cytellin 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

The clinical observation and treatment of young children with sitosterolemia has rarely been reported. We report clinical, biochemical, and molecular genetic observations and treatment outcomes for five Chinese children from four separate families presenting with sitosterolemia in whom we identified two new (Y329X, G269R) and three known (R446X, N437K, R389H) mutations in the ABCG5 gene. The R389H mutation was found in 50% of alleles. Three of these five patients received cholestyramine therapy with a very good response. However, all patients discontinued this therapy because of poor compliance. Finally, all patients were on ezetimibe therapy and had satisfactory total serum cholesterol levels, though their plant sterol levels were still higher than normal. Another noteworthy finding is that a female infant had a serum cholesterol level of 654 mg/dl at 7 months of age, despite being breast fed (with very tiny amounts of plant sterols) since birth and undergoing 4 months of ezetimibe administration. Although she failed to respond to ezetimibe during this period, she did show improvement when the therapy was started again at 2 years of age. It is possible that another 23-month-old female patient also responded more slowly to ezetimibe treatment than older patients.

Topics: Anticholesteremic Agents; Asian People; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP-Binding Cassette Transporters; Azetidines; Child; DNA Mutational Analysis; Ezetimibe; Female; Genetic Testing; Humans; Infant; Lipoproteins; Metabolism, Inborn Errors; Point Mutation; Sitosterols

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