phytosterols and Metabolism--Inborn-Errors

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 approximately 0.5 g d(-1) 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, beta-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.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP-Binding Cassette Transporters; Bile; Bile Acids and Salts; Cholesterol, Dietary; Humans; Intestinal Absorption; Lipoproteins; Metabolism, Inborn Errors; Mutation; Phytosterols; Sitosterols

Plant sterols have been investigated as one of the safe potential alternative methods in lowering plasma cholesterol levels. Several human studies have shown that plant sterols/stanols significantly reduce plasma total and LDL cholesterol. In this article, pharmacological characteristics of plant sterols/stanols have been summarized and discussed. In particular, experimental data that demonstrate the effects of dietary phytosterols on lipid metabolism and development of atherosclerotic lesions have been critically reviewed. Despite their similar chemical structures, phytosterols and cholesterol differ markedly from each other in regard to their pharmacological characteristics including intestinal absorption and metabolic fate. Compared to cholesterol, plant sterols have poor intestinal absorption. The most and best studied effects of plant sterols are their inhibition of intestinal cholesterol absorption. Other biological activities of phytosterols such as effects on lecithin:cholesterol acyltransferase activity, bile acid synthesis, oxidation and uptake of lipoproteins, hepatic and lipoprotein lipase activities and coagulation system have been linked to their anti-atherogenic properties. Moreover, evidence for beneficial effects of plant sterols on disorders such as cutaneous xanthomatosis, colon cancer and prostate hyperplasia has been discussed. Finally, the potential adverse effects of plant sterols as well as pathophysiology of hereditary sitosterolemia are also reviewed. In conclusion, more pharmacokinetic data are needed to better understand metabolic fate of plant sterols/stanols and their fatty acid esters as well as their interactions with other nutraceutical/pharmaceutical agents.

Topics: Animals; Clinical Trials as Topic; Humans; Metabolism, Inborn Errors; Phytosterols; Plants, Medicinal

Phytosterolaemia (sitosterolaemia) is a very rare inherited sterol storage disease characterized by tendon and tuberous xanthomas and by a strong predisposition to premature coronary atherosclerosis. In addition to increased or normal serum cholesterol, patients are found to have markedly elevated concentrations of the phytosterols sitosterol and campesterol. These sterols accumulate in all tissues, except the brain. Increased intestinal absorption of plant sterols, impaired biliary excretion, and decreased cholesterol synthesis are suggested as causes for this disease. However, the primary defect has not yet been identified. As well as dietary restrictions of cholesterol and plant sterols, therapeutic approaches based on interruption of the enterohepatic circulation of bile acids by administration of bile acid-binding resins or ileal bypass surgery have been recommended as therapeutic approaches to reduce all serum sterols. Administration of sitostanol, a nonabsorbable saturated plant sterol, showed a significant reduction of serum plant sterols and cholesterol in two patients with phytosterolaemia, presumably by competitive inhibition of sterol absorption.

Topics: Humans; Metabolism, Inborn Errors; Phytosterols

Topics: Animals; Bile Acids and Salts; Cholesterol; Humans; Hydroxylation; Metabolism, Inborn Errors; Molecular Structure; Phytosterols

Topics: Acid-Base Imbalance; Anemia, Hemolytic, Congenital; Erythrocytes, Abnormal; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Male; Metabolism, Inborn Errors; Middle Aged; Phytosterols; Thrombocytopenia

Dietary sitostanol has a hypocholesterolemic effect because it decreases the absorption of cholesterol. However, its effects on the sitostanol concentrations in the blood and tissues are relatively unknown, especially in patients with sitosterolemia and xanthomatosis. These patients hyperabsorb all sterols and fail to excrete ingested sitosterol and other plant sterols as normal people do. The goal of the present study was to examine the absorbability of dietary sitostanol in humans and animals and its potential long-term effect. Two patients with sitosterolemia were fed the margarine Benecol (McNeill Nutritionals, Ft. Washington, PA), which is enriched in sitostanol and campestanol, for 7-18 wk. Their plasma cholesterol levels decreased from 180 to 167 mg/dL and 153 to 113 mg/dL, respectively. Campesterol and sitosterol also decreased. However, their plasma sitostanol levels increased from 1.6 to 10.1 mg/dL and from 2.8 to 7.9 mg/dL, respectively. Plasma campestanol also increased. After Benecol withdrawal, the decline in plasma of both sitostanol and campestanol was very sluggish. In an animal study, two groups of rats were fed high-cholesterol diets with and without sitostanol for 4 wk. As expected, plasma and liver cholesterol levels decreased 18 and 53%, respectively. The sitostanol in plasma increased fourfold, and sitostanol increased threefold in skeletal muscle and twofold in heart muscle. Campestanol also increased significantly in both plasma and tissues. Our data indicate that dietary sitostanol and campestanol are absorbed by patients with sitosterolemia and xanthomatosis and also by rats. The absorbed plant stanols were deposited in rat tissues. Once absorbed by sitosterolemic patients, the prolonged retention of sitostanol and campestanol in plasma might increase their atherogenic potential.

Topics: Adolescent; Animals; Cholesterol; Diet; Female; Humans; Male; Metabolism, Inborn Errors; Middle Aged; Phytosterols; Rats; Rats, Wistar; Sitosterols; Tissue Distribution; Xanthomatosis

Margarine with added plant sterols lowers plasma cholesterol levels. It is of importance to know whether these margarines can be used safely in carriers of a hereditary disorder with increased absorption of plant sterols.. In an open feeding study of 8 weeks with a 2-week run-in period and 2 final weeks as a washout period on control margarine (0.3% plant sterols), two obligate heterozygous parents of a patient with classical sitosterolaemia were subjected for 4 weeks to a diet containing margarine enriched with plant sterols (8%). Fasting blood samples were taken weekly. Primary outcomes were plasma lipid and lipoprotein levels and plant sterol levels.. Both parents were hyperlipidaemic. Total plasma cholesterol levels were decreased by 11 and 12%, respectively, after 4 weeks of the consumption of 40 g day(-1) of plant sterol-enriched margarine. This was mainly due to changes in LDL-cholesterol, whereas the other lipoproteins, including lipoprotein(a), were unaffected. Total plant sterol levels increased maximally 139% from 0.31 to 0.82% of total sterols in the father, and maximally 83% from 0.32 to 0.66% of total sterols in the mother.. An intake of around 3 g day(-1) of plant sterols by subjects heterozygous for phytosterolaemia increased campesterol or sitosterol levels in blood to similar levels as found in normal subjects. In addition, plasma cholesterol levels were reduced to the same extent as in normal or hypercholesterolaemic individuals.

Topics: Adult; Cholesterol; Chromatography, Gas; Female; Heterozygote; Humans; Male; Margarine; Metabolism, Inborn Errors; Middle Aged; Phytosterols

Phytosterolaemia (sitosterolaemia) is a very rare inherited sterol storage disease characterized by tendon and tuberous xanthomas and by a predisposition to atherosclerosis. We here describe the first Scandinavian case. The 14-year-old female patient was found to have markedly elevated circulating levels of plant sterols (sitosterol, sitostanol, campesterol, stigmasterol), and the levels of these sterols were 20-50 times higher than in her healthy sister and heterozygous parents. In addition to the usual serum plant sterols we found a new major sterol in the patient tentatively identified as episterol or fecosterol (24-methyliden-cholest-7 (or 8)-en-3 beta-ol). A newly developed method based on the use of deuterium labelled cholesterol and plant sterols was used to measure sterol absorption in the patient and her relatives. Absorption of sitosterol averaged 20% in the patient and ranged from 4 to 8% in the relatives. Absorption of campesterol averaged 31% in the patient and ranged from 15 to 18% in her relatives. Absorption of cholesterol averaged 63% in the patient and ranged from 35 to 45% in the relatives. Cholesterol synthesis appeared to be reduced in the patient and was 46-52% of that of her relatives.

Topics: Adolescent; Adult; Cholestyramine Resin; Feces; Female; Humans; Intestinal Absorption; Lipids; Lipoproteins; Male; Metabolism, Inborn Errors; Phytosterols

Topics: Adolescent; Child; Female; Humans; Intestinal Absorption; Male; Metabolism, Inborn Errors; Phytosterols; Xanthomatosis