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Pathophysiological effects of aldosterone in cardiovascular tissues
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Pathophysiological effects of aldosterone in cardiovascular tissues Ricardo Rocha and Charles T. Stier, Jr The advent of antihypertensive therapy has resulted in a significant decrease in cardiovascular morbidity and mortality. Nevertheless, the incidence of heart failure, stroke and end-stage renal failure continues to increase. This trend suggests that a mechanism, independent of hypertension, is responsible for end-organ damage. Genetic and experimental models of hypertension have demonstrated that excess aldosterone induces severe injury in the heart, brain and kidneys, and that pharmacological antagonism of aldosterone or adrenalectomy markedly reduces myocardial injury, cerebral hemorrhage and renal vascular disease. In clinical studies, plasma aldosterone levels have been shown to correlate with left ventricular hypertrophy, stroke and renal dysfunction. Moreover, aldosterone antagonism has been shown to reduce morbidity and mortality in patients with heart failure. Thus, an increasing body of evidence now indicates that aldosterone is an independent risk factor for cardiovascular disease.
Ricardo Rocha* Pharmacia Corporation, Cardiovascular and Metabolic Diseases, 4901 Searle Parkway, Skokie, IL 60077, USA. *e-mail: ricardo.rocha@ pharmacia.com Charles T. Stier, Jr New York Medical College, Valhalla, NY 10595, USA.
Heart disease and stroke are the first and third leading causes of death, respectively, in the USA1. Although the percentage of hypertensive patients receiving treatment has increased, and blood pressure is now better controlled, the incidence of end-stage renal disease and the prevalence of heart failure continue to increase2. This suggests that blood pressure reduction alone is not sufficient to prevent end-organ damage and that the additional control of local and/or hormonal factors might be essential. Abnormal activation of the renin–angiotensin– aldosterone system (RAAS) correlates directly with the incidence and extent of endorgan damage3,4. Moreover, numerous clinical and experimental studies have demonstrated that blockade of the RAAS with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor antagonists provides significant cardiovascular protection5–9. Therefore, it has been proposed that overactivation of the RAAS represents a cardiovascular risk factor10. Although many of the mechanisms involved in Ang II-induced cardiovascular injury have been elucidated11, little is known about the contribution of aldosterone to the development of pathological changes in the kidney, brain and heart. This review will focus on the current concepts surrounding this topic. Novel concepts of aldosterone biology Epithelial versus non-epithelial aldosterone effects
The classic mineralocorticoid receptor (type I corticoid receptor) forms part of the steroid/thyroid/ retinoid/orphan-receptor family of nuclear transactivating factors12. When unbound, these receptors remain in an inactive but ligand-friendly conformation associated with a multiprotein complex http://tem.trends.com
of chaperones13. Upon binding aldosterone, the chaperones are released and the receptor–hormone complex is translocated into the nucleus. The complex then binds to hormone-response elements on DNA and interacts with transcription-initiation complexes and other transcription factors to modulate gene expression. In the kidney, mineralocorticoid receptors are located primarily in epithelial cells of the distal nephron. These receptors bind physiological glucocorticoids and mineralocorticoids with similar affinity. However, glucocorticoid binding is prevented by the enzyme 11-β-hydroxysteroid dehydrogenase type 2, which converts cortisol (in humans) or corticosterone (in rats) to inactive metabolites14, although it does not metabolize aldosterone. Activation of mineralocorticoid receptors by aldosterone induces the rapid expression of serum and glucocorticoid inducible kinase 1 which, when phosphorylated, activates the epithelial Na+ channel15. This initiates a cascade of events, leading to a rapid increase in Na+ and water reabsorption and promoting the tubular secretion of K+. Importantly, under normal conditions, this increase is transient and a rapid return to Na+ balance occurs, even in the presence of continued stimulation of the tubular epithelium by aldosterone16. The mechanisms mediating this effect have not been fully elucidated. Growing evidence supports the presence and activity of mineralocorticoid receptors in non-epithelial tissues. Such receptors have been identified in the heart17, brain18 and blood vessels19, and activation of these receptors can elicit important biological responses. In vitro stimulation of cultured neonatal rat cardiac myocytes with aldosterone, but not with dexamethasone, has an anabolic effect as assessed by increased leucine incorporation into protein20. This effect was significantly increased by the presence of increased glucose in the medium and involved activation of the protein kinase C (PKC) pathway. More recently, aldosterone has been shown to inhibit the sarcolemmal Na+–K+ pump21 through mechanisms that involve the epsilon isoform of PKC (Ref. 22). Using the isolated perfused rat heart, Moreau et al.23 have shown that aldosterone can decrease coronary blood flow and increase aortic flow and cardiac output. Finally, Vassort and co-workers24 have shown that aldosterone can upregulate Ca2+ transport into cardiomyocytes. Non-epithelial effects of aldosterone have also been demonstrated in the brain. Administration of low doses of aldosterone into the cerebral ventricles in
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rats induces hypertension, whereas the same doses administered systemically have no effect25. Similarly, intracerebroventricular infusion of non-diuretic doses of the mineralocorticoid receptor antagonist RU 28318 prevented the development of hypertension in aldosterone/salt hypertensive rats26, an intervention that did not prevent the pathological effects of aldosterone in the heart27. Thus, multiple lines of evidence indicate that aldosterone can activate nonepithelial mineralocorticoid receptors. However, the physiological or pathophysiological significance of these effects remains to be clarified. Rapid non-genomic effects of aldosterone
The above-mentioned, non-epithelial actions of aldosterone were typically slow to develop, consistent with aldosterone-induced activation of gene transcription. However, rapid effects of aldosterone in cardiovascular tissues have also been reported. In cultured vascular smooth muscle cells, aldosterone induced a prompt (<1 min) increase in intracellular Ca2+ concentration28. This increase was dependent on activation of phospholipase C and PKC and was elicited by subnanomolar concentrations of aldosterone, which are in the physiological range. Interestingly, the rapid effects of aldosterone on intracellular Ca2+ concentration were not inhibited by spironolactone. In addition, aldosterone induces rapid Na+ influx in vascular smooth muscle cells29, apparently via activation of Na+–H+ exchange29,30. The effects of aldosterone on Na+ influx were seen within 5 min, were mimicked by fludrocortisone and deoxycorticosterone (but not by hydrocortisone) and were inhibited by RU 28318, but not by canrenone or spironolactone29,30. A novel membrane receptor for aldosterone has been proposed to mediate these rapid effects. However, although membrane receptors for steroids have been cloned recently 31, a specific membrane receptor for aldosterone has yet to be identified. Moreover, Alzamora et al.30 have shown recently that non-genomic rapid effects of aldosterone can be blocked by the classic aldosterone antagonist RU 28318, indicating that the cytosolic aldosterone receptor might also be responsible for these rapid effects, either directly or through one of the chaperones released upon aldosterone binding to the receptor, as suggested previously32,33. Role of aldosterone in cardiovascular end-organ damage Experimental evidence
It has long been known that combined administration of the mineralocorticoid deoxycorticosterone acetate and sodium chloride to rats induces the development of severe hypertension and produces lesions in the brain34, heart35 and kidney36–39. Interestingly, these lesions are virtually identical to those seen in hypertensive models that display an abnormal activation of the RAAS, such as Ang II/salt hypertensive rats40 or stroke-prone spontaneously hypertensive rats (SHRSP)41,42. In studies to http://tem.trends.com
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determine the contribution of aldosterone to vascular lesion development in SHRSP, we have found that administration of aldosterone antagonists43,44 or adrenalectomy45 markedly reduced the incidence of stroke and the development of proteinuria and renal microvascular lesions in saline-drinking SHRSP. These vascular protective effects of aldosterone antagonism were not associated with significant reductions in blood pressure. These studies indicate that aldosterone plays a pivotal role in vascular lesion development in the brain and kidneys, which is unrelated to an effect on blood pressure. To examine further the pathological effects of aldosterone in the kidney in SHRSP, animals in which the endogenous RAAS was suppressed with captopril received either vehicle or aldosterone46. Captopril treatment reduced plasma aldosterone levels and prevented proteinuria and vascular injury in the kidney, but did not reduce hypertension. However, when exogenous aldosterone was administered in combination with captopril, proteinuria and renal vascular injury were fully restored. Aldosterone has also been shown to abolish the renal protection provided by combined ACE inhibition/Ang II type-I receptor antagonism in the remnant kidney model of hypertension47. These studies suggest that the beneficial effects of ACE inhibition in the kidney of SHRSP could be mediated, at least in part, by the inhibitory effects of these compounds on aldosterone synthesis. In recent studies, we have examined further the role of aldosterone in the development of cerebral lesions in SHRSP. Rats were placed on a 1% NaCl/stroke-prone rodent diet at nine weeks of age. At the same time, treatment with either eplerenone (100 mg kg−1 d−1, p.o.; n = 7) or vehicle (0.5% methylcellulose; n = 8) was started. SHRSP were maintained on these treatments until 19 weeks of age, at which time the animals that survived were sacrificed. Tail-cuff systolic blood pressure measured before death was similarly raised in the two groups (Fig. 1a). Starting at 13 weeks of age, vehicle-treated SHRSP began to show neurological signs of stroke and subsequently died (Fig. 1b). All of the vehicletreated SHRSP were dead by 18 weeks of age. In contrast, none of the eplerenone-treated littermates exhibited signs of stroke and all survived to 19 weeks of age, with the exception of one animal, which developed stroke signs and died at 18 weeks of age. Histopathological scoring of the brains revealed severe cerebral vascular and parenchymal lesions characteristic of ischemic and hemorrhagic stroke in untreated SHRSP (Figs 1c,2a), whereas cerebral injury in animals receiving eplerenone was markedly reduced (Figs 1c,2b). Consistent with a role of aldosterone in the development of cerebral pathology, MacLeod et al.48 have demonstrated that long-term exogenous administration of aldosterone blocked the ability of captopril to protect SHRSP against stroke. Thus, aldosterone seems to play a major role in the
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Fig. 1. Cerebral injury and survival with eplerenone. (a) Tail-cuff systolic blood pressure in salinedrinking, stroke-prone, spontaneously hypertensive rats (SHRSP) measured before death. (b) Survival curves for SHRSP treated with vehicle (light green circles, n = 8) or eplerenone (dark green circles, n = 7; 100 mg kg−1d−1; P <0.001). Arrow indicates when treatment began. (c) Histopathological scores for cerebral injury in SHRSP receiving either vehicle or eplerenone treatment (P <0.001).
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development of end-organ damage not only in the kidney but also in the brain. The effects of aldosterone on the heart have also been studied extensively. Several groups have demonstrated that hypertensive rat models in which Ang II and/or aldosterone is elevated display cardiac hypertrophy, with severe myocardial damage, which has been mostly characterized as myocardial fibrosis27,49–51. In those studies, when the aldosterone receptor was blocked with a low dose of spironolactone or canrenone, blood pressure was not significantly lowered although the development of myocardial fibrosis was markedly attenuated27,49,52. The locus at which aldosterone acts to induce myocardial fibrosis is not clear, and in vitro experimental findings are contradictory. An initial report by Brilla et al.53 suggested that aldosterone could directly stimulate cardiac fibroblasts to produce collagen. However, other investigators have failed to reproduce these http://tem.trends.com
findings54,55. We have recently identified a role for aldosterone in the development of vascular injury in the heart and kidneys of rats with Ang II-induced hypertension56. This effect was prevented by either eplerenone or adrenalectomy, independent of blood pressure reductions (Fig. 3). The vascular injury observed included lesions of segmental or circumferential fibrinoid necrosis of the media, panarterial inflammation and small foci of ischemic and necrotic damage in the myocardium (Fig. 4), or glomerular injury in the kidney. Similar vascular lesions have been reported in the heart of rats made hypertensive by aldosterone/salt treatment after four weeks50. We have also demonstrated recently that the vascular lesions induced by aldosterone in the heart are preceded by the induction of a vascular inflammatory phenotype, which triggers the perivascular leukocyte accumulation typically observed in the coronary arteries of aldosterone/salt hypertensive rats57. Thus, it is possible that the interstitial fibrosis induced by aldosterone in the heart is a secondary event in response to ischemic/necrotic damage resulting from the vascular inflammatory injury. Whether aldosterone causes this injury solely by its effects on epithelial tissues or whether activation of non-epithelial receptors also participates remains to be elucidated. Clinical evidence
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There is still scepticism about a role for aldosterone as an independent risk factor for cardiovascular disease. However, several clinical studies have shown that plasma aldosterone levels correlate with end-organ damage. Hené et al.58 studied 28 patients with varying degrees of chronic renal failure but similar levels of plasma K+ and plasma renin activity. Interestingly, as creatinine clearance fell below ~70 ml min−1, plasma aldosterone tended to increase. Duprez et al.59 found a significant correlation between plasma aldosterone levels and left ventricular mass in a population of patients with essential hypertension. Other groups have also reported correlations between plasma aldosterone levels and left ventricular hypertrophy60. Moreover, results from the CONSENSUS trial identified a significant correlation (P <0.003) between plasma aldosterone and mortality in patients with congestive heart failure61. A recent report demonstrated an inverse correlation between plasma aldosterone levels and arterial compliance in a population of essential hypertensive subjects, which was independent of blood pressure or age62. Thus, several studies have shown that aldosterone correlates with the severity of end-organ damage, and is probably an independent risk factor for cardiovascular events. Unlike other types of hypertension, primary aldosteronism (PA) is associated with elevated aldosterone levels and suppression of other components of the RAAS (Ref. 63). In general, it has been assumed that these patients do not display significant cardiovascular complications, an assumption that is not supported by the available data. In a classic report,
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Fig. 2. Cerebral histopathology with or without eplerenone. (a) Photomicrograph of cerebral cortex of a strokeprone, spontaneously hypertensive rat (SHRSP) receiving vehicle treatment, showing fibrinoid necrotic lesions in cerebral arteries (arrows) and liquefaction necrosis in the parenchyma. (b) Cerebral cortex of a SHRSP receiving eplerenone treatment and showing no damage. Scale bars ≈ 80 µm.
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Conn64 analyzed 145 cases of PA secondary to an aldosterone-producing adenoma; every patient had hypertension. More importantly, cardiomegaly was detected in 41% of the patients, retinopathy in 50% and proteinuria in 85%. Beevers et al.65 also identified a high incidence of adverse cardiovascular events in an analysis of 136 cases of PA. Recently, Nishimura et al.66 have investigated the incidence of cardiovascular complications in a population of patients with PA secondary to aldosterone-producing adenomas. These investigators identified cardiovascular complications in 34% of the patients: stroke was found in 16% and proteinuria in 24%. In addition, 78% of the patients in whom left ventricular mass index was evaluated had evidence of left ventricular hypertrophy (LVH). Finally, Grady et al.67 published a report of 32 renal biopsies obtained from patients with aldosterone-producing adenomas and showed that 56% had mild to severe arteriolar sclerosis, and 46% presented with interstitial fibrosis and tubular atrophy. Thus, there is a significant body of evidence that cardiovascular injury is common in patients with chronic PA. Cardiovascular events in patients with PA have usually been explained by the presence of accompanying hypertension. To determine the relative contribution of aldosterone in cardiovascular pathogenesis, independent of blood pressure, clinical studies have compared the incidence of cardiovascular events in patients with either PA or essential hypertension. Halimi and Mimram68 found an increased prevalence of albuminuria in a population of patients with PA http://tem.trends.com
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Fig. 3. Systolic blood pressure and myocardial damage. (a) Tail-cuff systolic blood pressure in saline-drinking rats receiving chronic treatment with L-NAME (40 mg kg−1day−1); circle, 1% NaCl; triangle, L-NAME + Ang II + 1% NaCl; diamond, L-NAME + Ang II + 1% NaCl + eplerenone; light green square, L-NAME + Ang II + 1% NaCl + ADX; dark green square, L-NAME + Ang II + 1% NaCl + ADX + ALDO, for a period of 14 days. On day 11, a subcutaneous infusion of vehicle or Ang II (50 ng min−1) was added to the treatment protocol. (b) Histopathological scores for myocardial necrosis in animals from the experiment in (a) on day 14. Abbreviations: ADX, adrenalectomy; ALDO, aldosterone; Ang II, angiotensin II; L-NAME, NGnitro-L-arginine methyl ester. Reproduced, with permission, from Ref. 56.
compared with matched subjects presenting with essential hypertension. A separate study compared 224 cases of PA with a similar number of patients with essential hypertension, in two groups matched by sex and age. The results showed that patients with PA had a significantly higher incidence of cerebral hemorrhage than did those with essential hypertension69. This incidence was greater in patients with PA, despite the higher levels of diastolic blood pressure and longer duration of hypertension in patients with essential hypertension. Another study compared the level of LVH in patients with PA or essential hypertension who displayed similar levels of blood pressure70. Despite
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0.9 0.8 0.7 0.6 0.5 0.0 0 Fig. 4. Effect of eplerenone on myocardial damage. Photomicrographs of serial myocardial sections from animals receiving L-NAME/angiotensin II treatment in the absence (a, b) or in the presence (c, d) of eplerenone (100 mg kg−1d−1). Sections were stained with hematoxylin and eosin (a, c) or the collagenspecific stain Picro-Sirius red (b, d). Arrowheads indicate areas of myocardial necrosis. Scale bars ≈ 65 µm. Abbreviation: L-NAME, NG-nitro-L-arginine methyl ester. Reproduced, with permission, from Ref. 56.
Acknowledgements The experimental work discussed here was funded, in part, by grants from the National Institutes of Health, MD, USA (HL-35522 to C.T.S.), from the American Heart Association New York State Affiliate (Grant-inAid 9859133 to C.T.S.) and from funds donated by Searle/Monsanto (St Louis, MO, USA).
similar levels of blood pressure and comparable age and gender distribution, PA patients demonstrated more severe and more frequent LVH and remodeling than did those with essential hypertension. In support of an association between hyperaldosteronism and increased risk for stroke, Litchfield et al.71 reported that patients with glucocorticoid remediable aldosteronism frequently develop stroke. LVH is also more common and severe in patients with PA than in patients with other types of secondary hypertension. For example, Denolle et al.72 showed that LVH was more frequent in patients with PA than in those with renovascular hypertension or pheochromocytoma. Thus, clinical evidence is now available that is consistent with the findings from animal studies suggesting a major role for aldosterone in the development of cardiovascular disease and stroke. Aldosterone antagonists
For more than 40 years, the mineralocorticoid receptor antagonist, spironolactone, has been available for the treatment of hypertension, hyperaldosteronism and edematous states, primarily in patients with uncompensated heart failure. The results of the Randomized Aldactone Evaluation Study (RALES) clearly demonstrated that low-dose mineralocorticoid receptor antagonist therapy markedly reduced morbidity and mortality in patients with severe heart failure, independent of hemodynamic effects73. In that study, administration of a low dose (~26 mg day−1) of the non-selective mineralocorticoid receptor antagonist, spironolactone, to patients receiving standard therapy, which included ACE inhibition and a diuretic, reduced mortality and morbidity in ~30% of patients with severe heart failure (Fig. 5). However, the beneficial effect of spironolactone was accompanied by significant side effects, namely gynecomastia and impotence, seen in
References 1 American Heart Association (1999) 2000 Heart and Stroke Statistical Update, American Heart Association 2 Joint National Committee on Prevention, Detection, Evaluation and Treatment of Blood
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Fig. 5. Aldosterone blockade reduces mortality and morbidity in patients with severe heart failure. The results from the RALES study with spironolactone showed a 30% risk reduction (95% confidence interval, 18% to 40%; P <0.001) in patients with NYHA class III or IV heart failure. Spironolactone and standard therapy (yellow); standard therapy, which was angiotensinconverting enzyme inhibitor plus loop diuretic ± digoxin (blue). Abbreviations: NYHA, New York Heart Association; RALES, randomized aldactone evaluation study. Reproduced, with permission, from Ref. 73.
10% of the patients in this group. Interestingly, hyperkalemia was not a significant side effect in this study. Gynecomastia and impotence reflect the relatively low selectivity of spironolactone, which, in addition to being an effective mineralocorticoid receptor antagonist, is also an androgen receptor antagonist and progesterone receptor agonist. The side effects of spironolactone via these receptors limit the use of this antagonist, particularly in young patients with hypertension or early stages of congestive heart failure. Novel, selective mineralocorticoid receptor antagonists such as eplerenone are currently under development and will eventually provide a more acceptable therapeutic profile. Conclusion
Accumulating evidence suggests that the classic characterization of aldosterone as an epithelial-acting, electrolyte-regulating hormone should be re-evaluated and extended. It is now clear that in addition to its epithelial effects, aldosterone has major functions in non-epithelial tissues that, under certain conditions, can lead to cardiovascular injury, renal disease and stroke. Thus, aldosterone should be considered as a crucial independent risk factor for end-organ damage in cardiovascular disease.
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63 Gómez-Sánchez, C.E. (1998) Primary aldosteronism and its variants. Cardiovasc. Res. 37, 8–13 64 Conn, J.W. et al. (1964) Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Am. J. Surg. 107, 159–172 65 Beevers, D.G. et al. (1976) Renal abnormalities and vascular complications in primary aldosteronism: evidence of tertiary hyperaldosteronism. Q. J. Med. 45, 401 66 Nishimura, M. et al. (1999) Cardiovascular complications in patients with primary aldosteronism. Am. J. Kidney Dis. 33, 261–266 67 Grady, R.W. et al. (1996) Renal pathology in patients with primary hyperaldosteronism
secondary to an adrenal cortical adenoma. Urology 48, 369–372 68 Halimi, J-M. and Mimram, A. (1995) Albuminuria in untreated patients with primary aldosteronism or essential hypertension. J. Hypertens. 13, 1801–1802 69 Takeda, R. et al. and the Research Committee of Disorders of Adrenal Hormones in Japan (1995) Vascular complications in patients with aldosterone producing adenoma in Japan: comparative study with essential hypertension. J. Endocrinol. Invest. 18, 370–373 70 Rossi, G.P. et al. (1996) Changes in left ventricular anatomy and function in hypertension and primary aldosteronism. Hypertension 27, 1039–1045
71 Litchfield, W.R. et al. (1998) Intracranial aneurysm and hemorrhagic stroke in glucocorticoid remediable aldosteronism. Hypertension 31, 445–450 72 Denolle, T. et al. (1993) Left ventricular mass and geometry before and after etiologic treatment in renovascular hypertension, aldosterone-producing adenoma, and pheochromocytoma. Am. J. Hypertens. 6, 907–913 73 Pitt, B. et al. (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. New Engl. J. Med. 341, 709–717
Dietary cholesterol absorption; more than just bile Kangmo Lu, Mi-Hye Lee and Shailendra B. Patel Absorption of dietary cholesterol from the intestine is an important part of cholesterol homeostasis and represents the first step that allows dietary cholesterol to exert its metabolic effects. Although the role of bile salts in the initial absorption of dietary cholesterol, by the formation of emulsions, is readily appreciated, the recognition that other molecular mechanisms might govern this process is only recently gaining momentum. Not only does the intestine regulate the amount of dietary cholesterol that enters the body; it is very selective with regard to the sterols that are allowed in. The human intestine is responsible for absorbing a significant amount of cholesterol each day. In addition to ~0.5 g d−11 of dietary cholesterol, many other sterols are also present in almost equal abundance in the normal diet. Approximately 0.4 g of plant sterols, such as sitosterol, brassicasterol and avanesterol, are also present. However, the human body seems to allow only cholesterol to enter and remain in the body, with almost negligible amounts of plant sterols being retained. That specific molecular mechanisms are responsible for this behavior is supported by the identification of the genetic defect(s) in a rare disorder, β-sitosterolemia (MIM 210250), where this process is disrupted. Such studies are now beginning to throw light on sterol absorption and excretion and elucidate the molecular mechanisms that govern these processes.
Kangmo Lu Mi-Hye Lee Shailendra B. Patel* Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, STR 541, 114 Doughty Street, Charleston, SC 29403, USA. *e-mail: [email protected]
Elevated plasma cholesterol level is a risk factor for atherosclerosis. The net effects of dietary cholesterol absorption, endogenous cholesterol synthesis and biliary cholesterol excretion regulate whole body cholesterol balance, either by breakdown to bile or via direct cholesterol excretion1–4. Because most of the cholesterol can only be disposed of via the biliary system, the enterohepatic circulation plays a crucial role in whole body sterol balance. Within the intestinal lumen, dietary cholesterol is presented to the brush border of mucosal enterocytes as a micelle formed by the action of bile salts, cholesterol and fatty acids. The initial point of contact between these http://tem.trends.com
micelles and the intestinal cells that absorb cholesterol occurs at the surface of the enterocyte brush border in the intestine. Cholesterol appears to be specifically removed from the micelles as part of the absorption process: cholesterol is absorbed principally in the duodenum and jejunum, but bile acids are not absorbed to an appreciable degree at these sites. Rather, specific bile acid transporters located in the ileum subsequently absorb bile acids, delivering these back to the liver and thus completing the enterohepatic circulation5,6. In addition, non-cholesterol sterols do not appear to be absorbed during this process. Thus, sitosterol, the major plant sterol, might be presented at the brush border membrane but appears to be largely excluded from entry and esterification, although a small amount (<2%) might be absorbed1,7,8. Because cholesterol moves into enterocytes from bile acid micelles, it is probable that cholesterol monomers, not cholesterol aggregates, are the species taken up. In addition, cholesterol synthesis contributes two to three times more cholesterol to the total body pool than does the absorption of dietary cholesterol, which occurs predominantly in the jejunum. In the intestinal mucosa, as in other tissues, 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase (EC 1.1.1.34) is the rate-limiting step in cholesterol synthesis, and its activity correlates with the cholesterol synthetic rate. However, in this review, the role of intestinal cholesterol synthesis, although important, will not be discussed. After absorption, free cholesterol and fatty acids are re-esterified in the enterocytes by the action of acyl-coenzyme A:cholesterol acyl-transferase
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Pathophysiological effects of aldosterone in cardiovascular tissues Ricardo Rocha and Charles T. Stier, Jr The advent of antihypertensive therapy has resulted in a significant decrease in cardiovascular morbidity and mortality. Nevertheless, the incidence of heart failure, stroke and end-stage renal failure continues to increase. This trend suggests that a mechanism, independent of hypertension, is responsible for end-organ damage. Genetic and experimental models of hypertension have demonstrated that excess aldosterone induces severe injury in the heart, brain and kidneys, and that pharmacological antagonism of aldosterone or adrenalectomy markedly reduces myocardial injury, cerebral hemorrhage and renal vascular disease. In clinical studies, plasma aldosterone levels have been shown to correlate with left ventricular hypertrophy, stroke and renal dysfunction. Moreover, aldosterone antagonism has been shown to reduce morbidity and mortality in patients with heart failure. Thus, an increasing body of evidence now indicates that aldosterone is an independent risk factor for cardiovascular disease.
Ricardo Rocha* Pharmacia Corporation, Cardiovascular and Metabolic Diseases, 4901 Searle Parkway, Skokie, IL 60077, USA. *e-mail: ricardo.rocha@ pharmacia.com Charles T. Stier, Jr New York Medical College, Valhalla, NY 10595, USA.
Heart disease and stroke are the first and third leading causes of death, respectively, in the USA1. Although the percentage of hypertensive patients receiving treatment has increased, and blood pressure is now better controlled, the incidence of end-stage renal disease and the prevalence of heart failure continue to increase2. This suggests that blood pressure reduction alone is not sufficient to prevent end-organ damage and that the additional control of local and/or hormonal factors might be essential. Abnormal activation of the renin–angiotensin– aldosterone system (RAAS) correlates directly with the incidence and extent of endorgan damage3,4. Moreover, numerous clinical and experimental studies have demonstrated that blockade of the RAAS with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor antagonists provides significant cardiovascular protection5–9. Therefore, it has been proposed that overactivation of the RAAS represents a cardiovascular risk factor10. Although many of the mechanisms involved in Ang II-induced cardiovascular injury have been elucidated11, little is known about the contribution of aldosterone to the development of pathological changes in the kidney, brain and heart. This review will focus on the current concepts surrounding this topic. Novel concepts of aldosterone biology Epithelial versus non-epithelial aldosterone effects
The classic mineralocorticoid receptor (type I corticoid receptor) forms part of the steroid/thyroid/ retinoid/orphan-receptor family of nuclear transactivating factors12. When unbound, these receptors remain in an inactive but ligand-friendly conformation associated with a multiprotein complex http://tem.trends.com
of chaperones13. Upon binding aldosterone, the chaperones are released and the receptor–hormone complex is translocated into the nucleus. The complex then binds to hormone-response elements on DNA and interacts with transcription-initiation complexes and other transcription factors to modulate gene expression. In the kidney, mineralocorticoid receptors are located primarily in epithelial cells of the distal nephron. These receptors bind physiological glucocorticoids and mineralocorticoids with similar affinity. However, glucocorticoid binding is prevented by the enzyme 11-β-hydroxysteroid dehydrogenase type 2, which converts cortisol (in humans) or corticosterone (in rats) to inactive metabolites14, although it does not metabolize aldosterone. Activation of mineralocorticoid receptors by aldosterone induces the rapid expression of serum and glucocorticoid inducible kinase 1 which, when phosphorylated, activates the epithelial Na+ channel15. This initiates a cascade of events, leading to a rapid increase in Na+ and water reabsorption and promoting the tubular secretion of K+. Importantly, under normal conditions, this increase is transient and a rapid return to Na+ balance occurs, even in the presence of continued stimulation of the tubular epithelium by aldosterone16. The mechanisms mediating this effect have not been fully elucidated. Growing evidence supports the presence and activity of mineralocorticoid receptors in non-epithelial tissues. Such receptors have been identified in the heart17, brain18 and blood vessels19, and activation of these receptors can elicit important biological responses. In vitro stimulation of cultured neonatal rat cardiac myocytes with aldosterone, but not with dexamethasone, has an anabolic effect as assessed by increased leucine incorporation into protein20. This effect was significantly increased by the presence of increased glucose in the medium and involved activation of the protein kinase C (PKC) pathway. More recently, aldosterone has been shown to inhibit the sarcolemmal Na+–K+ pump21 through mechanisms that involve the epsilon isoform of PKC (Ref. 22). Using the isolated perfused rat heart, Moreau et al.23 have shown that aldosterone can decrease coronary blood flow and increase aortic flow and cardiac output. Finally, Vassort and co-workers24 have shown that aldosterone can upregulate Ca2+ transport into cardiomyocytes. Non-epithelial effects of aldosterone have also been demonstrated in the brain. Administration of low doses of aldosterone into the cerebral ventricles in
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rats induces hypertension, whereas the same doses administered systemically have no effect25. Similarly, intracerebroventricular infusion of non-diuretic doses of the mineralocorticoid receptor antagonist RU 28318 prevented the development of hypertension in aldosterone/salt hypertensive rats26, an intervention that did not prevent the pathological effects of aldosterone in the heart27. Thus, multiple lines of evidence indicate that aldosterone can activate nonepithelial mineralocorticoid receptors. However, the physiological or pathophysiological significance of these effects remains to be clarified. Rapid non-genomic effects of aldosterone
The above-mentioned, non-epithelial actions of aldosterone were typically slow to develop, consistent with aldosterone-induced activation of gene transcription. However, rapid effects of aldosterone in cardiovascular tissues have also been reported. In cultured vascular smooth muscle cells, aldosterone induced a prompt (<1 min) increase in intracellular Ca2+ concentration28. This increase was dependent on activation of phospholipase C and PKC and was elicited by subnanomolar concentrations of aldosterone, which are in the physiological range. Interestingly, the rapid effects of aldosterone on intracellular Ca2+ concentration were not inhibited by spironolactone. In addition, aldosterone induces rapid Na+ influx in vascular smooth muscle cells29, apparently via activation of Na+–H+ exchange29,30. The effects of aldosterone on Na+ influx were seen within 5 min, were mimicked by fludrocortisone and deoxycorticosterone (but not by hydrocortisone) and were inhibited by RU 28318, but not by canrenone or spironolactone29,30. A novel membrane receptor for aldosterone has been proposed to mediate these rapid effects. However, although membrane receptors for steroids have been cloned recently 31, a specific membrane receptor for aldosterone has yet to be identified. Moreover, Alzamora et al.30 have shown recently that non-genomic rapid effects of aldosterone can be blocked by the classic aldosterone antagonist RU 28318, indicating that the cytosolic aldosterone receptor might also be responsible for these rapid effects, either directly or through one of the chaperones released upon aldosterone binding to the receptor, as suggested previously32,33. Role of aldosterone in cardiovascular end-organ damage Experimental evidence
It has long been known that combined administration of the mineralocorticoid deoxycorticosterone acetate and sodium chloride to rats induces the development of severe hypertension and produces lesions in the brain34, heart35 and kidney36–39. Interestingly, these lesions are virtually identical to those seen in hypertensive models that display an abnormal activation of the RAAS, such as Ang II/salt hypertensive rats40 or stroke-prone spontaneously hypertensive rats (SHRSP)41,42. In studies to http://tem.trends.com
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determine the contribution of aldosterone to vascular lesion development in SHRSP, we have found that administration of aldosterone antagonists43,44 or adrenalectomy45 markedly reduced the incidence of stroke and the development of proteinuria and renal microvascular lesions in saline-drinking SHRSP. These vascular protective effects of aldosterone antagonism were not associated with significant reductions in blood pressure. These studies indicate that aldosterone plays a pivotal role in vascular lesion development in the brain and kidneys, which is unrelated to an effect on blood pressure. To examine further the pathological effects of aldosterone in the kidney in SHRSP, animals in which the endogenous RAAS was suppressed with captopril received either vehicle or aldosterone46. Captopril treatment reduced plasma aldosterone levels and prevented proteinuria and vascular injury in the kidney, but did not reduce hypertension. However, when exogenous aldosterone was administered in combination with captopril, proteinuria and renal vascular injury were fully restored. Aldosterone has also been shown to abolish the renal protection provided by combined ACE inhibition/Ang II type-I receptor antagonism in the remnant kidney model of hypertension47. These studies suggest that the beneficial effects of ACE inhibition in the kidney of SHRSP could be mediated, at least in part, by the inhibitory effects of these compounds on aldosterone synthesis. In recent studies, we have examined further the role of aldosterone in the development of cerebral lesions in SHRSP. Rats were placed on a 1% NaCl/stroke-prone rodent diet at nine weeks of age. At the same time, treatment with either eplerenone (100 mg kg−1 d−1, p.o.; n = 7) or vehicle (0.5% methylcellulose; n = 8) was started. SHRSP were maintained on these treatments until 19 weeks of age, at which time the animals that survived were sacrificed. Tail-cuff systolic blood pressure measured before death was similarly raised in the two groups (Fig. 1a). Starting at 13 weeks of age, vehicle-treated SHRSP began to show neurological signs of stroke and subsequently died (Fig. 1b). All of the vehicletreated SHRSP were dead by 18 weeks of age. In contrast, none of the eplerenone-treated littermates exhibited signs of stroke and all survived to 19 weeks of age, with the exception of one animal, which developed stroke signs and died at 18 weeks of age. Histopathological scoring of the brains revealed severe cerebral vascular and parenchymal lesions characteristic of ischemic and hemorrhagic stroke in untreated SHRSP (Figs 1c,2a), whereas cerebral injury in animals receiving eplerenone was markedly reduced (Figs 1c,2b). Consistent with a role of aldosterone in the development of cerebral pathology, MacLeod et al.48 have demonstrated that long-term exogenous administration of aldosterone blocked the ability of captopril to protect SHRSP against stroke. Thus, aldosterone seems to play a major role in the
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development of end-organ damage not only in the kidney but also in the brain. The effects of aldosterone on the heart have also been studied extensively. Several groups have demonstrated that hypertensive rat models in which Ang II and/or aldosterone is elevated display cardiac hypertrophy, with severe myocardial damage, which has been mostly characterized as myocardial fibrosis27,49–51. In those studies, when the aldosterone receptor was blocked with a low dose of spironolactone or canrenone, blood pressure was not significantly lowered although the development of myocardial fibrosis was markedly attenuated27,49,52. The locus at which aldosterone acts to induce myocardial fibrosis is not clear, and in vitro experimental findings are contradictory. An initial report by Brilla et al.53 suggested that aldosterone could directly stimulate cardiac fibroblasts to produce collagen. However, other investigators have failed to reproduce these http://tem.trends.com
findings54,55. We have recently identified a role for aldosterone in the development of vascular injury in the heart and kidneys of rats with Ang II-induced hypertension56. This effect was prevented by either eplerenone or adrenalectomy, independent of blood pressure reductions (Fig. 3). The vascular injury observed included lesions of segmental or circumferential fibrinoid necrosis of the media, panarterial inflammation and small foci of ischemic and necrotic damage in the myocardium (Fig. 4), or glomerular injury in the kidney. Similar vascular lesions have been reported in the heart of rats made hypertensive by aldosterone/salt treatment after four weeks50. We have also demonstrated recently that the vascular lesions induced by aldosterone in the heart are preceded by the induction of a vascular inflammatory phenotype, which triggers the perivascular leukocyte accumulation typically observed in the coronary arteries of aldosterone/salt hypertensive rats57. Thus, it is possible that the interstitial fibrosis induced by aldosterone in the heart is a secondary event in response to ischemic/necrotic damage resulting from the vascular inflammatory injury. Whether aldosterone causes this injury solely by its effects on epithelial tissues or whether activation of non-epithelial receptors also participates remains to be elucidated. Clinical evidence
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There is still scepticism about a role for aldosterone as an independent risk factor for cardiovascular disease. However, several clinical studies have shown that plasma aldosterone levels correlate with end-organ damage. Hené et al.58 studied 28 patients with varying degrees of chronic renal failure but similar levels of plasma K+ and plasma renin activity. Interestingly, as creatinine clearance fell below ~70 ml min−1, plasma aldosterone tended to increase. Duprez et al.59 found a significant correlation between plasma aldosterone levels and left ventricular mass in a population of patients with essential hypertension. Other groups have also reported correlations between plasma aldosterone levels and left ventricular hypertrophy60. Moreover, results from the CONSENSUS trial identified a significant correlation (P <0.003) between plasma aldosterone and mortality in patients with congestive heart failure61. A recent report demonstrated an inverse correlation between plasma aldosterone levels and arterial compliance in a population of essential hypertensive subjects, which was independent of blood pressure or age62. Thus, several studies have shown that aldosterone correlates with the severity of end-organ damage, and is probably an independent risk factor for cardiovascular events. Unlike other types of hypertension, primary aldosteronism (PA) is associated with elevated aldosterone levels and suppression of other components of the RAAS (Ref. 63). In general, it has been assumed that these patients do not display significant cardiovascular complications, an assumption that is not supported by the available data. In a classic report,
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Conn64 analyzed 145 cases of PA secondary to an aldosterone-producing adenoma; every patient had hypertension. More importantly, cardiomegaly was detected in 41% of the patients, retinopathy in 50% and proteinuria in 85%. Beevers et al.65 also identified a high incidence of adverse cardiovascular events in an analysis of 136 cases of PA. Recently, Nishimura et al.66 have investigated the incidence of cardiovascular complications in a population of patients with PA secondary to aldosterone-producing adenomas. These investigators identified cardiovascular complications in 34% of the patients: stroke was found in 16% and proteinuria in 24%. In addition, 78% of the patients in whom left ventricular mass index was evaluated had evidence of left ventricular hypertrophy (LVH). Finally, Grady et al.67 published a report of 32 renal biopsies obtained from patients with aldosterone-producing adenomas and showed that 56% had mild to severe arteriolar sclerosis, and 46% presented with interstitial fibrosis and tubular atrophy. Thus, there is a significant body of evidence that cardiovascular injury is common in patients with chronic PA. Cardiovascular events in patients with PA have usually been explained by the presence of accompanying hypertension. To determine the relative contribution of aldosterone in cardiovascular pathogenesis, independent of blood pressure, clinical studies have compared the incidence of cardiovascular events in patients with either PA or essential hypertension. Halimi and Mimram68 found an increased prevalence of albuminuria in a population of patients with PA http://tem.trends.com
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Fig. 3. Systolic blood pressure and myocardial damage. (a) Tail-cuff systolic blood pressure in saline-drinking rats receiving chronic treatment with L-NAME (40 mg kg−1day−1); circle, 1% NaCl; triangle, L-NAME + Ang II + 1% NaCl; diamond, L-NAME + Ang II + 1% NaCl + eplerenone; light green square, L-NAME + Ang II + 1% NaCl + ADX; dark green square, L-NAME + Ang II + 1% NaCl + ADX + ALDO, for a period of 14 days. On day 11, a subcutaneous infusion of vehicle or Ang II (50 ng min−1) was added to the treatment protocol. (b) Histopathological scores for myocardial necrosis in animals from the experiment in (a) on day 14. Abbreviations: ADX, adrenalectomy; ALDO, aldosterone; Ang II, angiotensin II; L-NAME, NGnitro-L-arginine methyl ester. Reproduced, with permission, from Ref. 56.
compared with matched subjects presenting with essential hypertension. A separate study compared 224 cases of PA with a similar number of patients with essential hypertension, in two groups matched by sex and age. The results showed that patients with PA had a significantly higher incidence of cerebral hemorrhage than did those with essential hypertension69. This incidence was greater in patients with PA, despite the higher levels of diastolic blood pressure and longer duration of hypertension in patients with essential hypertension. Another study compared the level of LVH in patients with PA or essential hypertension who displayed similar levels of blood pressure70. Despite
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0.9 0.8 0.7 0.6 0.5 0.0 0 Fig. 4. Effect of eplerenone on myocardial damage. Photomicrographs of serial myocardial sections from animals receiving L-NAME/angiotensin II treatment in the absence (a, b) or in the presence (c, d) of eplerenone (100 mg kg−1d−1). Sections were stained with hematoxylin and eosin (a, c) or the collagenspecific stain Picro-Sirius red (b, d). Arrowheads indicate areas of myocardial necrosis. Scale bars ≈ 65 µm. Abbreviation: L-NAME, NG-nitro-L-arginine methyl ester. Reproduced, with permission, from Ref. 56.
Acknowledgements The experimental work discussed here was funded, in part, by grants from the National Institutes of Health, MD, USA (HL-35522 to C.T.S.), from the American Heart Association New York State Affiliate (Grant-inAid 9859133 to C.T.S.) and from funds donated by Searle/Monsanto (St Louis, MO, USA).
similar levels of blood pressure and comparable age and gender distribution, PA patients demonstrated more severe and more frequent LVH and remodeling than did those with essential hypertension. In support of an association between hyperaldosteronism and increased risk for stroke, Litchfield et al.71 reported that patients with glucocorticoid remediable aldosteronism frequently develop stroke. LVH is also more common and severe in patients with PA than in patients with other types of secondary hypertension. For example, Denolle et al.72 showed that LVH was more frequent in patients with PA than in those with renovascular hypertension or pheochromocytoma. Thus, clinical evidence is now available that is consistent with the findings from animal studies suggesting a major role for aldosterone in the development of cardiovascular disease and stroke. Aldosterone antagonists
For more than 40 years, the mineralocorticoid receptor antagonist, spironolactone, has been available for the treatment of hypertension, hyperaldosteronism and edematous states, primarily in patients with uncompensated heart failure. The results of the Randomized Aldactone Evaluation Study (RALES) clearly demonstrated that low-dose mineralocorticoid receptor antagonist therapy markedly reduced morbidity and mortality in patients with severe heart failure, independent of hemodynamic effects73. In that study, administration of a low dose (~26 mg day−1) of the non-selective mineralocorticoid receptor antagonist, spironolactone, to patients receiving standard therapy, which included ACE inhibition and a diuretic, reduced mortality and morbidity in ~30% of patients with severe heart failure (Fig. 5). However, the beneficial effect of spironolactone was accompanied by significant side effects, namely gynecomastia and impotence, seen in
References 1 American Heart Association (1999) 2000 Heart and Stroke Statistical Update, American Heart Association 2 Joint National Committee on Prevention, Detection, Evaluation and Treatment of Blood
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Fig. 5. Aldosterone blockade reduces mortality and morbidity in patients with severe heart failure. The results from the RALES study with spironolactone showed a 30% risk reduction (95% confidence interval, 18% to 40%; P <0.001) in patients with NYHA class III or IV heart failure. Spironolactone and standard therapy (yellow); standard therapy, which was angiotensinconverting enzyme inhibitor plus loop diuretic ± digoxin (blue). Abbreviations: NYHA, New York Heart Association; RALES, randomized aldactone evaluation study. Reproduced, with permission, from Ref. 73.
10% of the patients in this group. Interestingly, hyperkalemia was not a significant side effect in this study. Gynecomastia and impotence reflect the relatively low selectivity of spironolactone, which, in addition to being an effective mineralocorticoid receptor antagonist, is also an androgen receptor antagonist and progesterone receptor agonist. The side effects of spironolactone via these receptors limit the use of this antagonist, particularly in young patients with hypertension or early stages of congestive heart failure. Novel, selective mineralocorticoid receptor antagonists such as eplerenone are currently under development and will eventually provide a more acceptable therapeutic profile. Conclusion
Accumulating evidence suggests that the classic characterization of aldosterone as an epithelial-acting, electrolyte-regulating hormone should be re-evaluated and extended. It is now clear that in addition to its epithelial effects, aldosterone has major functions in non-epithelial tissues that, under certain conditions, can lead to cardiovascular injury, renal disease and stroke. Thus, aldosterone should be considered as a crucial independent risk factor for end-organ damage in cardiovascular disease.
Pressure (1997) The sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Blood Pressure. Arch. Intern. Med. 157, 2413–2446 3 Brunner, H.R. et al. (1972) Essential hypertension: renin and aldosterone, heart
attack and stroke. New Engl. J. Med. 286, 441–449 4 Alderman, M.H. et al. (1991) Association of the renin–sodium profile with the risk of myocardial infarction in patients with hypertension. New Engl. J. Med. 324, 1098–1104
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Dietary cholesterol absorption; more than just bile Kangmo Lu, Mi-Hye Lee and Shailendra B. Patel Absorption of dietary cholesterol from the intestine is an important part of cholesterol homeostasis and represents the first step that allows dietary cholesterol to exert its metabolic effects. Although the role of bile salts in the initial absorption of dietary cholesterol, by the formation of emulsions, is readily appreciated, the recognition that other molecular mechanisms might govern this process is only recently gaining momentum. Not only does the intestine regulate the amount of dietary cholesterol that enters the body; it is very selective with regard to the sterols that are allowed in. The human intestine is responsible for absorbing a significant amount of cholesterol each day. In addition to ~0.5 g d−11 of dietary cholesterol, many other sterols are also present in almost equal abundance in the normal diet. Approximately 0.4 g of plant sterols, such as sitosterol, brassicasterol and avanesterol, are also present. However, the human body seems to allow only cholesterol to enter and remain in the body, with almost negligible amounts of plant sterols being retained. That specific molecular mechanisms are responsible for this behavior is supported by the identification of the genetic defect(s) in a rare disorder, β-sitosterolemia (MIM 210250), where this process is disrupted. Such studies are now beginning to throw light on sterol absorption and excretion and elucidate the molecular mechanisms that govern these processes.
Kangmo Lu Mi-Hye Lee Shailendra B. Patel* Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, STR 541, 114 Doughty Street, Charleston, SC 29403, USA. *e-mail: [email protected]
Elevated plasma cholesterol level is a risk factor for atherosclerosis. The net effects of dietary cholesterol absorption, endogenous cholesterol synthesis and biliary cholesterol excretion regulate whole body cholesterol balance, either by breakdown to bile or via direct cholesterol excretion1–4. Because most of the cholesterol can only be disposed of via the biliary system, the enterohepatic circulation plays a crucial role in whole body sterol balance. Within the intestinal lumen, dietary cholesterol is presented to the brush border of mucosal enterocytes as a micelle formed by the action of bile salts, cholesterol and fatty acids. The initial point of contact between these http://tem.trends.com
micelles and the intestinal cells that absorb cholesterol occurs at the surface of the enterocyte brush border in the intestine. Cholesterol appears to be specifically removed from the micelles as part of the absorption process: cholesterol is absorbed principally in the duodenum and jejunum, but bile acids are not absorbed to an appreciable degree at these sites. Rather, specific bile acid transporters located in the ileum subsequently absorb bile acids, delivering these back to the liver and thus completing the enterohepatic circulation5,6. In addition, non-cholesterol sterols do not appear to be absorbed during this process. Thus, sitosterol, the major plant sterol, might be presented at the brush border membrane but appears to be largely excluded from entry and esterification, although a small amount (<2%) might be absorbed1,7,8. Because cholesterol moves into enterocytes from bile acid micelles, it is probable that cholesterol monomers, not cholesterol aggregates, are the species taken up. In addition, cholesterol synthesis contributes two to three times more cholesterol to the total body pool than does the absorption of dietary cholesterol, which occurs predominantly in the jejunum. In the intestinal mucosa, as in other tissues, 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase (EC 1.1.1.34) is the rate-limiting step in cholesterol synthesis, and its activity correlates with the cholesterol synthetic rate. However, in this review, the role of intestinal cholesterol synthesis, although important, will not be discussed. After absorption, free cholesterol and fatty acids are re-esterified in the enterocytes by the action of acyl-coenzyme A:cholesterol acyl-transferase
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