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Articles

Molecular Mechanisms of Sterol Absorption¹

Gladstone Institute of Cardiovascular Disease, Division of Endocrinology and Department of Medicine, University of California, San Francisco, CA 94141

	ABSTRACT

TOP ABSTRACT INTRODUCTION Regulation of Sterol Absorption... Novel Role for ABC... ABC Transporters: Defense... Role of Cholesterol Ester... LITERATURE CITED

 
Recent studies have significantly advanced our understanding of intestinal sterol absorption at the molecular level. Nuclear hormone receptors (such as liver X receptor, farnesoid X receptor and retinoid X receptor) regulate the absorption of dietary sterols by modulating the transcription of several important genes involved in cholesterol metabolism. One of these genes encodes a molecule [adenosine triphosphate-binding cassette (ABC) transporter] that transports dietary cholesterol from enterocytes back out to the intestinal lumen, thereby limiting the amount of cholesterol absorbed. ABC transporters also provide an efficient barrier against the absorption of plant sterols. Another key process that affects intestinal sterol absorption is the synthesis of cholesterol esters. Mice lacking the enzyme for cholesterol esterification in the small intestine have a reduced capacity to absorb dietary cholesterol and are protected against diet-induced hypercholesterolemia and gallstone formation. In addition to elucidating some of the molecular mechanisms of sterol absorption, these recent findings may lead to new therapeutic options to treat hypercholesterolemia.

KEY WORDS: • sterols • intestinal absorption • nuclear hormone receptors • ABC transporters • sitosterolemia • cholesterol esters

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Regulation of Sterol Absorption... Novel Role for ABC... ABC Transporters: Defense... Role of Cholesterol Ester... LITERATURE CITED

 
Sterols areessential constituents of cellular membranes in both animals and plants. They also serve as precursors of steroid hormones. Cholesterol is the sterol synthesized and utilized by animals, whereas sitosterol, campesterol and stigmasterol are some of the major sterols found in plants (Fig. 1 ). Although structurally similar, the plant sterols differ from cholesterol in possessing an additional methyl or ethyl group. This extra carbon group prevents the efficient absorption of plant sterols in the human intestine (1) .

View larger version (19K): [in this window] [in a new window]   Figure 1. Chemical structures of cholesterol and main plant sterols.

	Regulation of Sterol Absorption by Nuclear Hormone Receptors.

TOP ABSTRACT INTRODUCTION Regulation of Sterol Absorption... Novel Role for ABC... ABC Transporters: Defense... Role of Cholesterol Ester... LITERATURE CITED

 
Nuclear hormone receptors are intracellular proteins that regulate gene transcription. In the basal state, these receptors are inactive; when bound by ligands, they form complexes (or heterodimers) with one another and bind to promoters of genes to alter their transcriptional activity.

Two nuclear hormone receptors involved in the regulation of cholesterol homeostasis are the liver X receptor (LXR) and the farnesoid X receptor (FXR). The natural ligands for LXR and FXR are oxysterols (oxidized derivatives of cholesterol) and bile acids, respectively [reviewed in (2 –4) ]. To modulate transcriptional activity, ligand-activated LXR or FXR forms a heterodimer with one additional nuclear hormone receptor, the retinoid X receptor (RXR). These heterodimers then control the transcription of several important genes that participate in cholesterol metabolism, sometimes appearing to antagonize the effects of each other. For example, the LXR-RXR heterodimer induces the expression of cholesterol 7-hydroxylase (CYP7A1), the rate-limiting enzyme in the classic bile acid synthesis pathway (2 ,3) . In contrast, the FXR-RXR heterodimer represses CYP7A1 transcription (5) . It was unclear how the activation of both heterodimers would affect cholesterol metabolism in an animal model.

Because both the LXR-RXR and the FXR-RXR heterodimers can be activated by RXR ligands, Mangelsdorf and colleagues (6) administered an RXR ligand, the rexinoid LG268, to mice to identify LXR-RXR– and FXR-RXR–mediated changes in cholesterol homeostasis. Administration of the ligand resulted in a dose-dependent inhibition of cholesterol absorption. Two mechanisms were involved in this reduction in cholesterol absorption. In one mechanism, the FXR-RXR heterodimer suppressed CYP7A1 expression and decreased bile acid synthesis. Because nonpolar lipids such as cholesterol have a limited solubility in the aqueous environment of the intestinal lumen, bile acids are required to solubilize these nonpolar compounds and allow their absorption. By suppressing bile acid production, the activated FXR-RXR heterodimer decreased the solubilization and absorption of dietary cholesterol.

Even though activation of the LXR-RXR heterodimer could not counter the FXR-RXR–mediated suppression of CYP7A1 expression, the activated LXR-RXR heterodimer had a powerful effect on cholesterol homeostasis by inducing the expression of ABC transporters (specifically, ABCA1) in enterocytes. This increase in ABCA1 expression represented the second mechanism by which the administration of the RXR ligand decreased cholesterol absorption.

	Novel Role for ABC Transporters in Intestinal Sterol Absorption.

TOP ABSTRACT INTRODUCTION Regulation of Sterol Absorption... Novel Role for ABC... ABC Transporters: Defense... Role of Cholesterol Ester... LITERATURE CITED

 
ABC transporters are integral membrane proteins that couple the energy derived from the hydrolysis of ATP to the transport of various molecules across the cellular membrane (7) . Mutations in ABC transporters have been implicated in several diseases, including cystic fibrosis (transport of chloride ions) and adrenoleukodystrophy (transport of very-long-chain fatty acids). Recent studies have also demonstrated the importance of an ABC transporter (ABCA1) in cholesterol metabolism (8 ,9) . Defects in ABCA1 prevent the reverse transport of cholesterol from peripheral tissues back to the liver, resulting in Tangier disease, a condition characterized by the accumulation of cholesterol esters in peripheral tissues.

On the basis of the recent ABC transporter findings, Mangelsdorf and colleagues (6) hypothesized that ABCA1 may be involved in regulating the absorption of dietary cholesterol. Perhaps ABCA1 normally pumps cholesterol from enterocytes back out to the intestinal lumen, thereby limiting the amount of cholesterol absorbed. Indeed, they found that mice treated with the RXR ligand had increased intestinal expression of ABCA1, an increase that was mediated by the activation of the LXR-RXR heterodimer. Therefore, by increasing the expression of ABCA1 in the small intestine, the LXR-RXR heterodimer enhanced the efflux of cholesterol from enterocytes and limited cholesterol absorption. Given these findings, pharmacological activation of the nuclear hormone receptors RXR, LXR and FXR may represent a new treatment option for hypercholesterolemia in the future.

	ABC Transporters: Defense against Excess Sterol Absorption.

TOP ABSTRACT INTRODUCTION Regulation of Sterol Absorption... Novel Role for ABC... ABC Transporters: Defense... Role of Cholesterol Ester... LITERATURE CITED

 
In addition to transporting cholesterol, ABC molecules appear to be involved in the metabolism of plant sterols. Normally, the human intestine provides an efficient barrier against the absorption of plant sterols, i.e., <5% of dietary plant sterols are absorbed, compared with 40–60% of dietary cholesterol (10 ,11) . Because plant sterols are also preferentially removed by the liver and excreted into bile, plasma concentrations of plant sterols in most humans are low (12) .

This defense against the absorption of plant sterols is disrupted in sitosterolemia, a rare autosomal recessive disorder characterized by the accumulation of large amounts of plant sterols in most tissues (13) . Sitosterolemia patients also have increased absorption of dietary cholesterol and elevated plasma cholesterol levels. As a result, almost all patients develop coronary artery disease at an early age. The genetic defect was localized to chromosome 2p21 in 1998 (14) , and recently two groups independently identified the gene as a member of the ABC transporter family (15 ,16) .

One of these groups, Hobbs and colleagues (15) , was aided by the observation that activation of the LXR-RXR heterodimer increased the expression of ABCA1 in the small intestine and enhanced the efflux of cholesterol from enterocytes (6) . They therefore hypothesized that the gene involved in sitosterolemia may be a transporter protein and that the expression of this transporter may be induced by a LXR agonist. Thus, the investigators used DNA microarrays to search for genes that had increased expression in response to a synthetic LXR ligand.

One such gene, ABCG5, mapped to chromosome 2p21 and encoded a half-ABC transporter. Adjacent to ABCG5 was another half-ABC transporter gene (ABCG8). These two genes were similarly regulated. For example, both ABCG5 and ABCG8 were expressed in the small intestine and the liver and induced by a high cholesterol diet in mice. Available evidence suggests that these two half-transporters unite to form a full, active transporter. When functioning, this transporter may limit the absorption of both plant sterols and cholesterol by actively pumping them from enterocytes back into the intestinal lumen. The transporter may also promote the elimination of sterols in the liver by enhancing their excretion into bile. As a result, mutations in either gene could cause sitosterolemia. Indeed, mutations in ABCG8 most likely accounted for the disease in four of the nine families studied. Additional studies, including gene knockout experiments in animals, will be required to confirm and further elucidate the in vivo functions of these newly identified ABC transporters in cholesterol metabolism.

	Role of Cholesterol Ester Synthesis in Diet-Induced Hypercholesterolemia: Lessons from Mice Lacking Intestinal ACAT.

TOP ABSTRACT INTRODUCTION Regulation of Sterol Absorption... Novel Role for ABC... ABC Transporters: Defense... Role of Cholesterol Ester... LITERATURE CITED

 
Another molecule that plays a key role in the absorption of sterols is acyl CoA:cholesterol acyltransferase (ACAT), the enzyme that catalyzes the synthesis of cholesterol esters (Fig. 2 ) (17 –19) . In animals, cholesterol exists both as a free sterol and as esters of fatty acids. The esterification of free cholesterol within cells allows the cholesterol to be stored as a neutral lipid in cytosolic droplets. Cholesterol ester synthesis also participates in the packaging of cholesterol into lipoprotein particles for export. The precise role of cholesterol esterification in intestinal cholesterol absorption had been unclear. However, because enterocytes take up only free cholesterol but secrete mostly cholesterol esters onto lipoprotein particles (chylomicrons), cholesterol ester synthesis may be important in enhancing cholesterol absorption, perhaps by creating an intracellular diffusion gradient for free cholesterol (1) .

View larger version (14K): [in this window] [in a new window]   Figure 2. ACAT and cholesterol ester synthesis. Acyl CoA:cholesterol acyltransferase (ACAT) catalyzes the covalent joining of cholesterol and long-chain fatty acyl-CoA to form cholesterol esters.

This protection from diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice resulted from a decreased ability to absorb dietary cholesterol. When fed the high fat, high cholesterol diet, cholesterol absorption in ACAT2-deficient mice was 85% lower than in wild-type mice. These results indicate that under low dietary cholesterol conditions, cholesterol esterification was not required for efficient absorption. When dietary cholesterol content increased, however, the deficiency of cholesterol esterification activity limited the capacity for dietary cholesterol absorption. Given the high cholesterol content of the typical Western diet, inhibition of cholesterol esterification in the intestine may prove to be an effective means to prevent diet-induced hypercholesterolemia.

In summary, the tools of molecular biology and genetics have advanced the field of sterol absorption significantly. Recent studies have identified several new molecules and pathways that are involved in sterol absorption (Fig. 3 ). In addition to elucidating some of the molecular mechanisms of sterol absorption, these findings may offer new therapeutic options to treat hypercholesterolemia.

View larger version (25K): [in this window] [in a new window]   Figure 3. Molecular pathways involved in sterol absorption. The farnesoid X receptor–retinoid X receptor (FXR-RXR) heterodimer decreases bile acid production by suppressing cholesterol 7-hydroxylase (CYP7A1) expression, resulting in decreased solubilization of dietary sterols in the intestinal lumen. The liver X receptor–retinoid X receptor (LXR-RXR) heterodimer increases ATP-binding cassette (ABC) transporter expression in enterocytes, enhancing the excretion of sterols into the intestinal lumen. Both mechanisms lead to increased elimination of dietary sterols. Acyl CoA:cholesterol acyltransferase-2 (ACAT2) converts dietary free cholesterol into cholesterol esters, a step that is essential for the efficient incorporation of dietary cholesterol into lipoprotein particles. ACAT2 deficiency causes resistance to diet-induced hypercholesterolemia and gallstone formation.

	ACKNOWLEDGMENTS

 
The author thanks G. Howard and S. Ordway for editorial assistance and K. Buhman for helpful comments.

	FOOTNOTES

 
¹ Manuscript received 11 July 2001.

² Abbreviations used: ABC, ATP-binding cassette; ACAT, acyl CoA:cholesterol acyltransferase; CYP7A1, cholesterol 7-hydroxylase; FXR, farnesoid X receptor; LXR, liver X receptor; RXR, retinoid X receptor.

	LITERATURE CITED

TOP ABSTRACT INTRODUCTION Regulation of Sterol Absorption... Novel Role for ABC... ABC Transporters: Defense... Role of Cholesterol Ester... LITERATURE CITED

 

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