desmosterol and Hyperlipoproteinemia-Type-II

To assess causes for insufficient cholesterol-lowering response to pravastatin and plant stanol esters in children with heterozygous familial hypercholesterolemia (HeFH).. Nine of 16 children with HeFH who had not reached normocholesterolemia (< or =194 mg/dL [< or =5 mmol/L]) by 1 year after treatment (40 mg pravastatin and plant stanol ester) were called nonresponders. The 7 remaining children were responders. Serum noncholesterol sterol ratios (10(2) x mmol/mol of cholesterol), surrogate estimates of cholesterol absorption (cholestanol, campesterol, sitosterol) and synthesis (desmosterol and lathosterol), were studied at study baseline (on plant stanol esters) and during combination therapy with pravastatin and plant stanol esters.. Pravastatin decreased the serum levels of cholesterol and cholesterol synthesis markers, and increased the ratios of cholesterol absorption markers. Compared with the responders, the nonresponders had higher study baseline (on plant stanol esters) serum cholesterol concentrations (299 +/- 39 vs 251 +/- 35 mg/dL [7.7 +/- 1.0 vs 6.5 +/- 0.9 mmol/L]; P <.001) and higher respective ratios of campesterol (371 +/- 99 vs 277 +/- 67 10(2) x mmol/mol of cholesterol; P = .049) and sitosterol (176 +/- 37 vs 126 +/- 24 10(2) x mmol/mol of cholesterol; P = .008). The higher the ratio of cholestanol at study baseline, the smaller the 1-year percent reduction in cholesterol (r = .556; P = .025).. Pravastatin treatment increases the markers of cholesterol absorption and decreases those of cholesterol synthesis in HeFH during simultaneous inhibition of cholesterol absorption. Combined inhibition of cholesterol absorption and synthesis may not normalize serum lipids in those patients with the highest cholesterol levels, especially if signs of enhanced cholesterol absorption are detectable.

Topics: Adolescent; Anticholesteremic Agents; Child; Cholestanol; Cholesterol; Desmosterol; Female; Heterozygote; Humans; Hyperlipoproteinemia Type II; Male; Phytosterols; Pravastatin; Sitosterols; Triglycerides

Topics: Cholesterol; Cholesterol, LDL; Desmosterol; Humans; Hypercholesterolemia; Hyperlipidemias; Hyperlipoproteinemia Type II; Lipids; Sitosterols; Squalene; Stigmasterol

The hypocholesterolaemic effect of pravastatin 40 mg and lovastatin 40 mg daily has been compared in patients with familial hypercholesterolaemia (FH). Administration of the two drugs was separated by a three-month washout period. The reduction in total serum cholesterol after 1,2 and 4 weeks of treatment was similar after pravastatin (-23%, -32% and -32%) and lovastatin (-23%, -30% and -31%). The serum concentrations of LDL cholesterol were similarly reduced, whilst triglycerides, other lipoproteins, cholestanol and squalene were not altered. The reductions in the serum levels of the cholesterol precursor sterols, delta 8-cholesterol, desmosterol and lathosterol were not significantly different after either drug. The lack of difference suggests that cholesterol synthesis was equally inhibited by the two agents. In addition, the serum content of the plant sterols campesterol and sitosterol tended to be equally increased. The comparability of the increases suggests that the absorption and biliary elimination of the two sterols were equally affected by the two statins. Thus, no difference was found between the effects of pravastatin and lovastatin on the serum levels and metabolic precursors of cholesterol in FH during four weeks of treatment.

Topics: Adult; Aged; Cholesterol; Cholesterol, LDL; Desmosterol; Female; Humans; Hyperlipoproteinemia Type II; Isomerism; Lovastatin; Male; Middle Aged; Phytosterols; Pravastatin; Sitosterols; Triglycerides

The hypocholesterolemic and metabolic effects of ketoconazole (400 mg/d) alone (inhibits cholesterol synthesis at 14 alpha-demethylation of lanosterol) and in combination with cholestyramine (12 g/d), were studied in nine women with xanthomatous familial hypercholesterolemia (FH). In addition to serum lipoprotein levels, cholesterol precursors, fecal steroids, and cholesterol absorption were measured before and during the drug treatments. Serum total and low-density lipoprotein (LDL)-cholesterol were reduced by 19% and 22% with ketoconazole; the respective changes were 16% and 21% for cholestyramine, and 31% and 41% for the combined ketoconazole and cholestyramine treatment. Serum triglycerides, very-low-density lipoprotein (VLDL)-and high-density lipoprotein (HDL)-cholesterol levels were unchanged. Accumulation of cholesterol precursors in serum suggested that ketoconazole inhibited cholesterol synthesis at delta 8-sterol levels. Serum and fecal lanosterols were increased up to 20-fold and were interrelated. Their maximal serum level was 1.3 mg/DL and the lanosterol contents were negatively related to the serum cholesterol levels. The intestinal absorption and total intestinal fluxes of cholesterol were reduced by 27% and 29%. Cholesterol and bile acid synthesis were decreased by ketoconazole only when combined with cholestyramine. The synthesis of chenodeoxycholic acid was deeply hindered by ketoconazole. Thus, ketoconazole efficiently lowers serum total and LDL-cholesterol levels in FH patients, probably by inhibiting cholesterol synthesis and absorption. Effective biliary and fecal outputs of cholesterol precursors prevent their excessive increase in serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Cholesterol; Cholestyramine Resin; Desmosterol; Drug Therapy, Combination; Feces; Female; Humans; Hyperlipoproteinemia Type II; Intestinal Absorption; Ketoconazole; Lanosterol; Lipids; Lipoproteins; Middle Aged; Squalene

To evaluate the value of plasma cholesterol precursor sterols in the detection of bile acid malabsorption we measured these sterols in 14 familial hypercholesterolaemia patients, seven with and seven without an ileal exclusion. In the operated subjects bile acid malabsorption had induced a 4.8-fold increase in cholesterol synthesis, accompanied by a 1.9-5.1-fold increase in the plasma content of the eight cholesterol precursor sterols studied. There was no overlap between the two groups in any of these sterols, when total and free sterols were considered, and only three of the esterified sterols overlapped. The tri- and dimethyl sterols were mostly unesterified, monomethyl sterols modestly esterified and the demethylated sterols, especially desmosterol, were mainly esterified. The plasma lathosterol content segregated most clearly the patients with bile acid malabsorption from the controls. The lowest lathosterol value of the operated patients was 2.5-fold higher than the highest value of the control patients. Because lathosterol is the most abundant of the plasma cholesterol precursor sterols and is relatively easy to quantitate, it is suggested that plasma lathosterol measurement can be used in the detection of bile acid malabsorption.

Topics: Adult; Bile Acids and Salts; Cholestadienols; Cholestenes; Cholesterol; Desmosterol; Feces; Female; Humans; Hyperlipoproteinemia Type II; Ileum; Lanosterol; Male; Middle Aged; Squalene

The human bile contains several noncholesterol sterols, of which the cholesterol precursor sterols are quantitatively the most important. Detailed data on factors that regulate the amount of these sterols in the bile have not been available. In this study the effect of chronic stimulation of cholesterol synthesis on biliary cholesterol precursor sterol content was evaluated by measuring these sterols in the bile and plasma of familial hypercholesterolemia patients with and without ileal exclusion. In the operated patients cholesterol synthesis was fivefold increased, and cholesterol precursor sterols comprised 7% of the biliary sterols, compared with 2% in the control patients. All eight biliary cholesterol precursor sterols measured were significantly increased in the operated patients, and the increase was similar to that of respective sterols in plasma. Hence, the biliary methyl sterols were increased 2 to 4 times, the lathosterols 5 times, but demosterol only 1.5 times. The proportion of lathosterol was higher and that of lanosterol lower in the bile of the operated than in that of the control patients. We conclude that activation of cholesterol synthesis increases the amount of cholesterol precursor sterols in the bile in proportion to the increase of these sterols in plasma and to the overall cholesterol synthesis.

Topics: Bile; Cholestenes; Cholesterol; Desmosterol; Female; Humans; Hyperlipoproteinemia Type II; Ileum; Lanosterol; Male; Middle Aged

The true rate of cholesterogenesis in cultured monocyte-macrophages was determined from the incorporation of [2-14C]acetate into cholesterol, using the desmosterol (cholesta-5,24-dien-3 beta-ol) that accumulated in the presence of the drug triparanol to estimate the specific radioactivity of the newly formed sterols. It was shown that this procedure could be successfully adapted for use with cultured monocytes despite the accumulation of other unidentified biosynthetic intermediates. In cells maintained in 20% (v/v) whole serum approx. 25% of the sterol carbon was derived from exogenous acetate. Cholesterol synthesis was as high in normal cells as in cells from homozygous familial hypercholesterolaemic (FH) subjects and accounted for 50% of the increase in cellular cholesterol. The addition of extra low-density lipoprotein (LDL) reduced cholesterol synthesis, apparently through a decrease in the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). When incubated in lipoprotein-deficient serum some cells did not survive, but those that remained showed a normal increase in protein content; the amount of cellular protein and cholesterol in each well did not increase and cholesterol synthesis was reduced by over 80%. HMG-CoA reductase activity fell less dramatically and the proportion of sterol carbon derived from exogenous acetate increased, suggesting that the low rate of cholesterogenesis with lipoprotein-deficient serum was due to a shortage of substrate. The results indicate that under normal conditions monocyte-macrophages obtain cholesterol from endogenous synthesis rather than through receptor-mediated uptake of LDL, and that synthesis together with non-saturable uptake of LDL provides the majority of the cholesterol required to support growth.

Topics: Acetates; Acetic Acid; Cells, Cultured; Cholesterol; Desmosterol; Humans; Hyperlipoproteinemia Type II; Lipoproteins, LDL; Macrophages; Monocytes; Proteins; Triparanol