemical properties. However, the cellular expression pattern of these proteins is very different. CRBP1, a 14.6-kDa polypeptide, is expressed in many tissues, whereas CRBP2, a 16-kDa polypeptide, is expressed primarily in the absorptive cells of the small intestine. CRBP2 is one of the most abundant proteins and accounts for 1% of the total soluble proteins recovered from the jejunal mucosa. Its tissue distribution and abundance indicate that it is uniquely suited for retinol absorption by the intestine [for reviews, see (24 25 26) ].

In vitro studies indicated that CRBP2 can play several roles in the trafficking of retinol. It has been speculated that it can bind to specific transporters on the brush border membrane and permit facilitated diffusion. It can serve as a reservoir to keep the concentrations of free retinoids very low and protect cells from their detergent-like properties. More important, it may present retinoids to different enzymes and direct their metabolism. For example, retinol bound to CRBP2 is esterified primarily by lecithin-retinol acyltransferase (LRAT), but not by acyl-CoA-retinol acyltransferase (ARAT), and might be channeled mainly for secretion by intestinal cells (27) (Fig. 1) .

In vivo studies showed that CRBP2 mRNA levels are increased in the small intestine of retinoid-deficient rats (28) and rats fed long-chain fatty acids (29) . In Caco-2 cells, CRBP2 mRNA was increased after treatment of the differentiated cells with retinoic acid. More importantly, this resulted in increased absorption and intracellular esterification of radiolabeled retinol. Furthermore, absorption and esterification were also increased after the overexpression of CRBP2 in these cells (30) . These studies indicate that changes in CRBP2 expression result in the modulation of retinol metabolism (31 32 33) . However, it is not known whether the increased expression of CRBP2 results in increased secretion of retinyl esters in chylomicrons.

	Reesterification and Incorporation into Chylomicrons.

TOP ABSTRACT INTRODUCTION Hydrolysis of Retinyl Esters... Uptake of Vetinol by... Reesterification and... REFERENCES

 
Early studies in intact rats and humans clearly demonstrated that after uptake of newly absorbed retinol, the retinol was largely reesterified with long-chain fatty acids (mostly palmitate) and secreted into the lymphatic system along with other dietary lipids in chylomicrons. More recently, Caco-2 cells have been used to study mechanisms of vitamin A absorption that are difficult to study in intact animals. Differentiated Caco-2 cells were shown to express CRBP2, ARAT, LRAT and retinal reductase (11 ,12) . Studies on retinol secretion revealed that Caco-2 cells supplemented with no fatty acids secreted only free retinol. However, cells incubated with oleic acid were shown to secrete retinyl esters in addition to free retinol (12) . On the basis of these observations, it has been suggested that lipoprotein particles secreted by these cells may contain retinol and retinyl esters (12) . However, no data about the secretion of either free or esterified retinol as part of different lipoprotein particles were reported in these studies.

In enterocytes, two enzymes, LRAT and ARAT, have been identified that are involved in the esterification of free retinol (Fig. 1) . It has been suggested (but not shown) that retinyl esters formed by LRAT and ARAT may be targeted for secretion with chylomicrons and storage, respectively (19) . It is generally believed that retinol is secreted into the lymph mainly as retinyl palmitate. During metabolic studies, analysis of the plasma revealed that most of the retinyl esters are present in small chylomicrons (34) . Substantial amounts of retinyl esters are also found in large chylomicrons followed by smaller amounts in VLDL (34) . In contrast to triglycerides, cholesterol esters and other lipids, retinyl esters are not present in other lipoproteins such as intermediate density lipoproteins, LDL or HDL. These studies indicate that retinyl esters are present mainly in large and small chylomicrons and behave very differently from other neutral lipids such as triglycerides and cholesterol esters. What is the molecular basis for this specificity? How do intestinal cells incorporate retinyl esters into chylomicrons?

To understand the mechanism of secretion of RE by the intestine during fasting and postprandial states, we conducted studies in which differentiated Caco-2 cells were supplemented with radiolabeled retinol under conditions that support (postprandial) or do not support (fasting) chylomicron secretion (13) . After uptake, cells store retinol in both esterified and unesterified forms. Under fasting conditions, cells secrete variable amounts of free retinol, mainly unassociated with lipoproteins. However, under postprandial conditions, these cells secreted significant amounts of retinyl esters, mainly with chylomicrons. The secretion of retinyl esters with chylomicrons was independent of the rate of uptake of retinol and intracellular free and esterified retinol levels, and was dependent on the assembly and secretion of chylomicrons. The secretion of retinyl esters was correlated with the secretion of chylomicrons and not with total apolipoprotein B secretion. Inhibition of chylomicron secretion by Pluronic L81 decreased the secretion of retinyl esters and did not result in their increased secretion with smaller lipoproteins. These data strongly suggest that retinyl ester secretion by intestinal cells is a highly specific and regulated process that is dependent on the assembly and secretion of chylomicrons. Our data also indicate that retinyl ester incorporation into chylomicrons is not a passive process but is an exquisitely orchestrated event. Retinyl ester secretion does not occur at all times. It is induced when cells can assemble and secrete chylomicrons. Thus, it appears that intestinal cells may have a specific mechanism for the targeting of retinyl esters to nascent chylomicrons. These cells appear to wait for the assembly of chylomicrons before secreting retinyl esters.

Chylomicron assembly requires apoB48, microsomal triglyceride transfer protein (MTP), phospholipids and triglycerides and occurs in the endoplasmic reticulum (35 36 37) . ApoB48 is a structural protein for the assembly of these lipoproteins, whereas MTP is required for the lipidation of apoB48. We have provided evidence to suggest that different lipids are added onto apoB48 in discrete events during the formation of these lipoproteins (13 ,36 37 38) . First, large amounts of preformed phospholipids, probably from the membranes of the endoplasmic reticulum, are added onto nascent apoB polypeptides to form "primordial lipoproteins." In the second event, newly synthesized triglycerides are added in bulk to form "nascent lipoproteins." It appears that retinyl esters are added after chylomicron assembly as a final event of lipoprotein maturation just before secretion. Due to the specificity of the secretion of retinyl esters, we propose that retinyl esters can be used as signposts for the final stages of chylomicron assembly (36 ,37) .

The literature reviewed above suggests that the intestinal digestion and absorption of vitamin A is a highly complex process, and that a number of enzymes and other proteins participate in the process. Mice deficient in one or more proteins may define the redundancy and absolute requirement of various proteins in retinyl ester metabolism. In addition, overexpression of specific proteins might lead to better understanding of the role of individual proteins in vitamin A absorption. The development of highly specific inhibitors could also shed light on these issues. Furthermore, understanding the mechanisms of retinyl ester absorption may shed light on the mechanisms involved in the assembly and secretion of chylomicrons. Knowledge about the absorption of vitamin A may be valuable in studying the absorption of other fat-soluble micronutrients.

	FOOTNOTES

 
¹ Supported by National Institutes of Health grants DK44498, HL49879, DK46900, HL64272. M.M.H. is an established Investigator of the American Heart Association.

² Manuscript received 11 January 2001.

⁴ Abbreviations used: apo, apolipoprotein; ARAT, acyl-CoA:retinol acyltransferase; CEL, carboxyl ester lipase; CELKO, CEL knock out; CRBP, cellular retinol-binding protein; KO, knockout; LRAT, lecithin:retinol acyltransferase; MTP, microsomal triglyceride transfer protein; PLRP, pancreatic lipase-related protein; PTL, pancreatic triglyceride lipase; REH, retinyl ester hydrolase.

	REFERENCES

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