Cholesterol Precursor Sterols Research Articles

Free cholesterol, cholesterol precursor and plant sterol levels in atherosclerotic plaques are independently associated with symptomatic advanced carotid artery stenosis

Background and aimsCirculating sterols result either from cholesterol (CH) synthesis or intestinal uptake. They are mainly esterified and can be oxygenated. Sterols accumulate in atherosclerotic plaques whereby their clinical impact is uncertain. Here, we determined associations between circulating and plaque sterol levels in patients with advanced carotid artery stenosis in respect to a prior ischemic event and statin treatment. MethodsFree and esterified CH, CH precursors and plant sterols as well as oxysterols were quantified by liquid chromatography-tandem mass spectrometry in 63 consecutive patients undergoing carotid endarterectomy. ResultsCH, CH precursors, plant sterols and oxysterols accumulated in carotid artery plaques. Absolute circulating sterol levels were not predictive for their corresponding plaque levels. After normalisation to CH, plant sterol but not oxysterol levels correlated between plasma and plaques. Among the circulating sterols, oxysterols occurred proportionally less in plaques. Furthermore, CH and plant sterols were less esterified in plaques than in plasma.Patients who experienced a prior ischemic event (n = 29) and asymptomatic patients had, except for lanosterol, comparable circulating sterol levels. In contrast, the absolute plaque levels of free CH, CH precursors and plant sterols as well as oxysterols were increased in symptomatic compared to asymptomatic patients. These differences remained significant for free CH, precursors and 3 out of 4 analyzed plant sterols after adjustment to the most influencing covariates - statin treatment, type 2 diabetes and age. ConclusionsIncreased absolute plaque levels of free CH, precursors and plant sterols predict an ischemic event in patients with advanced carotid artery stenosis.

Cholesterol metabolism in cholestatic liver disease and liver transplantation: From molecular mechanisms to clinical implications

The aim of this review is to enlighten the critical roles that the liver plays in cholesterol metabolism. Liver transplantation can serve as gene therapy or a source of gene transmission in certain conditions that affect cholesterol metabolism, such as low-density-lipoprotein (LDL) receptor gene mutations that are associated with familial hypercholesterolemia. On the other hand, cholestatic liver disease often alters cholesterol metabolism. Cholestasis can lead to formation of lipoprotein X (Lp-X), which is frequently mistaken for LDL on routine clinical tests. In contrast to LDL, Lp-X is non-atherogenic, and failure to differentiate between the two can interfere with cardiovascular risk assessment, potentially leading to prescription of futile lipid-lowering therapy. Statins do not effectively lower Lp-X levels, and cholestasis may lead to accumulation of toxic levels of statins. Moreover, severe cholestasis results in poor micellar formation, which reduces cholesterol absorption, potentially impairing the cholesterol-lowering effect of ezetimibe. Apolipoprotein B-100 measurement can help distinguish between atherogenic and non-atherogenic hypercholesterolemia. Furthermore, routine serum cholesterol measurements alone cannot reflect cholesterol absorption and synthesis. Measurements of serum non-cholesterol sterol biomarkers - such as cholesterol precursor sterols, plant sterols, and cholestanol - may help with the comprehensive assessment of cholesterol metabolism. An adequate cholesterol supply is essential for liver-regenerative capacity. Low preoperative and perioperative serum cholesterol levels seem to predict mortality in liver cirrhosis and after liver transplantation. Thus, accurate lipid profile evaluation is highly important in liver disease and after liver transplantation.

Serum sterol levels indicate distorted cholesterol homeostasis in cirrhotic patients with primary biliary cirrhosis

Background: In humans new cholesterol derives from de novo synthesis and intestinal absorption. Serum cholesterol precursor (e.g., lathosterol, desmosterol) and plant sterol levels (e.g., sitosterol, campesterol) represent valid surrogate marker for cholesterol biosynthesis and intestinal absorption, respectively. Since chronic liver diseases modulate cholesterol homeostasis, we systematically investigated sterol serum levels in patients with primary biliary cirrhosis (PBC) with and without liver cirrhosis.

Desmosterol in Brain Is Elevated because DHCR24 Needs REST for Robust Expression but REST Is Poorly Expressed

Cholesterol synthesis in the fetal brain is inhibited because activity of DHCR24 (24-dehydrocholesterol reductase) is insufficient, causing concentrations of the precursor desmosterol to increase temporarily to 15-25% of total sterols at birth. We demonstrate that failure of DHCR24 to be adequately upregulated during periods of elevated cholesterol synthesis in the brain results from the presence in its promoter of the repressor element 1 (RE1) nucleotide sequence that binds the RE1-silencing transcription factor (REST) and that REST, generally reduced in neural tissues, uncharacteristically but not without precedent, enhances DHCR24 transcription. DHCR24 and REST mRNA levels are reduced 3- to 4-fold in fetal mouse brain compared to liver (p < 0.001). Chromatin immunoprecipitation assays suggested that REST binds to the human DHCR24 promoter in the vicinity of the predicted human RE1 sequence. Luminescent emission from a human DHCR24 promoter construct with a mutated RE1 sequence was reduced 2-fold compared to output from a reporter with wild-type RE1 (p < 0.005). Silencing REST in HeLa cells resulted in significant reductions of DHCR24 mRNA (2-fold) and DHCR24 protein (4-fold). As expected, relative concentrations of Δ²⁴-cholesterol precursor sterols increased 3- to 4-fold, reflecting the inhibition of DHCR24 enzyme activity. In contrast, mRNA levels of DHCR7 (sterol 7-dehydrocholesterol reductase), a gene essential for cholesterol synthesis lacking an RE1 sequence, and concentrations of HMGR (3-hydroxy-3-methyl-glutaryl-CoA reductase) enzyme protein were both unaffected. Surprisingly, a dominant negative fragment of REST consisting of just the DNA binding domain (about 20% of the protein) and full-length REST enhanced DHCR24 expression equally well. Furthermore, RE1 and the sterol response element (SRE), the respective binding sites for REST and the SRE binding protein (SREBP), are contiguous. These observations led us to hypothesize that REST acts because it is bound in close proximity to SREBP, thus amplifying its ability to upregulate DHCR24. It is likely that modulation of DHCR24 expression by REST persisted in the mammalian genome either because it does no harm or because suppressing metabolically active DHCR24 while providing abundant quantities of the multifunctional sterol desmosterol during neural development proved useful.

Cholesterol metabolism and serum non-cholesterol sterols: summary of 13 plant stanol ester interventions.

BackgroundThe efficacy and safety of plant stanols added to food products as serum cholesterol lowering agents have been demonstrated convincingly, but their effects on cholesterol metabolism and on serum non-cholesterol sterols is less evaluated. The aim of this study was to assess the validity of serum non-cholesterol sterols and squalene as bioindices of cholesterol synthesis and absorption, and to examine how the individual serum non-cholesterol sterols respond to consumption of plant stanols.MethodsWe collected all randomized, controlled plant stanol ester (STAEST) interventions in which serum cholestanol, plant sterols campesterol and sitosterol, and at least two serum cholesterol precursors had been analysed. According to these criteria, there was a total of 13 studies (total 868 subjects without lipid-lowering medication; plant stanol doses varied from 0.8 to 8.8 g/d added in esterified form; the duration of the studies varied from 4 to 52 weeks). Serum non-cholesterol sterols were assayed with gas–liquid chromatography, cholesterol synthesis with the sterol balance technique, and fractional cholesterol absorption with the dual continuous isotope feeding method.ResultsThe results demonstrated that during the control and the STAEST periods, the serum plant sterol/cholesterol- and the cholestanol/cholesterol-ratios reflected fractional cholesterol absorption, and the precursor sterol/cholesterol-ratios reflected cholesterol synthesis. Plant sterol levels were dose-dependently reduced by STAEST so that 2 g of plant stanols reduced serum campesterol/cholesterol-ratio on average by 32%. Serum cholestanol/cholesterol-ratio was reduced less frequently than those of the plant sterols by STAEST, and the cholesterol precursor sterol ratios did not change consistently in the individual studies emphasizing the importance of monitoring more than one surrogate serum marker.ConclusionsSerum non-cholesterol sterols are valid markers of cholesterol absorption and synthesis even during cholesterol absorption inhibition with STAEST. Serum plant sterol concentrations decrease dose-dependently in response to plant stanols suggesting that the higher the plant stanol dose, the more cholesterol absorption is inhibited and the greater the reduction in LDL cholesterol level is that can be achieved.Trial registrationClinical Trials Register # NCT00698256 [Eur J Nutr 2010, 49:111-117]

Cholesterol versus other sterols: How do they compare as physiological regulators of cholesterol homeostasis?

AbstractThere is a growing body of work indicating that maintaining cholesterol homeostasis involves oxysterol‐derivatives and sterol precursors of cholesterol. Their importance relative to cholesterol itself is a contentious area, which is difficult to address experimentally. In this review, the molecular basis of cholesterol homeostasis is briefly described, some of the major putative sterol regulators introduced, and the evidence that they may indeed serve as physiological regulators is discussed, along with caveats of this research. This review will also briefly address some recent literature ascribing physiological roles of non‐cholesterol sterols beyond cholesterol metabolism.

Cholesterol metabolism in pediatric short bowel syndrome after weaning off parenteral nutrition

Background Small intestine essentially regulates cholesterol homeostasis. Aims To evaluate cholesterol metabolism in short bowel syndrome (SBS). Methods 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). Results 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). Conclusion 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.

Familial Combined Hyperlipidemia Is Associated With Alterations in the Cholesterol Synthesis Pathway

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.

Very high plant stanol intake and serum plant stanols and non-cholesterol sterols

Today, consumers meet abundant supply of functional foods with plant stanol increments for serum cholesterol lowering purposes. However, efficacy and safety of plant stanols intake beyond 4 g/day have remained unexplored. We evaluated the effects of very high daily intake of plant stanols (8.8 g/day) as esters on cholesterol metabolism, and serum levels of plant sterols and stanols. In a randomized, double-blind, parallel study of 49 hypercholesterolemic subjects (mean age 62 years, range 41-73) consumed a test diet without (control, n = 24), and with added plant stanol esters (staest, n = 25) over 10 weeks followed by 4 weeks on home diet. Serum lipids, lipoprotein lipids, and non-cholesterol sterols were determined at baseline, during intervention, and 4 weeks afterwards. Cholesterol precursor sterol lathosterol reflected cholesterol synthesis, and serum plant sterols and cholestanol mirrored cholesterol absorption. When compared with controls, 8.8 g/day of plant stanols reduced serum and LDL cholesterol by 12 and 17% (P < 0.01 for both). Synthesis marker lathosterol was increased by 30%, while absorption markers decreased up to 62% when compared with controls (P < 0.001 for both). Serum plant stanols increased slightly, but significantly compared with controls (serum sitostanol during intervention, controls: 16 +/- 1 microg/dL, staest: 37 +/- 2 microg/dL, serum campestanol during intervention, controls: 0.5 +/- 0 microg/dL, staest: 9 +/- 1 microg/dL, P < 0.001 for both). Changes in serum cholesterol, non-cholesterol sterols, and plant stanols were normalized during post-treatment weeks. Serum plant stanol levels remained at comparable low levels as in studies with daily intake of 2-3 g, and were normalized in 4 weeks suggesting that daily intake of 8.8 g of plant stanols might not increase systemic availability of plant stanols, but reduces effectively serum cholesterol and plant sterol levels.

Serum cholesterol precursor and plant sterol levels indicate increased de novo cholesterol synthesis and decreased intestinal cholesterol absorption in German gallstone patients

Serum cholesterol precursor and plant sterol levels indicate increased de novo cholesterol synthesis and decreased intestinal cholesterol absorption in German gallstone patients

Abstract: S1-6 CHOLESTEROL ABSORPTION AND SYNTHESIS MARKERS FOR CARDIOVASCULAR DISEASE RISK.

Serum cholestanol was studied in relation to fecal cholestanol excretion and cholesterol metabolism in a random middle-aged population of 61 men. The serum concentrations of cholestanol ranged from 1.6 to 10.8 μmol/L and were positively correlated with those of serum total LDL and HDL cholesterol. In terms of millimole per mole of cholesterol, these correlations disappeared; inverse associations were found with VLDL cholesterol and triglyceride levels, the P/S ratio of dietary fat, and the amount of fecal plant sterols, but not with fecal cholestanol. The serum contents of cholestanol (1) were also closely positively associated with those of serum plant sterols (campesterol and sitosterol) and fractional cholesterol absorption, (2) were inversely related to the fecal excretion of neutral sterols and cholesterol synthesis which were measured either by the sterol balance technique or serum cholesterol precursor sterols (desmosterol and lathosterol), and (3) were unrelated to bile acid synthesis. Fecal cholestanol (mean = 12.5 mg/d) was (1) clearly higher than the dietary cholestanol intake (<2 mg/d), (2) unrelated to serum cholestanol, and (3) positively correlated with the intestinal cholesterol (dietary plus endogenous) flux as well as fecal plant sterols, neutral sterols, and bacterial products of cholesterol. The study emphasizes that, in normal men, high serum cholestanol levels reflect high efficiency of intestinal sterol absorption and low cholesterol synthesis. Thus, the changes in the serum contents of cholestanol are parallel with those of plant sterols and opposite to those of cholesterol precursor sterols.

Inhibition of cholesterol biosynthesis disrupts lipid raft/caveolae and affects insulin receptor activation in 3T3-L1 preadipocytes

Lipid rafts are plasma membrane microdomains that are highly enriched with cholesterol and sphingolipids and in which various receptors and other proteins involved in signal transduction reside. In the present work, we analyzed the effect of cholesterol biosynthesis inhibition on lipid raft/caveolae composition and functionality and assessed whether sterol precursors of cholesterol could substitute for cholesterol in lipid rafts/caveolae. 3T3-L1 preadipocytes were treated with distal inhibitors of cholesterol biosynthesis or vehicle (control) and then membrane rafts were isolated by sucrose density gradient centrifugation. Inhibition of cholesterol biosynthesis with either SKF 104976, AY 9944, 5,22-cholestadien-3β-ol or triparanol, which inhibit different enzymes on the pathway, led to a marked reduction in cholesterol content and accumulation of different sterol intermediates in both lipid rafts and non-raft domains. These changes in sterol composition were accompanied by disruption of lipid rafts, with redistribution of caveolin-1 and Fyn, impairment of insulin-Akt signaling and the inhibition of insulin-stimulated glucose transport. Cholesterol repletion abrogated the effects of cholesterol biosynthesis inhibitors, reflecting they were specific. Our results show that cholesterol is required for functional raft-dependent insulin signaling.

Effects of ezetimibe, simvastatin, atorvastatin, and ezetimibe–statin therapies on non-cholesterol sterols in patients with primary hypercholesterolemia

ABSTRACTBackground: Levels of cholesterol are regulated by its synthesis, absorption, and elimination. Plasma levels of phytosterols (e.g., sitosterol, campesterol) and ratios of these sterols to total cholesterol (TC) are reported to correlate with efficiency of intestinal cholesterol absorption, whereas levels of certain cholesterol precursor sterols (e.g., desmosterol, lathosterol) and their ratios to TC correlate with cholesterol biosynthesis. However, there is a paucity of published data concerning the effects of combined treatment using HMG-CoA reductase inhibitors (statins) and a cholesterol absorption inhibitor (ezetimibe) on these parameters.Objectives: To characterize the effects of ezetimibe co-administered with statins, compared with each treatment alone, on cholesterol precursor sterols and plasma phytosterol levels.Methods: A post-hoc analysis was performed to determine the effects of treatment with ezetimibe 10 mg, simvastatin (10–80 mg), and atorvastatin (10–80 mg), alone or in combination, on these non-cholesterol sterols using plasma samples from two randomized controlled trials involving patients with primary hypercholesterolemia (low-density lipoprotein [LDL-C] = 145–250 mg/dL; triglycerides ≤350 mg/dL; N = 975) but without a recent (≤6-month) history of coronary heart disease (CHD) or either uncontrolled or newly diagnosed diabetes mellitus.Results: Ezetimibe monotherapy significantly reduced plasma sitosterol and campesterol concentrations from baseline compared with placebo (both p < 0.001), whereas statins significantly lowered desmosterol and lathosterol levels (p < 0.001 vs. placebo). Co-administration of ezetimibe and statins significantly decreased plasma levels of all of these sterols (p < 0.001).Conclusions: The observed effects of co-administration of ezetimibe and statins on non-cholesterol sterols are consistent with net inhibition of sterol absorption (driven by ezetimibe) in conjunction with net inhibition of cholesterol synthesis (driven by statins). The potential influence of treatment-induced changes in phytosterols on cardiovascular risk warrants further investigation in long-term, prospective, randomized controlled trials. This post-hoc study was by nature exploratory, and, because data from such analyses are not customarily adjusted for multiple comparisons, some associations may have emerged as statistically significant by chance. Future prospective randomized controlled studies may help to confirm our findings and address other research issues, such as the generalizability of our findings to patients with CHD or diabetes mellitus and possible dose:response relationships between escalating statin (or ezetimibe–statin) doses and circulating non-cholesterol levels.

Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands

The liver X receptors (LXRs) are ligand-activated transcription factors that regulate the expression of genes controlling lipid metabolism. Oxysterols bind LXRs with high affinity in vitro and are implicated as ligands for the receptor. We showed previously that accumulation of selected dietary sterols, in particular stigmasterol, is associated with activation of LXR in vivo. In the course of the defining of structural features of stigmasterol that confer LXR agonist activity, we determined that the presence of an unsaturated bond in the side chain of the sterol was necessary and sufficient for activity, with the C-24 unsaturated cholesterol precursor sterols desmosterol and zymosterol exerting the largest effects. Desmosterol failed to increase expression of the LXR target gene, ABCA1, in LXRalpha/beta-deficient mouse fibroblasts, but was fully active in cells lacking cholesterol 24-, 25-, and 27-hydroxylase; thus, the effect of desmosterol was LXR-dependent and did not require conversion to a side chain oxysterol. Desmosterol bound to purified LXRalpha and LXRbeta in vitro and supported the recruitment of steroid receptor coactivator 1. Desmosterol also inhibited processing of the sterol response element-binding protein-2 and reduced expression of hydroxymethylglutaryl-CoA reductase. These observations are consistent with specific intermediates in the cholesterol biosynthetic pathway regulating lipid homeostasis through both the LXR and sterol response element-binding protein pathways.

Markers of absorption and synthesis of cholesterol in men with type 1 diabetes

Serum cholestanol and plant sterol ratios to cholesterol, surrogate markers of cholesterol absorption, are assumed to be high in type 1 diabetes (T1D), and the ratios of cholesterol precursor sterols (markers of synthesis) are assumed to be low reflecting downregulated cholesterol synthesis. To this end, we measured serum sterols with gas-liquid-chromatography in 56 men with T1D and in 18 controls to evaluate cholesterol metabolism. Subjects were categorised into tertiles by the cholestanol to cholesterol ratio of controls indicating low to high absorption of cholesterol. The ratios of the synthesis markers were negatively related to the absorption markers in controls, but less consistently in T1D. The absorption markers were positively related to each other, but interrelation of the synthesis markers was less consistent in T1D. In the low absorbers the absorption markers were higher in T1D than in controls (e.g. sitosterol ratio 173 +/- 9 in T1D vs 135 +/- 11 10(2) x mmol/mol of cholesterol in controls, p < 0.05). In the high absorbers, the absorption markers were similar in T1D and controls, but the synthesis markers were higher in T1D than in controls (e.g. lathosterol ratio 154 +/- 10 in T1D vs 120 +/- 5 10(2) x mmol/mol of cholesterol in controls, p < 0.05). Absorption and synthesis of cholesterol are less closely related to each other in T1D than in controls, but the markers of cholesterol absorption are interrelated also in T1D. Absorption of cholesterol is higher in T1D than in controls within the range of low absorption, but similar in those with relatively high cholesterol absorption.

Sterol Intermediates from Cholesterol Biosynthetic Pathway as Liver X Receptor Ligands

The liver X receptors (LXRs) are ligand-activated transcription factors that regulate the expression of genes controlling lipid metabolism. Oxysterols bind LXRs with high affinity in vitro and are implicated as ligands for the receptor. We showed previously that accumulation of selected dietary sterols, in particular stigmasterol, is associated with activation of LXR in vivo. In the course of the defining of structural features of stigmasterol that confer LXR agonist activity, we determined that the presence of an unsaturated bond in the side chain of the sterol was necessary and sufficient for activity, with the C-24 unsaturated cholesterol precursor sterols desmosterol and zymosterol exerting the largest effects. Desmosterol failed to increase expression of the LXR target gene, ABCA1, in LXRalpha/beta-deficient mouse fibroblasts, but was fully active in cells lacking cholesterol 24-, 25-, and 27-hydroxylase; thus, the effect of desmosterol was LXR-dependent and did not require conversion to a side chain oxysterol. Desmosterol bound to purified LXRalpha and LXRbeta in vitro and supported the recruitment of steroid receptor coactivator 1. Desmosterol also inhibited processing of the sterol response element-binding protein-2 and reduced expression of hydroxymethylglutaryl-CoA reductase. These observations are consistent with specific intermediates in the cholesterol biosynthetic pathway regulating lipid homeostasis through both the LXR and sterol response element-binding protein pathways.

Effect of Statins on Noncholesterol Sterol Levels: Implications for Use of Plant Stanols and Sterols

Normal serum contains small amounts of noncholesterol sterols, including those reflecting cholesterol absorption and those that are markers of cholesterol synthesis. Absorption marker sterols include serum plant sterols, whereas cholesterol precursor sterols correlate with whole-body synthesis of cholesterol. Thus, serum noncholesterol sterols, and especially their ratios to cholesterol, can be used to evaluate the major features of cholesterol metabolism (ie, synthesis and absorption). Statin treatment reduces serum cholesterol precursors but increases serum plant sterols severalfold, especially in subjects with high-absorption marker sterol levels indicative of efficient cholesterol and sterol absorption in general. Statin therapy is most effective in subjects with high serum cholesterol precursor levels. In subjects with high-absorption sterol markers, dietary cholesterol absorption inhibition (eg, with plant stanol and sterol ester margarine) needs to be combined with a statin to achieve effective serum cholesterol reduction. However, whereas dietary plant stanol esters reduce statin-induced elevations of serum plant sterol levels, serum plant sterol levels remain elevated during dietary plant sterol ester consumption. The clinical implication of high serum plant sterol levels is under active investigation.

Cholesterol metabolism in type 1 diabetes.

Little information is available on cholesterol absorption and synthesis in human type 1 diabetes. We studied these variables using serum cholesterol precursor sterol ratios to cholesterol as surrogate markers of cholesterol synthesis and those of cholestanol and plant sterols to reflect cholesterol absorption in seven type 1 diabetic subjects and in five age- and body weight-matched control subjects. Total and lipoprotein cholesterol levels were similar, but triglycerides in intermediate-density lipoprotein (IDL) and LDL were higher in type 1 diabetic than in control subjects. Most of the marker sterols were transported by LDL and HDL in both groups. The percentage of esterified cholesterol was lower in triglyceride-rich lipoproteins in diabetic patients than in control subjects. The ratios of the absorption marker sterols in serum were higher, and those of the synthesis markers were lower in type 1 diabetic than in control subjects. The increased cholestanol ratios were seen in all lipoproteins, and those of free and total plant sterols were mainly in LDL, whereas the decreased free and total synthesis markers were mainly in all lipoproteins. In conclusion, high absorption and low synthesis marker sterols seem to characterize human type 1 diabetes. These findings could be related to low expression of ABC G/5 G/8 genes, resulting in high absorption of cholesterol and sterols in general and low synthesis of cholesterol compared with type 2 diabetes.

Red cell and plasma plant sterols are related during consumption of plant stanol and sterol ester spreads in children with hypercholesterolemia

Objective To show whether the ratios of squalene and cholesterol precursor sterols to cholesterol and cholestanol and plant sterols to cholesterol change differently in plasma and especially in the red cells of hypercholesterolemic children during consumption of plant stanol and sterol ester spreads. Study design In a randomized, double-blind, crossover study, hypercholesterolemic children (n = 23) consumed low-fat plant stanol and sterol ester spreads for 5-week periods separated by a 5-week washout period. Plasma and red cell lipids, squalene, and noncholesterol sterols were measured before and at the end of each period. Results The plant stanol and sterol ester spreads lowered plasma total (−9% and −6%, respectively) and low-density lipoprotein (−12% and −9%) cholesterol but had no effect on red cell cholesterol, high-density lipoprotein cholesterol, or plasma triglycerides. The ratios of plasma and red cell sitosterol and campesterol to cholesterol decreased by 32% to 36% (P <.001) with the plant stanol ester and increased by 40% to 52% (P <.001) with the sterol ester spread. Conclusions Consumption of plant sterols increases and consumption of plant stanols decreases the ratios of plant sterols to cholesterol in red cells of hypercholesterolemic children proportionately to the respective changes in plasma. (J Pediatr 2003;142:524-31)

Cholesterol precursors and plant sterols in children with food allergy

The data on lipid metabolism in allergic children is limited. We investigated lipid and sterol metabolism in young children whose diets were restricted because of food allergy. Children in group A [n = 21; mean (+/- SD) age: 1.78 +/- 0.73 y] were allergic to fish, eggs, and either cow milk or cereals; those in group B (n = 31, aged 1.45 +/- 0.58 y) were allergic to fish, eggs, and both cow milk and cereals. Cholesterol precursor and plant sterol to cholesterol ratios (10(2) x micro mol/mmol cholesterol) and apolipoprotein E phenotype distributions were analyzed in 36 subjects. The control group for cholesterol precursor and plant sterol measurements consisted of 18 healthy age-matched children. The mean serum cholesterol concentration was 3.6 +/- 0.6 mmol/L, and HDL cholesterol was 1.03 +/- 0.3 mmol/L in group A. Corresponding values in group B were 3.4 +/- 0.7 and 1.09 +/- 0.2 mmol/L. The daily cholesterol intake was low: 61.3 +/- 36.0 mg in group A and 50.7 +/- 48.5 mg in group B. Cholesterol precursor plant sterol concentrations were significantly higher in allergic subjects than in control subjects. Allergic children with restricted diets have a low intake of cholesterol and relatively low serum cholesterol concentrations. Dietary intake of plant sterols was obviously increased because of supplementation with rapeseed oil, which is rich in plant sterols, leading to elevated plant sterol concentrations. Plant sterols may have inhibited cholesterol absorption, which in turn stimulated cholesterol synthesis in compensation, also explaining the increased precursor sterol ratios in serum in our subjects.