gamma-sitosterol and Arteriosclerosis

Topics: Arteriosclerosis; Cholestyramine Resin; Contraindications; Diagnosis, Differential; Genes, Recessive; Humans; Ion Exchange Resins; Lipid Metabolism, Inborn Errors; Phytosterols; Prognosis; Sitosterols; Xanthomatosis

Although plant sterols (phytosterols) and cholesterol have similar chemical structures, they differ markedly in their synthesis, intestinal absorption, and metabolic fate. Phytosterols inhibit intestinal cholesterol absorption, thereby lowering plasma total and low-density lipoprotein (LDL) cholesterol levels. In 16 recently published human studies that used phytosterols to reduce plasma cholesterol levels in a total of 590 subjects, phytosterol therapy was accompanied by an average 10% reduction in total cholesterol and 13% reduction in LDL cholesterol levels. Phytosterols may also affect other aspects of cholesterol metabolism that contribute to their antiatherogenic properties, and may interfere with steroid hormone synthesis. The clinical and biochemical features of hereditary sitosterolemia, as well as its treatment, are reviewed, and the effects of cholestyramine treatment in 12 sitosterolemic subjects are summarized. Finally, new ideas for future research into the role of phytosterols in health and disease are discussed.

Topics: Anticholesteremic Agents; Arteriosclerosis; Cholesterol; Cholestyramine Resin; Humans; Intestinal Absorption; Phytosterols; Sitosterols

Treatment with carbamazepine (CBZ) affects cholesterol concentrations, but little is known about the precise nature and underlying mechanisms of changes in lipoprotein metabolism. We investigated prospectively the effects of CBZ on lipid metabolism in normolipemic adults. In 21 healthy males, lipoprotein and noncholesterol sterol concentrations were measured before and during treatment with CBZ for 70 +/- 18 days. Thirteen subjects underwent kinetic studies of apolipoprotein-B (ApoB) metabolism with the use of endogenous stable isotope labeling. Lipoprotein kinetic parameters were calculated by multicompartmental modeling. Significant increases in total cholesterol, in ApoB-containing lipoproteins [very-low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low-density lipoprotein (LDL)], and in triglycerides, but not in high-density lipoprotein (HDL), were observed. Lipoprotein particle composition remained unchanged. Mean fractional catabolic and production rates of ApoB-containing lipoproteins were not significantly different, although mean production rates of VLDL and IDL were substantially increased (+46 +/- 139% and +30 +/- 97%, respectively), whereas mean production of LDL remained unchanged (+2.1 +/- 45.6%). Cholestanol in serum increased significantly but not the concentrations of plant sterols (campesterol, sitosterol) and the cholesterol precursors (lathosterol, mevalonic acid). There was a significant correlation between the decrease in free thyroxine and the increase in IDL cholesterol. Treatment with CBZ increases mainly ApoB-containing lipoproteins. CBZ seems not to influence endogenous cholesterol synthesis or intestinal absorption directly. The increase is neither related to increased ApoB production nor to decreased catabolism but is rather due to changes in the conversion cascade of IDL particles, most likely as an indirect effect through a decrease in thyroid hormones.

Topics: Adult; Anticonvulsants; Arteriosclerosis; Body Composition; Body Weight; Carbamazepine; Cholestanol; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Diet; Humans; Hydrocortisone; Intestinal Absorption; Lipoproteins; Male; Mevalonic Acid; Phytosterols; Sitosterols

Plant sterol supplementation reduces serum cholesterol concentration but may increase serum plant sterol concentrations, especially in children. We determined whether natural dietary plant sterols derived mainly from vegetable oil or margarine in early childhood affect serum concentrations of plant sterols (campesterol and sitosterol) and cholesterol precursor sterols (Delta-8 cholestenol, desmosterol, and lathosterol), reflecting endogenous cholesterol synthesis. We measured the serum sterol concentrations using gas liquid chromatography in 20 healthy 13-mo-old intervention children in a randomized, prospective study designed to decrease exposure of the children to known environmental atherosclerosis risk factors and in 20 control children. The diet of the intervention children was rich in plant sterols due to replacement of milk fat with vegetable fat, whereas the diet of the control children contained only small amounts of plant sterols. The intervention children consumed twice as much plant sterols as the control children (P < 0.001). Their serum concentrations of campesterol and sitosterol were 75% and 44% higher, respectively, than those in the control children (P < 0.001 for both), but serum cholesterol precursor sterol concentrations did not differ between the two groups. We conclude that doubling dietary plant sterol intake almost doubles serum plant sterol concentrations in 13-mo-old children, but has no effect on endogenous cholesterol synthesis. Relative intestinal absorption of natural plant sterols from the diet in early childhood is similar to that in adults.

Topics: Arteriosclerosis; Case-Control Studies; Cholesterol; Chromatography, Gas; Desmosterol; Diet Records; Female; Humans; Hypolipidemic Agents; Infant; Intestinal Absorption; Male; Margarine; Phytosterols; Plant Oils; Prospective Studies; Risk Factors; Sitosterols

Topics: Absorption; Animals; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Cholestyramine Resin; Clinical Trials as Topic; Food; Humans; Hypercholesterolemia; Phytosterols; Risk; Sitosterols

Sitosterolemia is an inherited recessive disease characterized by abnormally increased plasma and tissue plant sterol concentrations. Patients hyperabsorb sitosterol. In addition, hepatic, ileal, and mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme in the cholesterol biosynthetic pathway, is markedly suppressed in this disease. It is still controversial whether the down-regulation is due to accumulated sitosterol, but the effect of sitosterol on HMG-CoA reductase activity has not been studied in sitosterolemic tissues. To investigate whether sitosterol inhibits HMG-CoA reductase activity in sitosterolemia, we measured the enzyme activities in liver and cultured skin flbroblasts from patients. Hepatic HMG-CoA reductase activities in patients were decreased 76% (P < .05) as compared with results in control subjects. In contrast, HMG-CoA reductase activities in sitosterolemic fibroblasts were not decreased as compared with results in control fibroblasts, and the activities in all cells were up-regulated similarly when they were exposed to delipidated medium. Because the cultured sitosterolemic fibroblasts contained only trace amounts of plant sterols, we added 20 microg/mL sitosterol directly to the cell medium. Raising the intracellular sitosterol concentration to 7% of cellular cholesterol level increased HMG-CoA reductase activity 23% (P < .05), while the addition of the same amount of cholesterol to the cells reduced the activity 46% (P < .05). Thus, when sitosterolemic skin fibroblasts were used, it was possible to distinguish between the effects of cholesterol and those of sitosterol on the activity of HMG-CoA reductase. These results suggest that reduced HMG-CoA reductase activity in this disease is caused by secondary effects of unknown regulator(s) other than sitosterol.

Topics: Adolescent; Adult; Aorta, Thoracic; Arteriosclerosis; Cells, Cultured; Cholesterol; Female; Fibroblasts; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism, Inborn Errors; Male; Reference Values; Sitosterols

We measured the turnover and absorption of sitosterol and cholesterol, along with plasma sterol and lipoprotein concentrations, in one control and two subjects with sitosterolemia with xanthomatosis. All individuals consumed the same diet which contained approximately 500 mg/day of cholesterol and 250 mg/day of sitosterol. Sterol absorption was measured by the plasma dual-isotope ratio method and turnover by plasma isotope-kinetic analysis. In two sitosterolemic subjects, 28% and 63% of the sitosterol and 69% and 49% of the cholesterol were absorbed, respectively, compared to 4% of the sitosterol and 44% of the cholesterol in the control. As expected, plasma sitosterol specific activities decayed much more rapidly than cholesterol in the control subject. In contrast, plasma sitosterol and cholesterol specific activity-time curves were similar and decayed more slowly in the sitosterolemic subjects. In the control subject, the total sitotterol pool was 290 mg and was linearly related to low absorption (18 mg/day); whereas the total sitosterol pool was 17 times (4800 mg) and 13 times (3500 mg) larger, respectively, in the sitosterolemic subjects and was expanded out of proportion to increased absorption because of decreased removal. Daily cholesterol turnover and synthesis were markedly reduced in the sitosterolemic subjects. In four sitosterolemic subjects, plasma concentrations of total sterols, low density lipoproteins, and apolipoprotein B were increased, while those of high density lipoproteins and apolipoprotein A-I were low to normal. The low density lipoproteins were very similar to those of normal control subjects in density distribution, peak flotation rate, sterol-to-protein (apolipoprotein B) ratio, particle size, and morphology. These results demonstrate in patients with sitosterolemia with xanthomatosis that: 1) the absorption of sitosterol and cholesterol is enhanced; 2) tissue recognition between cholesterol and sitosterol is lost; 3) total exchangeable sitosterol pools are expanded out of proportion to absorption because of decreased excretion; 4) plasma sterol and lipoprotein concentrations favor tissue deposition; and 5) cholesterol synthesis is diminished. We postulate that the changes in sitosterol metabolism (increased absorption, loss of tissue sterol structural recognition, expanded pools, and hepatic retention) are a response to reduced cholesterol synthesis in these subject.

Topics: Absorption; Adolescent; Adult; Arteriosclerosis; Cholesterol; Female; Humans; Lipoproteins; Male; Sitosterols; Sterols; Xanthomatosis

14C-labeled C29- and C27-steroids were injected in rats, which were killed after 14 days. Phytosterols (C29) were excreted mainly as such, whereas C27-steroids were recovered essentially as water soluble metabolites. The total 14C-excretion was lower from 3-oxo, delta 4-steroids (5 alpha-stanol precursors) than from 3 beta-hydroxy,delta 5-steroids. 14C-Phytosterols were accumulated more than C27-steroids in liver, serum (mainly in HDL) and especially in adrenal glands and ovaries. In relation to serum, particularly the 5 alpha-stanols were enriched in the adrenal glands and ovaries. No striking lysosomal accumulation of any of the steroids was found.

Topics: Animals; Arteriosclerosis; Blood Proteins; Cricetinae; Female; Injections, Intraperitoneal; Lipid Metabolism, Inborn Errors; Liver; Rats; Rats, Inbred Strains; Sitosterols; Subcellular Fractions; Tissue Distribution

The antihypercholesterolemic activity of beta-sitosterol and beta-sitostanol was compared in male rabbits given a cholesterol-supplemented diet. beta-Sitosterol and beta-sitostanol were fed to these rabbits at the 0.5% level with cholesterol (0.5% and 0.2% in experiments I and II, respectively). The serum cholesterol level tended to be lower in rabbits fed beta-sitostanol than in the animals fed beta-sitosterol even in experiment I. The beta-sitostanol exhibited a significantly greater hypocholesterolemic activity in experiment II, LDL-cholesterol being decreased markedly. The liver cholesterol decreased in both groups of rabbits to a similar extent. beta-Sitostanol prevented more effectively the formation of dietary cholesterol-induced atheroma in the abdominal aorta than beta-sitosterol. It is most likely, together with the data reported previously on rats, that the hypocholesterolemic activity of beta-sitostanol results from the significantly greater inhibitory effect on the intestinal absorption of cholesterol than that of beta-sitosterol.

Topics: Animals; Anticholesteremic Agents; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Lipids; Lipoproteins; Liver; Male; Rabbits; Sitosterols; Sterols

Topics: Anticholesteremic Agents; Arteriosclerosis; Cholesterol; Geriatrics; Humans; Lipids; Lipoproteins; Sitosterols; Sterols

Topics: Arteriosclerosis; Blood Chemical Analysis; Cholesterol; Fatty Acids; Fatty Acids, Unsaturated; Geriatrics; Humans; Lipids; Pharmacology; Sitosterols; Sterols

Topics: Arteriosclerosis; Cholesterol; Humans; Hypercholesterolemia; Sitosterols; Sterols

Topics: Arteriosclerosis; Cholesterol; Estradiol; Hormones; Humans; Sitosterols; Sterols; Testosterone; Triiodothyronine; Vitamins

Topics: alpha-Linolenic Acid; Animals; Aorta; Arachidonic Acid; Arteriosclerosis; Cholesterol; Dogs; Estradiol; Hypercholesterolemia; Lipid Metabolism; Lipids; Sitosterols; Sterols

Topics: Animals; Arteriosclerosis; Diet; Humans; Hypercholesterolemia; Rats; Sitosterols; Steroids; Thiouracil

Topics: Animals; Arteries; Arteriosclerosis; Cholesterol; Diet; Fats; Humans; Hypercholesterolemia; Rats; Sitosterols; Steroids; Thiouracil

Topics: Arteriosclerosis; Atherosclerosis; Diet; Sitosterols; Steroids

Topics: Arteriosclerosis; Cholesterol; Diet; Diet, Fat-Restricted; Fats; Humans; Lipoproteins; Sitosterols; Steroids

Topics: Arachidonic Acid; Arteriosclerosis; Atherosclerosis; Cholesterol; Humans; Hypercholesterolemia; Safflower Oil; Sitosterols; Steroids

Topics: Arteriosclerosis; Sitosterols; Steroids

Topics: Animals; Arteriosclerosis; Cholesterol; Hypertension; Plaque, Atherosclerotic; Rabbits; Sitosterols; Steroids

Topics: Animals; Arteriosclerosis; Atherosclerosis; Cholestanol; Cholesterol; Rabbits; Sitosterols; Steroids

Topics: Animals; Arteriosclerosis; Atherosclerosis; Cholesterol; Rabbits; Sitosterols; Steroids