Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated A42 levels and the 4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimer's disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of A42 and A40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral A42 and A40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimer's disease. Lowered levels of A42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.A part from age, environmental factors have only slight influence on the incidence of Alzheimer's disease (AD). Very recently, two independent reports showed a strong decrease in the incidence of AD and dementia for patients that were treated with statins (1, 2). Both studies were retrospective, and statins were not given in any relation to dementia. Usually statins are prescribed for treatment of elevated serum cholesterol levels in patients. They reduce cholesterol levels by inhibiting the bottleneck enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. They are widely used drugs, well characterized and considered to be very safe for long-time treatment, and approved for use in elderly patients (3, 4).The 4 allele of the apolipoprotein E (apoE) is the major genetic risk factor for AD (5). Several lines of evidence indicate that apoE 4 and statins have a related influence on AD. The normal cellular function of apoE is uptake and delivery of lipids. The isoform apoE 4 correlates with an increased risk for atherosclerosis (6) and amyloid plaque formation (7). Moreover, elevated cholesterol uptake increases amyloid plaque formation or amyloid deposition (8,9). This correlation may be extended to A production, since cellular cholesterol levels affect neuronal A production in vitro (10). Initially, A has been a focus of AD research, because it was found to be the major constituent of the amyloid plaque. It is unknown whether the amyloid plaque is actively involved in the neurodegenerative process in AD or instead is a consequence of the disease process. More recently, however, A has been a focus of AD research not because of it presence in the amyloid plaque, but because an overproduction of a minor A isoform, A42, is linked to all identified inherited forms of AD (11-13).A is produced during normal cellular processing of the Alzheimer amyloid precursor protein (APP) (14) by -secretase and ␥-secretase (15). While the majority of all A isoforms produced is A40, Ϸ10% of total A ...
Cholesterol and other sterols exit the body primarily by secretion into bile. In patients with sitosterolemia, mutations in either of two ATP-binding cassette (ABC) half-transporters, ABCG5 or ABCG8, lead to reduced secretion of sterols into bile, implicating these transporters in this process. To elucidate the roles of ABCG5 and ABCG8 in the trafficking of sterols, we disrupted Abcg5 and Abcg8 in mice (G5G8 ؊/؊ ). The G5G8 ؊/؊ mice had a 2-to 3-fold increase in the fractional absorption of dietary plant sterols, which was associated with an Ϸ30-fold increase in plasma sitosterol. Biliary cholesterol concentrations were extremely low in the G5G8 ؊/؊ mice when compared with wild-type animals (mean ؍ 0.4 vs. 5.5 mol͞ml) and increased only modestly with cholesterol feeding. Plasma and liver cholesterol levels were reduced by 50% in the chow-fed G5G8 ؊/؊ mice and increased 2.4-and 18-fold, respectively, after cholesterol feeding. These data indicate that ABCG5 and ABCG8 are required for efficient secretion of cholesterol into bile and that disruption of these genes increases dramatically the responsiveness of plasma and hepatic cholesterol levels to changes in dietary cholesterol content.ATP-binding cassette transporters ͉ sitosterolemia ͉ bile ͉ knockout mice S itosterolemia is a rare autosomal recessive disorder characterized by the accumulation of plant and animal sterols in blood and tissues (1, 2). Affected subjects with this disorder develop large deposits of cholesterol in their skin, tendons, and coronary arteries. The accumulation of plant and animal sterols in the blood is caused by an increase in the fractional absorption of sterols from the diet and a decrease in the secretion of sterols into the bile, which is the major route of exit of sterols from the body (3, 4).A striking feature of sitosterolemia is the precipitous fall in plasma cholesterol that follows reductions in dietary cholesterol intake, especially in young patients (5, 6). When normal individuals are switched from a high cholesterol, high fat diet to a low cholesterol, low fat diet, plasma levels of cholesterol fall Ϸ10-20%; in patients with sitosterolemia, plasma cholesterol can fall by Ͼ45% (5, 6). The hypercholesterolemia of sitosterolemia is also sensitive to treatment with bile-acid resins, which stimulate the conversion of cholesterol to bile acids, another pathway for removal of cholesterol from the body.The pathognomonic feature of sitosterolemia is the elevation in plasma sitosterol, the most abundant plant sterol (1). Sitosterolemic patients also accumulate other sterols in plasma including a variety of plant sterols (campesterol, stigmasterol, and avenasterol) and shellfish sterols (brassicasterol, 24-methylene cholesterol, and 22-dehydrocholesterol) (1, 7). In normal individuals these sterols are poorly absorbed and preferentially secreted into the bile (8-10). These sterols comprise only Ϸ1% of plasma and tissue sterols in normal individuals but Ϸ15% of circulating and tissue sterols in sitosterolemia (11).Studies of sitoste...
We have investigated whether side chainhydroxylated cholesterol species are important for elimination of cholesterol from the brain. Plasma concentrations of 24-hydroxycholesterol (24-OH-Chol) in the internal jugular vein and the brachial artery in healthy volunteers were consistent with a net flux of this steroid from the brain into the circulation, corresponding to elimination of -4 mg cholesterol during a 24-h period in adults. Results of experiments with rats exposed to '802were also consistent with a flux of 24-OH-Chol from the brain into the circulation. No other oxysterol measured showed a similar behavior as 24-OH-Chol. These results and the finding that the concentration of 24-OH-Chol was 30-to 1500-fold higher in the brain than in any other organ except the adrenals indicate that the major part of 24-OH-Chol present in the circulation originates from the brain. Both the 24-OH-Chol present in the brain and in the circulation were the 24S-stereoisomer. In contrast to other oxysterols, levels of plasma 24-OH-Chol were found to be markedly dependent upon age. The ratio between 24-OH-Chol and cholesterol in plasma was -5 times higher during the first decade of life than during the sixth decade. There was a high correlation between levels of 24-OH-Chol in plasma and cerebrospinal fluid. It is suggested that the flux of 24-OHChol from the brain is important for cholesterol homeostasis in this organ. The brain is the most cholesterol-rich organ in the body. However, surprisingly little is known about the mechanism regulating cholesterol homeostasis in this organ. Very little cholesterol is taken up from circulating lipoproteins due to the efficient blood-brain barrier (1). The local synthesis of cholesterol is also very low, and it has been reported that only -0.1% of newly synthesized cholesterol in adult monkeys is present in the brain (2). If this is valid also in adult humans, only 1-2 mg of cholesterol would be synthesized each day. From in vitro experiments on slices of rat brain, it was calculated that the half-life of cholesterol is -6 months (3). However, the very low uptake and synthesis of cholesterol in the brain must be balanced by some mechanism for removal of cholesterol. If very little high-density lipoprotein-dependent cholesterol transport occurs, the possibility should be considered that there is a conversion of cholesterol into metabolites that may pass the blood-brain barrier more easily than cholesterol itself.Recently, we described a new mechanism for elimination of intracellular cholesterol in macrophages, involving conversion of cholesterol into 27-hydroxycholesterol (27-OH-Chol; also denoted (25R)-cholest-5-ene-3/3,26-diol) and 3,B-hydroxy-5-cholestenoic acid (4). These compounds are more polar than cholesterol and easily transported out from the cells (4, 5). We have also shown that there is a continuous flux of 27-OH-Chol and other 27-oxygenated steroids from extrahepatic sources to the liver, where these compounds are rapidly metabolized into bile acids (5).We have previous...
A high intake of dietary fiber, particularly of the soluble type, above the level recommended by the ADA, improves glycemic control, decreases hyperinsulinemia, and lowers plasma lipid concentrations in patients with type 2 diabetes.
Age-associated decline in regeneration capacity limits the restoration of nervous system functionality after injury. In a model for demyelination, we found that old mice fail to resolve the inflammatory response initiated after myelin damage. Aged phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation and phagolysosomal membrane rupture and stimulated inflammasomes. Myelin debris clearance required cholesterol transporters, including apolipoprotein E. Stimulation of reverse cholesterol transport was sufficient to restore the capacity of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of cholesterol into crystals and thereby inducing a maladaptive immune response that impedes tissue regeneration.
These findings indicate that dietary cholesterol, possibly in the form of modified plasma lipoproteins, is an important risk factor for the progression to hepatic inflammation in diet-induced NASH.
Based on LDL-C lowering and the absence of adverse signals, this EAS Consensus Panel concludes that functional foods with plant sterols/stanols may be considered 1) in individuals with high cholesterol levels at intermediate or low global cardiovascular risk who do not qualify for pharmacotherapy, 2) as an adjunct to pharmacologic therapy in high and very high risk patients who fail to achieve LDL-C targets on statins or are statin- intolerant, 3) and in adults and children (>6 years) with familial hypercholesterolaemia, in line with current guidance. However, it must be acknowledged that there are no randomised, controlled clinical trial data with hard end-points to establish clinical benefit from the use of plant sterols or plant stanols.
Background-Ezetimibe has been shown to inhibit cholesterol absorption in animal models, but studies on cholesterol absorption in humans have not been performed thus far. Methods and Results-The effect of ezetimibe (10 mg/d) on cholesterol absorption and synthesis, sterol excretion, and plasma concentrations of cholesterol and noncholesterol sterols was investigated in a randomized, double-blind, placebo-controlled, crossover study in 18 patients with mild to moderate hypercholesterolemia. Treatment periods lasted 2 weeks with an intervening 2-week washout period. Fractional cholesterol absorption rates averaged 49.8Ϯ13.8% on placebo and 22.7Ϯ25.8% on ezetimibe, indicating a reduction of 54% (geometric mean ratio; PϽ0.001). Cholesterol synthesis increased by 89% from 931Ϯ1027 mg/d on placebo to 1763Ϯ1098 mg/d on ezetimibe (PϽ0.001), while the ratio of lathosterol-to-cholesterol, an indirect marker of cholesterol synthesis, was increased by 72% (PϽ0.001). Bile acid synthesis was insignificantly increased (placebo: 264Ϯ209 mg/d, ezetimibe: 308Ϯ184 mg/d; Pϭ0.068). Mean percent changes from baseline for LDL and total cholesterol after ezetimibe treatment were Ϫ20.4% and Ϫ15.1%, respectively (PϽ0.001 for both), whereas campesterol and sitosterol were decreased by Ϫ48% and Ϫ41%, respectively. Conclusion-In humans, ezetimibe inhibits cholesterol absorption and promotes a compensatory increase of cholesterol synthesis, followed by clinically relevant reductions in LDL and total cholesterol concentrations. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols sitosterol and campesterol, suggesting an effect on the absorption of these compounds as well.
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