Disease relevance of Harzol

• Sitosterolemia and xanthomatosis together are a disease characterized by premature cardiovascular disease, and by elevated plasma concentrations of total sterols and of plant sterols, especially sitosterol which is hyperabsorbed [1].
• Significant improvement in symptoms and urinary flow parameters show the effectiveness of beta-sitosterol in the treatment of benign prostatic hyperplasia [2].
• Letter: Beta-sitosterol and chenodeoxycholic acid in the treatment of cholesterol gallstones [3].
• In patients with advanced primary biliary cirrhosis serum cholestanol, a 5 alpha-derivative of cholesterol, is markedly increased, and cholesterol precursors, which are indicators of cholesterol synthesis, are clearly reduced, as is the ratio of plant sterols (campesterol/sitosterol) [4].
• Sitosterolemia is a disease characterized by very high levels of sitosterol and other plant sterols and premature atherothrombotic vascular disease [5].

High impact information on Harzol

• Addition of stigmasterol, but not sitosterol, inhibited SREBP-2 processing and reduced cholesterol synthesis [6].
• Patients with sitosterolemia with xanthomatosis, who have elevated microsomal cholestanol and sitosterol, showed reduced cholesterol 7 alpha-hydroxylase activity relative to the activity in control subjects (13.9 and 14.7 vs. 20.3 +/- 0.9 pmol/nmol P-450 per min, P less than 0.01) [7].
• Surprisingly, high plasma beta-sitosterol and campesterol concentrations were even further elevated in Abcg5-null mice on treatment with the synthetic LXR agonist T0901317 (0.015% dietary supplementation, 10 days), whereas these concentrations were reduced by approximately 75% in wild-type mice [8].
• Five of his twelve sibs had tendon and tuberous xanthomas, and increased plasma plant sterols, particularly beta-sitosterol [9].
• Growth of cells cultured in beta-sitosterol and NB-598 was restored by adding small amounts of cholesterol to the medium [10].

Chemical compound and disease context of Harzol

• Diet, nutrition intake, and metabolism in populations at high and low risk for colon cancer. Dietary cholesterol, beta-sitosterol, and stigmasterol [11].
• beta-Sitosterol, beta-Sitosterol Glucoside, and a Mixture of beta-Sitosterol and beta-Sitosterol Glucoside Modulate the Growth of Estrogen-Responsive Breast Cancer Cells In Vitro and in Ovariectomized Athymic Mice [12].
• We hypothesized that the phytosterols beta-sitosterol (BSS), beta-sitosterol glucoside (BSSG), and Moducare (MC; BSS:BSSG = 99:1) could modulate the growth of estrogen-dependent human breast cancer cells in vitro and in vivo [12].
• This study indicates that the combination of sitosterol (3 x 1 g/d) plus bezafibrate (1 x 200 mg/d) is an alternate, acceptable, safe, and effective therapeutic approach for treatment of severe hypercholesterolemia in children with high-risk familial hypercholesterolemia [13].
• Norviburtinal was found to be the most active compound but had little selectivity for melanoma cell lines whilst isopinnatal also showed some cytotoxic activity. beta-Sitosterol was found to be comparatively inactive [14].

Biological context of Harzol

• Segregation analysis of the sitosterol levels showed that the phenotype of sitosterolemia was controlled by a rare autosomal recessive gene [15].
• Plasma cholesterol concentrations increased 120% in the sitosterol-infused rats and 29% in the untreated human homozygotes [16].
• We investigated hepatic cholesterol homeostasis in four homozygous sitosterolemic subjects from two unrelated families who showed enhanced absorption, diminished removal and increased tissue and plasma concentrations of sitosterol (24-ethyl cholesterol) [16].
• With recombinant high density lipoprotein particles, the esterification rate of cholesterol by LCAT was only 15% greater than for sitosterol [17].
• However, whereas FC induces caspase-dependent apoptosis through activation of the unfolded protein response and JNK, sitosterol-induced death is caspase-independent and involves neither the unfolded protein response nor JNK [5].

Anatomical context of Harzol

• As with FC loading, sitosterol-induced macrophage death requires sterol trafficking to the endoplasmic reticulum, and sitosterol-enriched endoplasmic reticulum membranes show evidence of membrane protein dysfunction [5].
• In support of this hypothesis, we show here that macrophages incubated with sitosterol-containing lipoproteins accumulate free sterols and undergo death in the absence of an ACAT inhibitor [5].
• More than 90% of these radiolabeled sterols underwent exchange at 37 degrees C with unlabeled sterols in vesicles over a period of 12-14 h in the presence of 2% (w/v) albumin. beta-[14C]Sitosterol exchange was characterized by biphasic exchange kinetics, indicative of two pools of sitosterol molecules in the cell membrane [18].
• Compared with ACAT1, ACAT2 selectively esterified cholesterol even when sitosterol was loaded into the microsomes [17].
• A recombinant StAR protein lacking the first N-terminal 62 amino acid residues that includes the mitochondrial targeting sequence was shown to stimulate the transfer of cholesterol and beta-sitosterol from liposomes to heat-treated mitochondria in a dose-, time-, and temperature-dependent manner [19].

Associations of Harzol with other chemical compounds

• Surprisingly, whereas the sesterterpenes (Delta(7(20))-haslenes) in R. setigera were made by the MVA pathway, as were the related triterpenoid rhizenes and desmosterol, in H. ostrearia the structurally similar Delta(6(17))-haslenes and the major sterol, 24-ethylcholest-5-en-3beta-ol, were instead biosynthesized by the MEP route [20].
• The incorporation of [1-13C]- and [2,3,4,5-13C4]1-deoxy-D-xylulose into beta-carotene, lutein, phytol, and sitosterol in a cell culture of Catharanthus roseus was analyzed by NMR spectroscopy [21].
• Since plant sterols are plentiful in vegetarian diets, we studied the effect of beta-sitosterol on colon tumor formation in rats treated with the carcinogen N-methyl-N-nitrosourea [22].
• It was shown that polar metabolites were formed by intermediate oxidation of the 3 beta-hydroxyl group (loss of 3H from 3 alpha-3H-labeled sitosterol) and that the most polar fraction did not contain a hydroxyl group at C7 (retention of 3H in 7 alpha,7 beta-3H2-labeled sitosterol) [23].
• Sitosterol-containing Lipoproteins Trigger Free Sterol-induced Caspase-independent Death in ACAT-competent Macrophages [5].

Gene context of Harzol

• ABCA1, however, may play a role in beta-sitosterol absorption [24].
• Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile [25].
• These effects were correlated with the impairment of [3H]AA release, cyclooxygenase-2 (COX-2) expression, and prostaglandin E(2)/leukotriene B(4) synthesis in RAW 264.7 cultures stimulated by PMA. beta-Sitosterol exerted its effects after 3-6 h of preincubation [26].
• The effect on ABCA1 and ApoAI expression was even stronger (5.7- and 2.6-fold, respectively) with beta-sitosterol-containing micelles [27].
• The effect of increased hepatic sitosterol on the regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol 7 alpha-hydroxylase in the rat and sitosterolemic homozygotes [16].

Analytical, diagnostic and therapeutic context of Harzol

• Concentrations of ezetimibe and its glucuronide in serum, urine, and feces, as well as cholesterol, lathosterol, and the plant sterols campesterol and sitosterol in serum, were quantified by use of liquid chromatography and gas chromatography with mass spectrometric detection [28].
• Plasma campesterol and sitosterol concentrations were higher (P < 0.01) in the NS group and sitosterol concentrations were lower (P < 0.01) in the SS group than in the control group [29].
• Changes in biliary and fecal bile acids in mice after treatments with diosgenin and beta-sitosterol [30].
• Human small intestine organ cultures were incubated with mixed micelles containing bile acid, phospholipid, and cholesterol or its nonabsorbable analogue, sitosterol; trace amounts of labeled cholesterol or sitosterol were added to the micelles [31].
• EZ and GLUC in serum, urine, and feces, and cholesterol, campesterol, and sitosterol in serum, were assayed using liquid chromatography (LC)-tandem mass spectrometry and LC-mass spectrometry methods, respectively [32].

References