desmosterol and lathosterol

Non-cholesterol sterols are validated biomarkers for intestinal cholesterol absorption and endogenous cholesterol synthesis. However, their use in metabolic disturbances has not been systematically explored. Therefore, we conducted a systematic review to provide an overview of non-cholesterol sterols as markers for cholesterol metabolism in different metabolic disorders. Potentially relevant studies were retrieved by a systematic search of three databases in July 2018 and ninety-four human studies were included. Cholesterol-standardized levels of campesterol, sitosterol and cholestanol were collected to reflect cholesterol absorption and those of lathosterol and desmosterol to reflect cholesterol synthesis. Their use as biomarkers was examined in the following metabolic disorders: overweight/obesity (

Topics: Biomarkers; Cardiovascular Diseases; Cholesterol; Desmosterol; Diabetes Mellitus; Humans; Intestinal Absorption; Intestinal Diseases; Kidney Diseases; Liver Diseases; Metabolic Diseases; Obesity; Overweight; Phytosterols; Sitosterols; Sterols

Human studies have shown diurnal rhythms of cholesterol and bile acid synthesis, but a better understanding of the role of the circadian system in cholesterol homeostasis is needed for the development of targeted interventions to improve metabolic health. Therefore, we performed a systematic literature search on the diurnal rhythms of cholesterol synthesis and absorption markers and of bile acid synthesis markers. We also examined the diurnal rhythms of the cholesterol synthesis markers lathosterol and desmosterol, and of the cholesterol absorption markers cholestanol, campesterol, and sitosterol in serum samples from the Bispebjerg study. These samples were collected every three hours over a 24-hour period in healthy males (

Topics: Adolescent; Adult; Bile Acids and Salts; Biomarkers; Cholestanol; Cholesterol; Circadian Rhythm; Desmosterol; Female; Humans; Intestinal Absorption; Male; Middle Aged; Phytosterols; Sitosterols; Time Factors; Young Adult

Subjects with high HDL-C show elevated plasma markers of cholesterol absorption and reduced markers of cholesterol synthesis. We evaluated the effect of dalcetrapib, a cholesteryl ester transfer protein modulator, on markers of cholesterol homeostasis in healthy subjects.. Dalcetrapib was administered daily with or without ezetimibe in a randomized, open-label, crossover study in 22 healthy subjects over three 7-day periods: dalcetrapib 900 mg, ezetimibe 10mg, dalcetrapib 900 mg plus ezetimibe 10mg. Plasma non-cholesterol sterols lathosterol and desmosterol (cholesterol synthesis markers) and campesterol, β-sitosterol and cholestanol (intestinal cholesterol absorption markers) were measured. A hamster model was used to compare the effect of dalcetrapib and torcetrapib with or without ezetimibe on these markers and determine the effect of dalcetrapib on cholesterol absorption.. Dalcetrapib increased campesterol, β-sitosterol, and cholestanol by 27% (p = 0.001), 32% (p < 0.001), and 12% (p = 0.03), respectively, in man (non-cholesterol sterol/cholesterol ratio). Dalcetrapib+ezetimibe reduced campesterol by 11% (p = 0.02); β-sitosterol and cholestanol were unaffected. Lathosterol and desmosterol were unchanged with dalcetrapib, but both increased with ezetimibe alone (56-148%, p < 0.001) and with dalcetrapib + ezetimibe (32-38%, p < 0.001). In hamsters, dalcetrapib and torcetrapib increased HDL-C by 49% (p = 0.04) and 72% (p = 0.003), respectively. Unlike torcetrapib, dalcetrapib altered cholesterol homeostasis towards increased markers of cholesterol absorption; cholesterol synthesis markers were unaffected by either treatment. Dalcetrapib did not change plasma (3)H-cholesterol level but increased (3)H-cholesterol in plasma HDL vs non-HDL, after oral dosing of labeled cholesterol.. Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis.

Topics: Amides; Animals; Anticholesteremic Agents; Azetidines; Biomarkers; Cholestanol; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cricetinae; Cross-Over Studies; Desmosterol; Esters; Ezetimibe; Homeostasis; Humans; Intestinal Absorption; Lipid Metabolism; Male; Mesocricetus; Models, Animal; Phytosterols; Quinolines; Sitosterols; Sulfhydryl Compounds; Switzerland

Cholesterol homeostasis, defined as the balance between absorption and synthesis, influences circulating cholesterol concentrations and subsequent coronary heart disease (CHD) risk. Statin therapy targets the rate-limiting enzyme in cholesterol biosynthesis and is efficacious in lowering CHD events and mortality. Nonetheless, CHD events still occur in some treated patients. To address differences in outcome during pravastatin therapy (40 mg/day), plasma markers of cholesterol synthesis (desmosterol, lathosterol) and fractional cholesterol absorption (campesterol, sitosterol) were measured, baseline and on treatment, in the Prospective Study of Pravastatin in the Elderly at Risk trial participants with (cases, n = 223) and without (controls, n = 257) a CHD event. Pravastatin therapy decreased plasma LDL-cholesterol and triglycerides and increased HDL-cholesterol concentrations to a similar extent in cases and controls. Decreased concentrations of the cholesterol synthesis markers desmosterol (-12% and -11%) and lathosterol (-50% and -56%) and increased concentrations of the cholesterol absorption markers campesterol (48% and 51%) and sitosterol (25% and 26%) were observed on treatment, but the magnitude of change was similar between cases and controls. These data suggest that decreases in cholesterol synthesis in response to pravastatin treatment were accompanied by modest compensatory increases in fractional cholesterol absorption. The magnitude of these alterations were similar between cases and controls and do not explain differences in outcomes with pravastatin treatment.

Topics: Aged; Aged, 80 and over; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Desmosterol; Female; Homeostasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Phytosterols; Pravastatin; Sitosterols; Triglycerides

We hypothesized that (I) certain features in cholesterol metabolism at baseline could predict a response to statins, (II) good and poor responders to statins have a differential profile of serum and fecal sterols and (III) serum non-cholesterol sterols reflect cholesterol metabolism on statins.. We examined serum lipids, serum and fecal cholesterol, cholesterol precursors, cholestanol and phytosterols and cholesterol metabolism among 20 hypercholesterolemic men at baseline and on 16-wk simvastatin/fluvastatin treatment. At baseline, the mean of serum cholestanol/cholesterol was 11% lower but those of lathosterol/cholesterol, lathosterol/cholestanol, desmosterol/cholesterol, desmosterol/cholestanol were 36-65% higher among good than poor responders (p<0.05 for each). On statins, reductions in ratios of serum precursor sterols and increases of absorption sterols were 1.8-2.9 times higher among good than poor responders (p<0.05 for each). In the whole study group, changes from baseline values of lathosterol/cholestanol were related to those of cholesterol and LDL-C in serum (r=+0.513 and +0.451, p=0.021 and 0.046, respectively). Serum lathosterol ratios to cholesterol, cholestanol and sitosterol consistently reflected a ratio of cholesterol synthesis (mg/d/kg)/fractional cholesterol absorption (%) (r-range +0.456 to +0.727, p<0.05 for each).. Low serum baseline ratios to cholesterol of lathosterol, cholestenol and desmosterol, but a high ratio of cholestanol predicted a poor response to statins. Good responders were characterized by more profound reductions of serum and fecal (lathosterol) precursor sterols and increases of serum absorption marker sterol ratios on statins. Serum surrogate sterol markers of cholesterol metabolism were applicable in evaluating cholesterol absorption and synthesis also on statins.

Topics: Cholestanol; Cholesterol; Desmosterol; Double-Blind Method; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Lipids; Male; Middle Aged; Simvastatin; Sterols

Clinical safety of consuming plant stanol ester spreads during pregnancy and lactation, the impact on maternal and infant serum and breast-milk cholesterol and the ratios (micromol/mmol of cholesterol) of synthesis and absorption markers were evaluated. Pregnant women (n 21) were randomised to control and dietary intervention groups, the intervention including advice to follow a balanced diet and to consume spreads enriched with plant stanol esters. Participants were followed during and after pregnancy and their infants up to 1 year of age. A mean 1.1 (sd 0.4) g consumption of plant stanols during pregnancy and 1.4 (sd 0.9) g 1 month post-partum increased sitostanol and the markers for cholesterol synthesis, lathosterol, lathosterol/campesterol and lathosterol/sitosterol, and reduced a marker for cholesterol absorption, campesterol, in maternal serum. In breast milk, desmosterol was lower in the intervention group, while no differences were detected between the groups in infants' serum. Plant stanol ester spread consumption had no impact on the length of gestation, infants' growth or serum beta-carotene concentration at 1 and 6 months of age, but the cholesterol-adjusted serum beta-carotene concentration was lowered at 1 month in the intervention group. Plant stanol ester spread consumption appeared safe in the clinical setting, except for potential lowering of infants' serum beta-carotene concentration, and was reflected in the markers of cholesterol synthesis and absorption in mothers' serum, encouraging further studies in larger settings.

Topics: Analysis of Variance; beta Carotene; Biomarkers; Child Development; Cholesterol; Desmosterol; Female; Humans; Infant; Infant, Newborn; Lactation; Margarine; Milk, Human; Phytosterols; Pregnancy; Safety; Sitosterols; Squalene

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

Carbohydrate modification based on rye bread and pasta enhances early insulin secretion in subjects with the metabolic syndrome.. Because the actions of insulin and cholesterol metabolism are interrelated, the question is raised of whether it is possible to alter cholesterol metabolism by means of dietary carbohydrate modification.. We investigated the 12-wk effects of dietary carbohydrate modification on cholesterol synthesis and absorption by measuring the ratios of surrogate markers of precursor (cholestenol, desmosterol, and lathosterol) and absorption (cholestanol and plant sterols) sterols to cholesterol and their association to glucose metabolism in 74 subjects with the metabolic syndrome. The subjects were randomly assigned to diets with rye bread and pasta (RPa) or oat, wheat bread, and potato (OWPo) as the main carbohydrate source (34% and 37% of energy intake, respectively).. During the study, serum cholesterol concentrations remained unchanged. Cholesterol synthesis was lower (6-10% for cholestenol and lathosterol; P < 0.05) and absorption higher (9%; P < 0.05 for sitosterol) with the OWPo diet than at baseline. With the RPa diet, cholesterol absorption was lower and synthesis higher than with the OWPo diet. The increment in the glucose area under the curve with the RPa diet was positively related to baseline cholesterol synthesis (eg, lathosterol; r = 0.480, P < 0.05) and negatively to absorption (for cholestanol; r = -0.520, P < 0.05). In the combined group, the changes in the cholestanol ratio and the insulinogenic index were interrelated (r = -0.464, P < 0.001).. Carbohydrate modifications had dissimilar effects on cholesterol metabolism. Consumption of RPa, as compared with OWPo, may be clinically more favorable because it seems to inhibit the absorption of cholesterol, a factor crucial in the development of arterial atherosclerosis.

Topics: Adult; Aged; Area Under Curve; Avena; Blood Glucose; Cholesterol; Desmosterol; Dietary Carbohydrates; Female; Glycemic Index; Humans; Insulin; Insulin Secretion; Intestinal Absorption; Male; Metabolic Syndrome; Middle Aged; Secale; Solanum tuberosum; Triticum

The HDL Atherosclerosis Treatment Study (HATS) demonstrated a clinical benefit in coronary artery disease patients with low HDL cholesterol (HDL-C) levels treated with simvastatin and niacin (S-N) or S-N plus antioxidants (S-N+A) compared with antioxidants alone or placebo. Angiographically documented stenosis regressed in the S-N group but progressed in all other groups. To assess the mechanism(s) responsible for these observations, surrogate markers of cholesterol absorption and synthesis were measured in a subset of 123 HATS participants at 24 months (on treatment) and at 38 months (off treatment). Treatment with S-N reduced desmosterol and lathosterol levels (cholesterol synthesis indicators) 46% and 36% (P < 0.05), respectively, and elevated campesterol and beta-sitosterol levels (cholesterol absorption indicators) 70% and 59% (P < 0.05), respectively, relative to placebo and antioxidant but not S-N+A. Treatment with antioxidants alone had no significant effect. Combining S-N with antioxidants reduced desmosterol and lathosterol by 37% and 31%, and elevated campesterol and beta-sitosterol levels by 54% and 46%, but differences did not attain significance. Mean change in percent stenosis was positively associated with a percent change in lathosterol (r = 0.26, P < 0.005) and negatively associated with a percent change in beta-sitosterol (r = -0.21, P < 0.01). These data suggest that changes in stenosis were attributable, in part, to changes in cholesterol metabolism.

Topics: Antioxidants; Cholesterol; Constriction, Pathologic; Coronary Artery Disease; Desmosterol; Drug Therapy, Combination; Female; Humans; Hypolipidemic Agents; Lipoproteins, HDL; Male; Middle Aged; Niacin; Simvastatin; 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

Coronary patients with low baseline ratios of serum cholestanol and plant sterols to cholesterol (indicating low cholesterol absorption) but not those with high ratios (high absorption) experienced reduced recurrences of coronary events during simvastatin treatment in the Scandinavian Simvastatin Survival Study. Thus, in the present study, serum cholesterol, its precursor sterols (reflecting cholesterol synthesis), plant sterols (campesterol and sitosterol), and cholestanol were measured before and during a 5-year period of placebo treatment (n=433) and simvastatin treatment (n=434) in patients from a subgroup of the Scandinavian Simvastatin Survival Study to determine whether changes in cholesterol synthesis and serum levels were related to cholesterol absorption. Serum cholesterol level was unchanged, the ratios of cholesterol precursor sterols to cholesterol were decreased, and the ratios of plant sterols to cholesterol were increased in relation to increasing baseline ratios of cholestanol quartiles. The latter predicted 5-year ratios and simvastatin-induced reductions of the precursor sterols, with the lowering of the ratios (cholesterol synthesis reduction) being almost twice higher in the lowest versus the highest quartile. The ratios of plant sterols, especially campesterol, to cholesterol were markedly increased during simvastatin treatment, mostly in subjects with the highest baseline cholestanol quartiles. Simvastatin reduced serum cholesterol more (P=0.003) in the lowest versus the highest cholestanol quartile during the 5-year treatment period. The results show for the first time that baseline cholesterol metabolism, measured by serum noncholesterol sterols, predicts the effectiveness of simvastatin in reducing cholesterol synthesis and serum levels of cholesterol. The drug suppresses the synthesis of cholesterol markedly more effectively in subjects with high than with low baseline synthesis but reduces respective serum cholesterol levels less markedly than synthesis. Subjects with high cholesterol absorption and low synthesis may need a combination therapy to lower more effectively their serum cholesterol levels and prevent an increase in the levels of plant sterols.

Topics: Anticholesteremic Agents; Body Weight; Cholestanol; Cholesterol; Coronary Disease; Desmosterol; Humans; Phytosterols; Placebos; Simvastatin; Sitosterols; Sterols

Our aim was to investigate whether intestinal binding of bile acids by guar gum, a dietary fibre, relieves cholestasis and pruritus in intrahepatic cholestasis of pregnancy.. Forty-eight pregnant women with cholestasis and pruritus were randomized double-blind to guar gum and placebo until the time of delivery, and 20 healthy pregnant women were used as control subjects. The pruritus score and serum bile acids, lipids and non-cholesterol sterols were measured at baseline, at least 2 weeks after treatment, just before delivery and up to 4 weeks after delivery.. The increase in serum bile acids and worsening of pruritus were prevented by guar gum in relation to placebo (P < 0.05). Serum cholesterol was unchanged, but increased cholesterol precursor sterol values suggested that cholesterol synthesis was increased by guar gum. Serum cholestanol proportion, an indicator of cholestasis, was related to pruritus but was unaffected by guar gum.. We conclude that in intrahepatic cholestasis of pregnancy and pruritus, guar gum treatment is beneficial in relieving pruritus, even although indicators of cholestasis are only partially reduced.

Topics: Administration, Oral; Adult; Cholestanol; Cholestasis, Intrahepatic; Cholesterol; Desmosterol; Dietary Fiber; Double-Blind Method; Female; Galactans; Humans; Mannans; Phytosterols; Plant Gums; Pregnancy; Pregnancy Complications; Pruritus; Random Allocation; Sitosterols

It is controversial whether atherosclerosis is linked to increased intestinal cholesterol absorption or synthesis in humans. The aim of the present study was to relate atherosclerosis to the measurements of plasma markers of cholesterol synthesis (desmosterol, lathosterol) and absorption (campesterol, sitosterol). In healthy male (n=344), non-obese, non-diabetics, belonging to the city of São Paulo branch of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), we measured in plasma these non-cholesterol sterol markers, together with their anthropometric, dietary parameters, traditional atherosclerotic risk factors, and blood chemistry, coronary arterial calcium score (CAC), and ultrasonographically measured common carotid artery intima-media thickness (CCA-IMT). Cases with CAC>zero had the following parameters higher than cases with CAC = zero: age, waist circumference (WC), plasma total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and non-high density lipoprotein-cholesterol (non HDL-C). Plasma desmosterol and campesterol, duly corrected for TC, age, body mass index (BMI), waist circumference (WC), hypertension, smoking, and the homeostasis model assessment-insulin resistance (HOMA-IR) correlated with CAC, but not with CCA-IMT. The latter related to increased age, BMI, waist circumference (WC), and systolic blood pressure (SBP). Plasma HDL-C concentrations did not define CAC or CCA-IMT degrees, although in relation to the lower tertile of HDL-C in plasma the higher tertile of HDL-C had lower HOMA-IR and concentration of a cholesterol synthesis marker (desmosterol). Present work indicated that increased cholesterol synthesis and absorption represent primary causes of CAD, but not of the common carotid artery atherosclerosis.

Topics: Adult; Aged; Atherosclerosis; Biomarkers; Body Mass Index; Brazil; Calcium; Carotid Artery, Common; Carotid Intima-Media Thickness; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Vessels; Cross-Sectional Studies; Desmosterol; Female; Humans; Intestinal Absorption; Intestinal Mucosa; Longitudinal Studies; Male; Middle Aged; Phytosterols; Prospective Studies; Sitosterols; Tomography, X-Ray Computed; Ultrasonography

We developed a simple and robust liquid chromatographic/mass spectrometric method (LC-MS) for the quantitative analysis of 10 sterols from the late part of cholesterol synthesis (zymosterol, dehydrolathosterol, 7-dehydrodesmosterol, desmosterol, zymostenol, lathosterol, FFMAS, TMAS, lanosterol, and dihydrolanosterol) from cultured human hepatocytes in a single chromatographic run using a pentafluorophenyl (PFP) stationary phase. The method also avails on a minimized sample preparation procedure in order to obtain a relatively high sample throughput. The method was validated on 10 sterol standards that were detected in a single chromatographic LC-MS run without derivatization. Our developed method can be used in research or clinical applications for disease-related detection of accumulated cholesterol intermediates. Disorders in the late part of cholesterol synthesis lead to severe malformation in human patients. The developed method enables a simple, sensitive, and fast quantification of sterols, without the need of extended knowledge of the LC-MS technique, and represents a new analytical tool in the rising field of cholesterolomics.

Topics: Cholecalciferol; Cholesterol; Chromatography, Liquid; Desmosterol; Fluorobenzenes; Gene Deletion; Hep G2 Cells; Hepatocytes; Humans; Lanosterol; Mass Spectrometry; Phenols; Reproducibility of Results; Sterols

The dynamics of cholesterol homeostasis and the development of cardiovascular disease (CVD) are complex and multifactorial, to which adds individual variability in the proportion of cholesterol from exogenous versus endogenous sources. The aim of this study was to undertake the first characterization of cholesterol absorption and synthesis profiles in Portuguese hypercholesterolemic adults through the quantification of surrogate markers, and the analysis of the predictive value of age and sex on the cholesterol homeostasis biomarkers.. Serum samples for the measurement of lipid profiles and cholesterol homeostasis markers were obtained for 100 men and 112 women, aged 30-65, with TC ≥ 5.2 mmol/L (~200mg/dL) and/or LDL-C ≥ 2.6 mmol/L (~100mg/dL), none of whom were on any lipid-lowering therapy.. Overall, sex-specific significant differences were observed in the cholesterol homeostasis markers and lipid profiles; women had lower cholesterol synthesis marker concentrations (P<0.01 for lathosterol) and lipid parameters (except for HDL-C concentrations). Age-related significant differences were also found, including higher concentrations of cholesterol absorption markers in association with increasing age.. In our study, the predictors of higher levels of cholesterol absorption markers were higher age and female gender.

Topics: Adult; Age Factors; Aged; Biomarkers; Cholestanol; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cross-Sectional Studies; Desmosterol; Diet; Female; Homeostasis; Humans; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Portugal; Sex Factors; Sitosterols; Triglycerides

The inflammatory component of non-alcoholic steatohepatitis (NASH) can lead to irreversible liver damage. Therefore there is an urgent need to identify novel interventions to combat hepatic inflammation. In mice, omitting cholesterol from the diet reduced hepatic inflammation. Considering the effects of plant sterol/stanol esters on cholesterol metabolism, we hypothesized that plant sterol/stanol esters reduces hepatic inflammation. Indeed, adding plant sterol/stanol esters to a high-fat-diet reduced hepatic inflammation as indicated by immunohistochemical stainings and gene expression for inflammatory markers. Finally, adding sterol/stanol esters lowered hepatic concentrations of cholesterol precursors lathosterol and desmosterol in mice, which were highly elevated in the HFD group similarly as observed in severely obese patients with NASH. In vitro, in isolated LPS stimulated bone marrow derived macrophages desmosterol activated cholesterol efflux whereas sitostanol reduced inflammation. This highly interesting observation that plant sterol/stanol ester consumption leads to complete inhibition of HFD-induced liver inflammation opens new venues in the treatment and prevention of hepatic inflammation.

Topics: Animals; Cholesterol; Desmosterol; Dietary Fats; Female; Humans; Inflammation; Liver; Macrophages; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Phytosterols

Two recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL.. Markers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001).. The present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.

Topics: Adult; Biomarkers; Cholesterol; Cohort Studies; Desmosterol; Family; Female; Humans; Hyperlipidemia, Familial Combined; Isomerism; Male; Middle Aged; Models, Biological; Multivariate Analysis; Netherlands; Proprotein Convertase 9; Proprotein Convertases; Regression Analysis; Reproducibility of Results; Serine Endopeptidases; Up-Regulation

Phytosterols (PS; β-sitosterol and campesterol) and cholesterol precursors (CP; desmosterol and lathosterol) have been suggested as important biochemical markers of cholesterol intestinal absorption and liver biosynthesis, respectively. Given that these compounds appear in human blood in low amounts, sensitive and accurate methodology is required, such as gas chromatography-mass spectrometry (GC-MS) the most frequently used. One of the most critical factors of the GC analytical determination is the step of derivatization. Thus, the main objective of the present study was compare and select the better (one out of three) silylation mixtures as follows: N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide/ammonium iodide (MTBSTFA:NH(4)I), N-O-bis-(trimethylsilyl) trifluoroacetamide/trimethylchlorosilane (BSTFA:TMCS), and N-methyl-N-(trimethylsilyl)-trifluoroacetamide/1,4-dithioerythritol/trimethyliodosilane (MSTFA:DTE:TMIS). The results of this study are discussed and accompanied by a brief review on the importance and principles of derivatization process, specifically in silylation reactions in GC-MS sterols analyses. Furthermore, a scrutiny of some published results is presented, along with additional information about mass spectral data of these potentially useful compounds. Interestingly, the results of the study showed that from the three validated methodologies, the selected one, based on the best relation specificity/sensibility, is MSTFA:DTE:TMIS. With this silylation procedure for simultaneous determination of PS and CP in human serum by GC-MS in selected ion monitoring (SIM) mode, good linearity (r(2)≥0.931), precision (repeatability ranging from 0.92 to 3.91 CV and intermediate precision ranging from 5.12 to 6.33) and recoveries (≥93.6%) were obtained. Thus, it proved to be a helpful methodology in the quantification of predominant serum cholesterol origin in each patient.

Topics: Acetamides; Cholesterol; Desmosterol; Dithioerythritol; Fluoroacetates; Gas Chromatography-Mass Spectrometry; Humans; Indicators and Reagents; Linear Models; Organosilicon Compounds; Phytosterols; Reproducibility of Results; Sensitivity and Specificity; Trifluoroacetic Acid; Trimethylsilyl Compounds

Familial combined hyperlipidemia (FCH) is a common familial lipid disorder characterized by increases in plasma total cholesterol, triglyceride, and apolipoprotein B-100 levels. In light of prior metabolic and genetic research, our purpose was to ascertain whether FCH cases had significant abnormalities of plasma markers of cholesterol synthesis and absorption as compared to unaffected kindred members.. Plasma levels of squalene, desmosterol, and lathosterol (cholesterol synthesis markers) and campesterol, sitosterol, and cholestanol (cholesterol absorption markers) were measured by gas-liquid chromatography in 103 FCH patients and 240 normolipidemic relatives (NLR). Squalene, desmosterol, and lathosterol levels were 6% (0.078), 31%, (P<0.001) and 51% (P<0.001) higher in FCH as compared to NLR, and these differences were especially pronounced in women. An interaction with obesity was also noted for a subset of these markers. We did not observe any apparent differences for the cholesterol absorption markers among FCH patients and NLR.. Our data indicate that both men and women with FCH have alterations in the cholesterol synthesis pathway, resulting in 51% higher levels of lathosterol (and additionally desmosterol in women). Plasma levels of the cholesterol precursor sterol squalene were only slightly increased (6%), suggesting enhanced conversion of squalene to lathosterol in this disorder.

Topics: Adult; Aged; Biomarkers; Cholestanol; Cholesterol; Desmosterol; Female; Humans; Hyperlipidemia, Familial Combined; Intestinal Absorption; Male; Middle Aged; Phytosterols; Sex Characteristics; Sitosterols; Squalene

Cerebral and extracerebral cholesterol metabolism are altered in Alzheimer's disease (AD) as indicated by reduced plasma levels of the cholesterol elimination products 24S-hydroxycholesterol, which is of cerebral origin, and of 27-hydroxycholesterol, which is formed extracerebrally. However, it has to be evaluated, if changes of cholesterol metabolism in the whole body or in the CNS are exclusively due to the altered elimination of cholesterol or are also due to altered de novo synthesis in AD. We investigated CSF and plasma levels of cholesterol and of its precursors lanosterol, lathosterol and desmosterol in AD patients and non-demented controls. We found CSF levels of cholesterol (p=0.011), absolute levels of all investigated cholesterol precursors (each p<0.001) and ratios of cholesterol precursors/cholesterol (each <0.01) to be lower in AD patients as compared to controls. In plasma, the absolute levels of lanosterol (p=0.026) and lathosterol (p<0.001) and the ratio of lathosterol/cholesterol (p=0.002) but none of the other investigated parameters were reduced in AD patients (p>0.1). Furthermore, ratios of desmosterol/lathosterol in CSF (p=0.023) and plasma (p=0.009) were higher in AD patients as compared to controls. Our data support the hypothesis that cholesterol metabolism is altered in AD and further suggest that especially cholesterol de novo synthesis within the CNS of AD patients might be reduced. These findings raise doubt on a beneficial effect of cholesterol lowering treatment in manifest AD.

Topics: Aged; Aged, 80 and over; Alleles; Alzheimer Disease; Apolipoprotein E4; Case-Control Studies; Cholesterol; Desmosterol; Female; Gene Frequency; Humans; Lanosterol; Male; Middle Aged; Models, Biological

Small intestine essentially regulates cholesterol homeostasis.. To evaluate cholesterol metabolism in short bowel syndrome (SBS).. Cholesterol precursors (e.g., cholestenol, desmosterol and lathosterol) and plant sterols (campesterol and sitosterol), respective markers of cholesterol synthesis and absorption, were determined in SBS patients (n=12) an average of 31 months after weaning off parenteral nutrition and in age-matched controls (n=80).. Among patients, serum cholesterol precursor sterol to cholesterol ratios were 2-10 times higher (P<0.0001 for each). Those without any remaining ileum had 1.2-2.8 times higher precursor sterol to cholesterol ratios than those with an ileal remnant (P<0.05 for each). Serum cholesterol concentration, campesterol/cholesterol and campesterol/sitosterol were 34-39% lower (P<0.05 for each) in relation to controls. Bile acid absorption was markedly impaired (2.4 (0.2-3.2)%). Plant sterol ratios reflected the absolute length of remaining jejunum (r=0.625-0.663), and precursor sterol ratios inversely that of ileum (r=-0.589 to 0.750, P<0.05 for all).. After weaning off parenteral nutrition, patients with pediatric onset SBS continue to have marked intestinal malabsorption of bile acids and moderate cholesterol malabsorption resulting in decreased serum cholesterol despite a marked compensatory increase in cholesterol synthesis.

Topics: Bile Acids and Salts; Child; Child, Preschool; Cholesterol; Desmosterol; Humans; Intestinal Absorption; Intestine, Small; Malabsorption Syndromes; Parenteral Nutrition; Phytosterols; Short Bowel Syndrome; Sterols; Time Factors

Our recent studies have focused on cholesterol synthesis in mouse models for 7-dehydrosterolreductase (DHCR7) deficiency, also known as Smith-Lemli-Opitz syndrome. Investigations of such mutants have relied on tissue and blood levels of the cholesterol precursor 7-dehydrocholesterol (7DHC) and its 8-dehydro isomer. In this investigation by gas chromatography/mass spectrometry (GC/MS) we have identified and quantified cholesterol and its precursors (7DHC, desmosterol, lathosterol, lanosterol and cholest-7,24-dien-3β-ol) in mouse hair. The components were characterized and their concentrations were compared to those found in mouse skin and serum. Hair appeared unique in that desmosterol was a major sterol component, almost matching in concentration cholesterol itself. In DHCR7 deficient mice, dehydrodesmosterol (DHD) was the dominant hair Δ(7) sterol. Mutant mouse hair had much higher concentrations of 7-dehydrosterols relative to cholesterol than did serum or tissue at all ages studied. The 7DHC/C ratio in hair was typically about sevenfold the value in serum or skin and the DHD/D ratio was 100× that of the serum 7DHC/C ratio. Mutant mice compensate for their DHCR7 deficiency with maturity, and the tissue and blood 7DHC/C become close to normal. That hair retains high relative concentrations of the dehydro precursors suggests that the apparent up-regulation of Dhcr7 seen in liver is slower to develop at the site of hair cholesterol synthesis.

Topics: Animals; Cholesterol; Dehydrocholesterols; Desmosterol; Disease Models, Animal; Gas Chromatography-Mass Spectrometry; Hair; Lanosterol; Mice; Mutation; Oxidoreductases Acting on CH-CH Group Donors; Skin; Smith-Lemli-Opitz Syndrome; Sterols

To show tracking of cholesterol metabolism, the ratios to cholesterol of e.g. serum cholestenol, desmosterol, and lathosterol, reflecting cholesterol synthesis, and cholestanol, campesterol, avenasterol and sitosterol, reflecting cholesterol absorption, were measured 21 years apart.. In random population samples initially comprising 12- (n=162), 15- (n=158), and 18-year-old (n=148) males participating in the Cardiovascular Risk in Young Finns Study, serum sterols and squalene were measured with gas-liquid chromatography in 1980 and 2001. Quartiles of cholestanol, indicating low to high cholesterol absorption, were defined from the cholestanol values in 1980. Serum cholesterol increased in the oldest age group only, but synthesis markers (except desmosterol) increased in all age groups after the follow-up (e.g. lathosterol, total population +47.3+/-2.6% (SE), P<0.001). Campesterol (+69.0+/-3.0%, P<0.001) and sitosterol increased, avenasterol was unchanged, and cholestanol decreased (-6.2+/-0.7%, P<0.001), respectively. The 1980 synthesis and absorption markers were interrelated with respective values 21 years later in all age groups and quartiles (e.g. lathosterol, total population 1980 vs. 2001 r=0.460, cholestanol 1980 vs. 2001 r=0.593, P<0.001 for both). Synthesis markers were highest in the first and lowest in the fourth quartile both in 1980 and 2001 (e.g. 2001, desmosterol, quartile 1, 99+/-9, quartile 4, 83+/-2 microg/mg of cholesterol, P<0.05).. Cholesterol metabolism is significantly tracked in adolescent males over the follow-up of 21 years. Thus, high cholesterol synthesis and low absorption characterize subjects with the lowest cholestanol quartile, while those with the highest quartile have low synthesis and high absorption in both adolescence and later in young adult life.

Topics: Adolescent; Adult; Age Factors; Biomarkers; Body Mass Index; Cardiovascular Diseases; Child; Child, Preschool; Cholestanol; Cholesterol; Chromatography, Gas; Chromatography, Liquid; Desmosterol; Female; Finland; Follow-Up Studies; Humans; Intestinal Absorption; Male; Phytosterols; Population Surveillance; Registries; Risk Factors; Sitosterols; Time Factors

It has been suggested that plant sterol absorption is increased in type 1 diabetes mellitus (T1DM) and that this may relate to the increased cardiovascular risk seen in T1DM. The cardiovascular benefit of lowering low-density lipoprotein-cholesterol with statin medication has also been shown to be influenced by plant sterol absorption.. The relationship between sterol concentrations, coronary artery disease (CAD), and the use of statin medications in T1DM was compared between participants with CAD (Minnesota codes 1.1, 1.2, 1.3, 4.1-4.3, 5.1-5.3, and 7.1; n = 82), from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, and those without (n = 213). Serum sterol concentrations reflecting cholesterol absorption (β-sitosterol and campesterol) and synthesis (desmosterol and lathosterol) were assayed and analyzed by gas chromatography and were expressed as a ratio of total cholesterol (×10(3)).. No differences were observed in markers of cholesterol absorption between individuals with and without CAD. In patients with CAD, significantly lower levels were observed for both sterol markers reflecting cholesterol synthesis compared with individuals without CAD [desmosterol: 0.34 vs 0.42, respectively (P = 0.003); lathosterol 0.47 vs 0.54, respectively (P = 0.019)]. Further stratification by statin medication use revealed significantly lower levels of synthesis-reflecting sterols in individuals taking statin medication, particularly those with CAD.. Although previous reports suggest that higher levels of cholesterol absorption in T1DM potentially increase cardiovascular risk in this population, the present data suggest no differences in cholesterol absorption between T1DM individuals with and without CAD.

Topics: Adult; Cholesterol; Cholesterol, LDL; Coronary Artery Disease; Desmosterol; Diabetes Mellitus, Type 1; Female; Humans; Male; Middle Aged; Phytosterols; Sitosterols

Lipoprotein distribution of non-cholesterol sterols was studied to evaluate in which lipoproteins they are carried in type 2 diabetes with body weight ranging from normal to overweight.. Serum and lipoprotein squalene and non-cholesterol sterols were quantitated with gas-liquid chromatography in 33 diabetic subjects separated into normal (BMI < or = 25 kg/m2, n=10) and overweight (BMI > 25 kg/m2, n=23) groups.. Two-thirds of the non-cholesterol sterols were carried in LDL and one-fifth in HDL, whereas squalene was mainly in VLDL and LDL in both groups. In overweight versus normal weight subjects, the absorption marker concentrations and ratios to cholesterol in serum and lipoproteins were lower and those of synthesis higher. In both groups the synthesis and absorption markers were interrelated in all lipoproteins suggesting intact regulation of cholesterol metabolism. The absorption marker ratios to cholesterol were mostly carried in HDL (cholestanol) and IDL (campesterol and sitosterol), and synthesis markers in VLDL and IDL regardless of overweight. Synthesis marker ratios were underestimated in serum versus VLDL and IDL, and those of absorption markers in serum versus IDL and HDL (p<0.05 for all). Squalene was related to lathosterol in all lipoprotein fractions (e.g., in LDL r=+0.501, p<0.01) suggesting that in diabetes squalene, too, is an indicator of cholesterol synthesis.. The absorption sterols are carried in IDL and HDL, and the synthesis markers in VLDL and IDL regardless of weight. The lipoprotein squalene and non-cholesterol sterol ratios were under- or overestimated in serum, and whether their evaluation in lipoproteins versus in serum only gives better information on cholesterol metabolism should be investigated further also in normal population.

Topics: Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Desmosterol; Diabetes Mellitus, Type 2; Female; Humans; Lipoproteins; Male; Middle Aged; Overweight; Squalene

The purpose of this study was to investigate, whether low vs. high absorption of cholesterol affects the postprandial lipid clearance (squalene as the surrogate marker) and postprandial cholesterol metabolism evaluated with plasma levels of cholesterol absorption (cholestanol and plant sterols) and synthesis markers (desmosterol and lathosterol).. Fifteen normo- or mildly hypercholesterolemic men were divided into low or high cholesterol absorbers on the basis of plasma cholestanol to cholesterol ratio and they volunteered to an oral fat load test containing fat 35 g/m(2) body surface.. Plasma squalene to cholesterol ratio did not differ between the groups throughout the postprandial follow-up of 8 h. The level differences in the plasma absorption and synthesis markers seen at baseline remained between the groups, so that in high absorbers the absorption markers remained high and synthesis markers low throughout the postprandial follow-up. The postprandial response curves of desmosterol (p<0.05) and lathosterol (p=0.052) to cholestanol decreased linearly in the low, but not in the high absorbers.. Low vs. high absorption of cholesterol does not affect the first 8-h postprandial lipid clearance. The metabolic profile of cholesterol is maintained postprandially. The postprandial decrease in cholesterol synthesis differs in low vs. high absorbers especially through the desmosterol pathway.

Topics: Absorption; Adult; Aged; Cholestanol; Cholesterol; Desmosterol; Humans; Male; Middle Aged; Phytosterols; Postprandial Period; Squalene

A newly developed high-performance liquid chromatography/mass spectrometry (HPLC/MS) method has been successfully used to analyze plasma concentrations of various phytosterols (cholestanol and beta-sitosterol) and cholesterol metabolites (desmosterol and lathosterol). This was based on an unusual solvent combination of water/methanol vs. methanol/acetone/n-hexane applied on a Purospher Star RP-18e (125 x 2 mm, 3 microm) column, which proved excellent for the separation, identification and quantification of plasma sterols. Simple solid-phase extraction preparation of plasma samples was performed, followed by the developed fast and robust HPLC separation. Results on four groups of people were compared, those with low, normal and high plasma cholesterol levels and those with high cholesterol levels on statin therapy, and the results were evaluated using linear discriminant analysis (LDA). Variable selection for LDA was achieved using backward removal selection. Highly discriminatory variables were the ratios of desmosterol to sitosterol and of lathosterol to total plasma cholesterol. The latter ratio was also excellent for distinguishing subjects on statin therapy. The success rate of classification was 100%. The present pilot study shows the potential of HPLC/MS analysis and chemometrics for studying cholesterol-related disorders and warrants future full-scale medical study.

Topics: Cholestanol; Cholesterol; Chromatography, High Pressure Liquid; Desmosterol; Discriminant Analysis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Mass Spectrometry; Pilot Projects; Sitosterols; Sterols

We measured serum cholesterol concentrations and synthesis markers (e.g. serum lathosterol to cholesterol ratio), and absorption markers (e.g. serum campesterol to cholesterol ratio) of cholesterol in 319 good responders (GR; dose 20 mg up to 1 year) and in 115 poor responders (PR; dose increased at 6 weeks to 40 mg) among Finnish participants in the Scandinavian Simvastatin Survival Study at baseline, 6 weeks and 1 year of the simvastatin treatment. The baseline cholesterol level and the ratios of the absorption markers were higher and those of the synthesis markers lower in PR than GR. The ratios of the precursor sterols were negatively related to the baseline cholesterol in GR only (P=0.003). The cholesterol levels, and the ratios of the precursor sterols were decreased and those of the absorption marker sterols increased less consistently in PR than GR by 20 mg, the group differences being only slightly lessened by the dose addition to 40 mg. One-year differences were still frequently significant. The baseline cholesterol concentrations were negatively related to the reduction of the precursor sterol ratios in GR, the change of cholesterol being positively related to those of the synthesis markers and negatively to those of the absorption markers only in PR. Thus, patients needing large statin dose for cholesterol normalization have high absorption and low synthesis of cholesterol, yet baseline synthesis is inversely related to cholesterol level only in GR. The synthesis rate is less markedly reduced by the large than by the small statin dose in the PR, and the reduction is related, in contrast to that in the GR, to lowering of cholesterol.

Topics: Cholestanol; Cholesterol; Desmosterol; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Simvastatin; Sitosterols

The purpose of the study was to investigate whether cholesterol metabolism is associated with coronary artery disease (CAD) in postmenopausal women.. Although hypercholesterolemia, a predominant risk factor of CAD, is related to cholesterol metabolism, the association between cholesterol metabolism and CAD is not well known.. In addition to conventional coronary risk factors, fasting serum squalene, delta8-cholestenol, desmosterol, lathosterol (indicators of cholesterol synthesis), cholestanol, campesterol and sitosterol (indicators of cholesterol absorption) were measured in 48 50- to 55-year-old consecutive women with angiographically verified CAD and in 61 age-matched healthy controls.. The coronary patients had elevated ratios of squalene (p < 0.001), desmosterol (p = 0.005), campesterol (p = 0.028) and sitosterol (p = 0.022) to cholesterol, but had lower respective lathosterol value (p = 0.041) compared with the controls, despite similar serum cholesterol levels. Adjusted for age, body mass index, family history of CAD, smoking, hypertension, serum triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol level and glycosylated hemoglobin A1c% (GHbA1c), the ratios of squalene (odds ratio, 1.36; 95% confidence interval, 1.17 to 1.57), lathosterol (0.98; 0.97 to 0.99), campesterol (1.01; 1.00 to 1.01) and sitosterol (1.01; 1.00 to 1.03) were significantly associated with the risk of CAD. In addition, family history of CAD and GHbA1c% were also independently related to the presence of CAD.. The results suggest that women with elevated ratios of serum squalene, campesterol and sitosterol to cholesterol and low respective lathosterol values have enhanced risk for CAD. Thus, enhanced absorption and reduced synthesis of cholesterol may be related to coronary atherosclerosis.

Topics: Case-Control Studies; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Desmosterol; Fasting; Female; Glycated Hemoglobin; Humans; Middle Aged; Phytosterols; Postmenopause; Prevalence; Radiography; Reproducibility of Results; Risk Factors; Sensitivity and Specificity; Sitosterols; Squalene

Total lipid extraction, solid-phase extraction, saponification, derivatization to trimethylsilyl ether derivatives, then capillary gas-liquid chromatography were used for quantitative analysis of sitosterol, campesterol, stigmasterol, sitostanol, campestanol, lathosterol, desmosterol, and lanosterol in human serum. Details of quality control integral to the accuracy and precision of analyses are included. The method limits of detection and quantitation, respectively, ranged from 0.05 microg/ml and 0.2 microg/ml for sitostanol to 0.4 microg/ml and 1.2 microg/ml for campesterol and campestanol. Analytes were measured at concentrations of 120 ng/ml to 6 microg/ml with standard deviations of 0.02 to 0.12 microg/ml for 55 analyses of a control serum sample conducted over a 2-month period.

Topics: Cholesterol; Chromatography, Gas; Desmosterol; Humans; Phytosterols; Quality Control; Reference Standards; Sitosterols; Time Factors

NIDDM and the metabolic syndrome are characterized by a low serum, HDL cholesterol content and a high triglyceride level, whereas total and LDL cholesterol concentrations are not necessarily elevated. Variable results have been reported on cholesterol absorption, elimination, and synthesis in NIDDM, but no studies are available on subjects within the normal range of blood glucose. From serum samples collected in 1985 from 203 nondiabetic men aged 51-66 years, we examined lipids, cholesterol precursors (reflecting cholesterol synthesis), and plant sterols and cholestanol (reflecting cholesterol absorption) in relation to fasting blood glucose. The findings prompted us (in 1993) to further examine 11 men from the highest and lowest glucose thirds of 203 nondiabetic men by additional dietary, serum, and fecal analyses for absorption, elimination, and synthesis of cholesterol and insulin sensitivity. In 1985, blood glucose was significantly related to LDL apolipoprotein B (P = 0.05) but not to LDL cholesterol (P = 0.19). Significantly higher serum lathosterol and desmosterol-to-cholesterol proportions and lower plant sterol and cholestanol proportions in the highest rather than the lowest glucose thirds suggested that the subjects with high normal blood glucose had decreased absorption and enhanced synthesis of cholesterol. In 1993, men with the lowest glucose versus those with the highest glucose had a lower waist-to-hip ratio, plasma HbA1c, fasting and postload insulin and glucose values, and a higher insulin sensitivity index. In agreement with the 1985 non-cholesterol sterol data, direct analyses of cholesterol metabolism showed further higher cholesterol absorption efficiency (P = 0.03) and serum plant sterol and cholestanol proportions (P < 0.001). Despite a slightly lower dietary cholesterol intake, cholesterol synthesis (P = 0.02) and serum lathosterol (P < 0.01) and desmosterol (P < 0.01) proportions were lowest in men with the lowest glucose third. We conclude that noncholesterol sterols in serum exhibits a long-lasting correlation with blood glucose level in a nondiabetic male population. Low intestinal absorption and high synthesis of cholesterol characterize men with high normal blood glucose. Differences in cholesterol metabolism could be due to underlying insulin effects associated with obesity-like fat distribution and may thus imply novel aspects in the metabolic interrelation between insulin and cholesterol in humans.

Topics: Aged; Analysis of Variance; Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Desmosterol; Fasting; Humans; Insulin; Intestinal Absorption; Male; Middle Aged; Reference Values; Triglycerides

The role of cholestasis and ileal dysfunction on sterol metabolism was studied in 79 patients with inflammatory bowel diseases (IBDs) and in 23 irritable bowel syndrome (IBS) controls by determining serum sterol/cholesterol proportions. The sterols included cholesterol precursors (delta 8-cholestenol, desmosterol and lathosterol), markers of cholesterol synthesis, cholestanol and plant sterols (campesterol and sitosterol), markers of cholesterol absorption and biliary secretion. The IBD patients were subgrouped into distal ulcerative colitis (dUC, n = 21), pancolitis (pUC, n = 29), ileal Crohn's disease (iCD, n = 20) and colonic Crohn's disease (cCD, n = 9). The cholestanol proportions were increased in the 3 colonic IBD groups, up to two times in cCD patients and seven times in a case with clinically overt primary sclerosing cholangitis, but were within the control IBS levels in the patients with iCD. The sitosterol, but not campesterol, proportion was significantly increased only in the pUC group. In the iCD group only the serum precursor sterol proportions, especially those for delta 8-cholestenol and lathosterol, were elevated probably due to ileal dysfunction induced bile acid malabsorption and compensatorily increased cholesterol synthesis. In conclusion, the findings suggest that the increased cholestanol proportion in colonic IBD is determined mainly by impaired biliary elimination of this sterol, while in ileal affision the dominating change in sterol balance is activated cholesterol synthesis. Thus increased serum cholestanol is a novel finding in colonic IBD, apparently indicating the presence of subclinical cholestasis in a marked number (20-50%) of IBD patients.

Topics: Adult; Analysis of Variance; Biomarkers; Biopsy; Cholestanol; Cholesterol; Colonic Diseases, Functional; Desmosterol; Female; Humans; Inflammatory Bowel Diseases; Male; Phytosterols

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

To investigate the regulation of serum levels of cholesterol precursor sterols and plant sterols, these noncholesterol sterols, fatty acids, and various parameters of cholesterol metabolism were analyzed in 63 volunteers from a randomly selected Finnish male population sample of 100 subjects, aged 50 years, who had normal dietary habits. Serum levels of cholesterol precursors, desmosterol and lathosterol (in terms of micrograms/mg cholesterol), were negatively related to both the fractional and absolute absorption of dietary cholesterol and serum high density lipoprotein (HDL) cholesterol, and positively related to overall cholesterol synthesis and serum very low density lipoprotein (VLDL) cholesterol. Serum levels of the plant sterols, campesterol and sitosterol, exhibited positive correlations with the polyunsaturated/saturated fatty acid ratio of dietary fat, the linoleic acid contents of plasma and dietary lipids, the amount of dietary plant sterols (as indicated by fecal output), fractional and absolute absorption of dietary cholesterol, and HDL cholesterol, but were inversely related to the overall cholesterol synthesis and VLDL cholesterol. Stepwise multiple regression analysis revealed that the serum level of campesterol was associated with fractional cholesterol absorption, dietary plant sterols, and biliary cholesterol secretion, and that of sitosterol with dietary plant sterols, cholesterol synthesis, fractional cholesterol absorption, and biliary cholesterol secretion. Thus, the serum non-cholesterol sterols are significant indicators of cholesterol absorption and synthesis even under basal conditions and, since gas liquid chromatographic determination of these sterols is quite simple, their measurement may be valuable for monitoring cholesterol metabolism in large-scale epidemiologic studies.

Topics: Absorption; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Cholesterol, LDL; Desmosterol; Dietary Fats; Fatty Acids; Humans; Isomerism; Male; Middle Aged; Phytosterols; Random Allocation; Sitosterols

The hypocholesterolaemic mechanism of activated charcoal was studied in seven patients with primary hypercholesterolaemia. The reduction of serum cholesterol was correlated with the serum concentrations of cholesterol precursors and of two plant sterols. Activated charcoal, 8 g t.i.d. for 4 weeks, reduced serum concentration of total cholesterol by 27% (P less than 0.01). The effect was accompanied by a moderate elevation (P less than 0.05) in serum squalene and desmosterol concentrations and by a marked increase (up to 300-700%) in serum lathosterol and delta 8 lathosterol concentrations. The levels of two plant sterols, campesterol and beta-sitosterol, were unchanged or only slightly decreased by the use of activated charcoal. The decrease of serum cholesterol concentration had significant negative correlations with serum lathosterol and delta 8 lathosterol, and significant positive correlations with serum cholestanol and beta-sitosterol. These observations suggest an increased cholesterol synthesis upon treatment with activated charcoal, probably caused by the interference with the enterohepatic circulation of bile acids.

Topics: Anticholesteremic Agents; Charcoal; Cholesterol; Desmosterol; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Sitosterols

The proximate cholesterol precursors lathosterol, 7-dehydrocholesterol and desmosterol supported the growth of NS-1 and X63 mouse myeloma cells. These cells and X63.653 cells are cholesterol auxotrophs, yet each was able to convert [3H]lathosterol to [3H]cholesterol. These results are consistent with the conclusion that cholesterol auxotrophy in these myeloma cells is due to a deficiency in 3-ketosteroid reductase activity. The steroid hormones testosterone, progesterone and hydrocortisone could not replace cholesterol as a medium supplement. These results provide a greater understanding of the cholesterol auxotrophy characteristic of cell lines clonally-derived from the MOPC 21 myeloma tumor, and they provide a rational basis for the use of sterols in defined culture medium for mouse myeloma cells.

Topics: 3-Hydroxysteroid Dehydrogenases; Animals; Cell Division; Cholestadienols; Cholesterol; Culture Media; Dehydrocholesterols; Desmosterol; Hormones; Hydrocortisone; Isomerism; Mice; Multiple Myeloma; Progesterone; Testosterone; Tumor Cells, Cultured

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

Repeated topical application of 3-methylcholanthrene to the backs of BALB/c mice lowered the tissue levels of lathosterol and provitamin D3, intermediates in one of the cholesterol biosynthetic pathways (the delta 7 pathway), though the activities of lathosterol 5-desaturase and provitamin D3 7-reductase were similar to those of control animals. These results seemed to indicate that carcinogen treatment exerted a depressive effect at some earlier step(s) than lathosterol synthesis. However, the content of cholesterol in mouse skin was not lowered in these animals, suggesting that another biosynthetic pathway might be activated. When diazacholesterol, which is known to inhibit the conversion of desmosterol to cholesterol, was administered together with the carcinogen, a marked accumulation of desmosterol was observed compared to animals given only diazacholesterol. Since desmosterol is an intermediate in the pathway in which the delta 24 double bond is reduced at the final step (the delta 24 pathway), this seemed to suggest that the delta 24 pathway was activated by carcinogen treatment.

Topics: Administration, Topical; Animals; Azacosterol; Cholecalciferol; Cholesterol; Chromatography, Gas; Desmosterol; Female; Lanosterol; Methylcholanthrene; Mice; Mice, Inbred BALB C; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Skin

The possibility that the serum concentrations of various cholesterol precursors may reflect the activity of the hepatic HMG-CoA reductase was investigated in humans under different conditions. The serum levels of squalene, free and esterified lanosterol, (4 alpha, 4 beta, 14 alpha-trimethyl-5 alpha-cholest-8, 24-dien-3 beta-ol), two dimethylsterols (4 alpha, 4 beta-dimethyl-5 beta-cholest-8-en-3 beta-ol and 4 alpha, 4 beta-dimethyl-5 alpha-cholest-8, 24-dien-3 beta-ol), two methostenols (4 alpha-methyl-5 alpha-cholest-7-en-3 beta-ol and 4 alpha-methyl-5 alpha-cholest-8-en-3 beta-ol), two lathosterols (5 alpha-cholest-7-en-3 beta-ol and 5 alpha-cholest-8-en-3 beta-ol) and desmosterol (cholest-5, 24-dien-3 beta-ol) were measured in untreated patients (n = 7) and patients treated with cholestyramine (QuestranR, 8 g twice daily for 2-3 weeks, n = 5) or chenodeoxycholic acid (15 mg/kg body weight daily for 3-4 weeks, n = 8) prior to elective cholecystectomy. The activity of the hepatic microsomal HMG-CoA reductase was measured in liver biopsies taken in connection with the operation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Cholesterol; Chromatography, Gas; Desmosterol; Esters; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Male; Microsomes, Liver; Middle Aged; Squalene

Enhanced biliary secretion and high faecal excretion of cholesterol are associated with increased cholesterol synthesis in coeliac disease. We have further investigated cholesterol synthesis in coeliac disease by determining the concentrations of faecal steroids and cholesterol precursors in serum, with and without a gluten free diet and while taking cholestyramine. The levels of unesterified methyl sterols and free and esterified lathosterol, but not those of squalene and desmosterol, were increased in proportion to the level of cholesterol synthesis, as measured with the sterol balance technique. Serum esterified methyl sterol concentrations were also slightly higher but, unlike free methyl sterols or lathosterol, they were not significantly correlated with cholesterol synthesis. The gluten free diet decreased the level of cholesterol synthesis, and the levels of lathosterol and free methyl sterols. There was less decrease in the concentration of esterified methyl sterols, and an insignificant decrease in the concentrations of squalene and desmosterol. Cholestyramine lowered the serum cholesterol concentration and increased that of serum free methyl sterols less in the patients than in the controls, and the increase was proportionate to increase of cholesterol elimination (or synthesis). The increase of serum free methyl sterols per unit of the increase of cholesterol elimination (or synthesis) was three times higher in the bile acid malabsorption caused by cholestyramine than in the cholesterol malabsorption caused by gluten enteropathy. On the other hand, the decrease in the level of serum cholesterol relative to the increase in cholesterol elimination (or synthesis) was higher in cholesterol malabsorption due to coeliac disease than in cholestyramine induced bile acid malabsorption. Effective secretion of newly synthesised and/or absorbed cholesterol directly into the bile could be a factor in the marked decrease of the serum cholesterol concentration in coeliac disease.

Topics: Celiac Disease; Cholesterol; Cholestyramine Resin; Desmosterol; Feces; Glutens; Humans; Lipid Metabolism; Steroids