Plasma Lathosterol Concentrations Research Articles

Plasma lathosterol measures rates of cholesterol synthesis and efficiency of dietary phytosterols in reducing the plasma cholesterol concentration

Because the plasma campesterol/cholesterol ratio does not differ between groups that absorb different amounts of cholesterol, the authors investigated whether the plasma Phytosterols (PS) relate to the body's cholesterol synthesis rate measured as non-cholesterol sterol precursors (lathosterol). The authors studied38non-obese volunteers (58±12years; Low-Density Lipoprotein Cholesterol ‒ LDL-C≥ 130mg/dL) randomly assigned to consume 400mL/day of soy milk (Control phase) or soy milk+PS (1.6 g/day) forfourweeks in a double-blind, cross-over study. PS and lathosterol were measured in plasma by gas chromatography coupled to mass spectrophotometry. PS treatment reduced plasma total cholesterol concentration (-5.5%, p<0.001), LDL-C (-7.6%, p<0.001), triglycerides (-13.6%, p<0.0085), and apolipoprotein B (apoB) (-6.3%, p<0.008), without changing high density lipoprotein cholesterol (HDL-C concentration), but plasma lathosterol, campesterol and sitosterol expressed per plasma cholesterol increased. The lathosterol-to-cholesterol plasma ratio predicted the plasma cholesterol response to PS feeding. The highest plasma lathosterol concentration during the control phase was associated with a lack of response of plasma cholesterol during the PS treatment period. Consequently, cholesterol synthesis in non-responders to dietary PS being elevated in the control phase indicates these cases resist to further synthesis rise, whereas responders to dietary PS, having in the control phase synthesis values lower than non-responders, expand synthesis on alimentary PS. Responders absorb more PS than non-responders, likely resulting from responders delivering into the intestinal lumen less endogenous cholesterol than non-responders do, thus facilitating greater intestinal absorption of PS shown as increased plasma PS concentration.

Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties.

Lathosterolosis is a rare defect of cholesterol synthesis. Only four previous cases have been reported, two of whom were siblings. We report a fifth patient, with a relatively mild phenotype. He presented at 5years of age with bilateral posterior cataracts, which were managed with lensectomies and intraocular lens implants. He also had learning difficulties, with a full-scale IQ of 64 at 11years of age. His head circumference is between the 0.4th and 2nd centiles, and he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted nostrils, long philtrum and clinodactyly of toes). The diagnosis was established after sequencing a panel of genes associated with cataracts, which revealed compound heterozygous SC5D mutations: c.479C>G p.(Pro160Arg) and c.630C>A p.(Asp210Glu). The plasma lathosterol concentration was markedly raised at 219.8μmol/L (control range 0.53-16.0), confirming the diagnosis. The c.630C>A p.(Asp210Glu) mutation has been reported in one previous patient, who also had a relatively mild phenotype (Ho et al., JIMD Rep 12:129-134, 2014). The mutation leads to a relatively conservative amino acid substitution, consistent with some residual enzyme activity. Our patient's family did not notice any benefit from treatment with simvastatin. In summary, milder patients with lathosterolosis may present with learning difficulties, cataracts and very subtle dysmorphism. The diagnosis will be missed unless plasma sterols are analysed or relevant genes sequenced.

The Interpretation of Cholesterol Balance Derived Synthesis Data and Surrogate Noncholesterol Plasma Markers for Cholesterol Synthesis under Lipid Lowering Therapies

The cholesterol balance procedure allows the calculation of cholesterol synthesis based on the assumption that loss of endogenous cholesterol via fecal excretion and bile acid synthesis is compensated by de novo synthesis. Under ezetimibe therapy hepatic cholesterol is diminished which can be compensated by hepatic de novo synthesis and hepatic extraction of plasma cholesterol. The plasma lathosterol concentration corrected for total cholesterol concentration (R_Lath) as a marker of de novo cholesterol synthesis is increased during ezetimibe treatment but unchanged under treatment with ezetimibe and simvastatin. Cholesterol balance derived synthesis data increase during both therapies. We hypothesize the following. (1) The cholesterol balance data must be applied to the hepatobiliary cholesterol pool. (2) The calculated cholesterol synthesis value is the sum of hepatic de novo synthesis and the net plasma—liver cholesterol exchange rate. (3) The reduced rate of biliary cholesterol absorption is the major trigger for the regulation of hepatic cholesterol metabolism under ezetimibe treatment. Supportive experimental and literature data are presented that describe changes of cholesterol fluxes under ezetimibe, statin, and combined treatments in omnivores and vegans, link plasma R_Lath to liver function, and define hepatic de novo synthesis as target for regulation of synthesis. An ezetimibe dependent direct hepatic drug effect cannot be excluded.

Impact of buttermilk consumption on plasma lipids and surrogate markers of cholesterol homeostasis in men and women

Background and aimsSphingolipids (SL) are important components of the milk fat globule membrane (MFGM) found in buttermilk. While studies in animal models suggest that dietary SL may have cholesterol-lowering properties, data in human are lacking. The aim of this study was to investigate the impact of buttermilk consumption on plasma lipids and surrogate markers of cholesterol (C) homeostasis in humans. Methods and resultsMen and women (n = 34) with serum LDL-C <5.0 mmol/L at screening (mean LDL-C = 3.8 mmol/L) were recruited in this double-blinded randomized crossover placebo controlled study. Their diets were supplemented with 45 g/d of buttermilk and with 45 g/d of a macro/micronutrient matched placebo (4 weeks each in random order). Serum lipid concentrations and surrogate markers of cholesterol homeostasis were measured post diet and compared using mixed models for repeated measures. Consumption of buttermilk led to reduction in serum cholesterol (−3.1%, P = 0.019), LDL-C (−3.1%, P = 0.057) and triacylglycerol (−10.7%, P = 0.007). Buttermilk consumption increased plasma lathosterol concentrations (+12.1%, P = 0.001), but multiple regression analysis indicated that variations in β-sitosterol concentrations (P = 0.002) were the only significant predictor of the LDL-C response to buttermilk consumption. ConclusionButtermilk consumption may be associated with reduced cholesterol concentrations in men and women, primarily through inhibition of intestinal absorption of cholesterol. Registration numberThis trial is registered at clinicaltrials.gov as NCT01248026.

Comparison of the impact of trans fatty acids from ruminant and industrial sources on surrogate markers of cholesterol homeostasis in healthy men

Mechanisms by which trans fatty acids (TFA) from industrial (iTFA) and ruminant (rTFA) sources alter cholesterol homeostasis are virtually unknown. We compared the impact of dietary iTFA and rTFA on surrogate markers of cholesterol absorption (β-sitosterol and campesterol) and synthesis (lathosterol) in healthy men. In a randomized, controlled double-blind crossover study, 38 healthy men consumed three experimental isoenergetic diets for 4 wk each. The three diets were (i) high in iTFA (10.2 g/2500 kcal), (ii) high in rTFA (10.2 g/2500 kcal) and (iii) control diet low in TFA from any source (2.2 g/2500 kcal). The sum of plasma β-sitosterol and campesterol concentrations was significantly reduced after the iTFA diet compared with the control diet (-12%, p=0.050). The reduction in combined β-sitosterol and campesterol levels was larger in magnitude after the rTFA diet (-29% versus the control diet and -20% versus the iTFA diet, p<0.0001). The TFA-rich diets had no impact on plasma lathosterol concentrations. Very high intakes of rTFA and iTFA decrease cholesterol absorption but have no impact on cholesterol synthesis. Consumption of rTFA reduces cholesterol absorption to a greater extent than iTFA, but this difference does not ultimately affect plasma cholesterol concentrations.

Effect of Ezetimibe on Hepatic Fat, Inflammatory Markers, and Apolipoprotein B-100 Kinetics in Insulin-Resistant Obese Subjects on a Weight Loss Diet

OBJECTIVENonalcoholic fatty liver disease is highly prevalent in obese and type 2 diabetic individuals and is strongly associated with dyslipidemia and inflammation. Weight loss and/or pharmacotherapy are commonly used to correct these abnormalities.RESEARCH DESIGN AND METHODSWe performed a 16-week intervention trial of a hypocaloric, low-fat diet plus 10 mg/day ezetimibe (n = 15) versus a hypocaloric, low-fat diet alone (n = 10) on intrahepatic triglyceride (IHTG) content, plasma high sensitivity–C-reactive protein (hs-CRP), adipocytokines, and fetuin-A concentrations and apolipoprotein (apo)B-100 kinetics in obese subjects. ApoB-100 metabolism was assessed using stable isotope tracer kinetics and compartmental modeling; liver and abdominal fat contents were determined by magnetic resonance techniques.RESULTSBoth weight loss and ezetimibe plus weight loss significantly (all P < 0.05) reduced body weight, visceral and subcutaneous adipose tissues, insulin resistance and plasma triglycerides, VLDL–apoB-100, apoC-III, fetuin-A, and retinol-binding protein-4 and increased plasma adiponectin concentrations. Compared with weight loss alone, ezetimibe plus weight loss significantly (all P < 0.05) decreased IHTG content (−18%), plasma hs-CRP (−53%), interleukin-6 (−24%), LDL cholesterol (−18%), campesterol (−59%), and apoB-100 (−14%) levels, with a significant increase in plasma lathosterol concentrations (+43%). The LDL–apoB-100 concentration also significantly fell with ezetimibe plus weight loss (−12%), chiefly owing to an increase in the corresponding fractional catabolic rate (+29%). The VLDL–apoB-100 secretion rate fell with both interventions, with no significant independent effect of ezetimibe.CONCLUSIONSAddition of ezetimibe to a moderate weight loss diet in obese subjects can significantly improve hepatic steatosis, inflammation, and LDL–apoB-100 metabolism.

Effect of plant sterols and glucomannan on lipids in individuals with and without type II diabetes

The purpose of this study was to determine whether supplements of plant sterols and/or glucomannan improve lipid profile and cholesterol biosynthesis in mildly hypercholesterolemic type II diabetic and non-diabetic subjects and to compare the response of these two subject groups to the treatments. A randomized, crossover study consisting of four phases of 21 days, with each phase separated by a 28-day washout. The Mary Emily Clinical Nutrition Research Unit of McGill University. Eighteen non-diabetic individuals and 16 type II diabetic individuals aged 38-74 years. Subjects were supplemented with plant sterols (1.8 g/day), glucomannan (10 g/day), a combination of glucomannan and plant sterols, and a placebo, provided in the form of bars. Overall plasma cholesterol concentrations were lowered (P<0.05) after combination treatment (4.72+/-0.20 mmol/l) compared to control (5.47+/-0.18 mmol/l). Plasma low-density lipoprotein (LDL) cholesterol concentrations were decreased (P<0.05) after glucomannan (3.16+/-0.14 mmol/l) and combination treatments (2.95+/-0.16 mmol/l) compared to control (3.60+/-0.16 mmol/l). The results of lipid profiles did not differ between subject groups. Overall plasma lathosterol concentrations, an index of cholesterol biosynthesis, were lowered (P<0.05) after the combination treatment compared to the plant sterol treatment. The results suggest that glucomannan and a combination of glucomannan and plant sterols substantially improves plasma LDL cholesterol concentrations. Forbes Medi-Tech Inc., Vancouver, British Columbia, Canada.

A Novel Inhibitor of Oxidosqualene:Lanosterol Cyclase Inhibits Very Low–Density Lipoprotein Apolipoprotein B100 (ApoB100) Production and Enhances Low-Density Lipoprotein ApoB100 Catabolism Through Marked Reduction in Hepatic Cholesterol Content

Inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC), an enzyme in the cholesterol synthesis pathway, has the unique ability to inhibit cholesterol synthesis while simultaneously enhancing oxysterol synthesis. Our objectives were to determine, in vivo, if a novel OSC inhibitor reduced low-density lipoprotein (LDL) cholesterol and to define the mechanism(s) involved. Miniature pigs received the OSC inhibitor RO0717625 or placebo and a diet containing fat (34% of energy) and 400 mg per day of cholesterol. Treatment decreased plasma total cholesterol (-20%) and LDL cholesterol (-29%). Apolipoprotein B (apoB) kinetic parameters were determined. Very low-density lipoprotein (VLDL) apoB pool size decreased 22% because of inhibition of VLDL production (-43%). LDL apoB pool size decreased 22% because of a 1.5-fold increase in fractional catabolic rate (FCR). The increased FCR was associated with a 2-fold increase in hepatic LDL receptor mRNA. Hepatic total and microsomal cholesterol were reduced by 16% and 27%, respectively. Plasma lathosterol concentrations decreased 57%, reflecting inhibition of hepatic cholesterol synthesis. Treatment reduced plasma plant sterols and decreased postprandial cholesterol transport in chylomicrons. A novel OSC inhibitor, RO0717625, decreased VLDL and LDL apoB100 through decreased VLDL production and enhanced LDL clearance. Thus, OSC represents a potential therapeutic target for dyslipidemia.

Genetic variant of the SREBF-1 gene is significantly related to cholesterol synthesis in man

Sterol regulatory element binding proteins-1 and -2 (SREBPs) are transcription factors controlling lipid homeostasis in human cells. The G-allele carriers of the SREBF-1 gene C–G polymorphism in exon 18c and coding for glycine at the protein level (G952G) have shown to associate more frequently with obesity and type 2 diabetes than the C-allele carriers. However, the C-allele has suggested to be linked to dyslipidemia. Thus, our aim was to study effect of the SREBF-1 gene polymorphism (G952G) on sterol metabolism in man. Ninety-five subjects with moderate hypercholesterolemia participated in this study and 14 homozygous CC carriers of the SREBF-1 (G952G) gene were found. Plasma lathosterol concentration and lathosterol-to-cholesterol ratio, markers of endogenous cholesterol synthesis, were significantly higher in CC homozygous subject compared to others. Similarly muscle cholesterol ( p = 0.045) and lathosterol ( p = 0.054) concentrations were elevated in the CC homozygotes supporting the view that endogenous cholesterol synthesis rate is SREBF-1 genotype-dependent.

Genetic analysis of indicators of cholesterol synthesis and absorption: lathosterol and phytosterols in Dutch twins and their parents.

Significant familial aggregation was observed for plasma levels of lathosterol (an indicator of whole-body cholesterol synthesis) and plant sterols campesterol and beta-sitosterol (indicators of cholesterol absorption) in 160 Dutch families consisting of adolescent mono- and dizygotic twin pairs and their parents. For lathosterol a moderate genetic heritability in parents and offspring (29%) was found. In addition, shared environment also contributed significantly (37%) to variation in plasma lathosterol concentrations in twin siblings. However, a model with different genetic heritabilities in the two generations (10% in parents and 68% in offspring) fitted the data almost as well. For plasma plant sterol concentrations high heritabilities were found. For campesterol heritability was 80% and for beta-sitosterol it was 73%, without evidence for differences in heritability between sexes or generations. No influence of common environmental influences shared by family members was seen for either campesterol or beta-sitosterol. Taken together, these results confirm and expand the hypothesis that individual differences in plasma levels of noncholesterol sterols are moderately (lathosterol) to highly (plant sterols) heritable.

Effects of dietary coconut oil, butter and safflower oil on plasma lipids, lipoproteins and lathosterol levels.

The aim of this present study was to determine plasma levels of lathosterol, lipids, lipoproteins and apolipoproteins during diets rich in butter, coconut fat and safflower oil. The study consisted of sequential six week periods of diets rich in butter, coconut fat then safflower oil and measurements were made at baseline and at week 4 in each diet period. Forty-one healthy Pacific island polynesians living in New Zealand participated in the trial. Subjects were supplied with some foods rich in the test fats and were given detailed dietary advice which was reinforced regularly. Plasma lathosterol concentration (P < 0.001), the ratio plasma lathosterol/cholesterol (P=0.04), low density lipoprotein (LDL) cholesterol (P<0.001) and apoB (P<0.001) levels were significantly different among the diets and were significantly lower during coconut and safflower oil diets compared with butter diets. Plasma total cholesterol, HDL cholesterol and apoA-levels were also significantly (P< or =0.001) different among the diets and were not significantly different between buffer and coconut diets. These data suggest that cholesterol synthesis is lower during diets rich in coconut fat and safflower oil compared with diets rich in butter and might be associated with lower production rates of apoB-containing lipoproteins.

4.P.277 Direct association between the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 and plasma mevalonic acid and lathosterol concentrations in normolipidaemic subjects

4.P.277 Direct association between the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 and plasma mevalonic acid and lathosterol concentrations in normolipidaemic subjects

Plasma Lathosterol as a Screening Test for Bile Acid Malabsorption Due to Ileal Resection: Correlation with 75SeHCAT Test and Faecal Bile Acid Excretion

1. Plasma lathosterol concentration, known to reflect cholesterol and bile acid synthesis, was evaluated as a screening test for bile acid malabsorption, comparing it with faecal bile acid measurements, SeHCAT test and Schilling test in 22 subjects of whom six were healthy controls and 16 had Crohn's disease with ileal resections of varying length. 2. Plasma lathosterols and other non-cholesterol sterols were determined by GLC. Faecal bile acids were measured by GLC, and SeHCAT retention times by gamma camera. The study subjects were divided into two groups according to the degree of bile acid malabsorption: controls (faecal bile acids < 10 mg day-1 kg-1, n = 9) and bile acid malabsorption (faecal bile acids > 10 mg day-1 kg-1, n = 13). 3. Faecal bile acid excretion was 5.9 +/- 1.0 mg day-1 kg-1 in control subjects and 45.7 +/- 6.1 mg day-1 kg-1 in the bile acid malabsorption group. The biological half-life of 75SeHCAT (T1/2) was 95.6 +/- 16.3 h and 14.1 +/- 4.1 h, respectively. Plasma lathosterol levels were significantly elevated in patients with bile acid malabsorption (742 +/- 84 micrograms/ml compared with 400 +/- 59 micrograms/ml in control subjects) and correlated closely with faecal bile acid levels (r = 0.779, P < 0.001), with 75SeHCAT T1/2 (r = -0.524, P < 0.05) and with Schilling test (r = -0.591, P < 0.05). Significant correlations were also obtained for delta 8-cholestenol with faecal bile acids (r = 0.784, P < 0.001) and 75SeHCAT (r = -0.505, P < 0.05). The biological half-life of SeHCAT correlated with faecal bile acid excretion (r = -0.702, P < 0.001). Using mean+2 SD of lathosterol (In micrograms/ml cholesterol) as a cut-off value and 10 mg day-1 kg-1 as the upper limit for faecal bile acid excretion, the test gives 100% sensitivity and 82% specificity for plasma lathosterol determination to detect bile acid malabsorption. 4. The results indicate that both the 75SeHCAT test and plasma lathosterol detect bile acid malabsorption in patients with ileal resections for Crohn's disease. However, plasma lathosterol is a simpler and less expensive method.

Effect of simvastatin on plasma lipid and lipoprotein concentrations and low-density lipoprotein metabolism in the nephrotic syndrome.

1. The effect of inhibiting the rate-limiting enzyme (3-hydroxy-3-methylglutaryl-CoA reductase, EC 1.1.1.88) in cholesterol synthesis on plasma lipid and lipoprotein concentrations was investigated in 16 patients with primary glomerular disease, heavy proteinuria, well-preserved renal function and hypercholesterolaemia. 2. Detailed studies of low-density lipoprotein metabolism were performed on eight patients before and after 12 weeks of simvastatin therapy. Radioiodinated tracers were used to quantify the fractional catabolic rate of low-density lipoprotein by apolipoprotein B/E receptors and alternative pathways. 3. Simvastatin produced consistent reductions in total plasma cholesterol concentration (median 36.9%), plasma low-density lipoprotein-cholesterol concentration (43.6%) and apolipoprotein B pool size (29.9%). 4. In contrast, the changes in kinetic parameters of low-density lipoprotein metabolism showed no clear pattern. Although an increase in the receptor-mediated catabolism of low-density lipoprotein was demonstrated in five patients, no change or a slight decrease was seen in three patients. Production rates were not significantly altered, although there was a slight decrease in the median value (from 12.4 to 9.7 mg day-1 kg-1). Plasma lathosterol concentration was reduced in all eight patients (range 34-71%), indirectly confirming significant inhibition of cholesterol synthesis. 5. These results suggest that, as in patients with primary moderate hyperlipidaemia, the significant cholesterol-lowering effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in the nephrotic syndrome is accompanied by variable changes in lipoprotein metabolism. The reasons for this heterogeneous response are unclear. This reflects our limited understanding of the metabolic basis of nephrotic hyperlipidaemia and the relationship between hepatic sterol synthesis and plasma lipoprotein kinetics.

Plasma Non-Cholesterol Sterols in Patients with Non-Insulin Dependent Diabetes Mellitus

Plasma plant sterol concentrations (an index of cholesterol absorption efficiency) and plasma lathosterol concentration (an index of cholesterol synthesis rate) were measured in 52 patients with non-insulin dependent diabetes mellitus (NIDDM) and 36 non-diabetic controls. Plasma plant sterol concentrations were significantly (P less than 0.01) lower in diabetic patients (campesterol: men -36%, women -48%; betasitosterol: men -35%, women -42%). Fasting serum insulin levels were inversely correlated with plasma plant sterol concentrations in diabetic patients (campesterol: r = -0.347, P = 0.012; betasitosterol: r = -0.345, P = 0.012) and in non-diabetic men (campesterol: r = -0.578, P = 0.039; betasitosterol: r = -0.702, P = 0.008). Serum insulin levels were also correlated significantly with plasma lathosterol concentration in diabetic patients (r = 0.295, P = 0.034). The results of this study suggest that absorption of plant sterols and possibly cholesterol from the diet may be reduced in hyperinsulinemic diabetics.

Plasma noncholesterol sterols in male distance runners and sedentary men

Plasma lathosterol concentration is taken to be an index of the rate of cholesterol synthesis and plasma concentrations of plant sterols just as campesterol and betasitosterol are taken to be indeces of cholesterol absorption efficiency. These noncholesterol sterols were measured in plasma from 14 male distance runners and 10 sedentary men. Plasma lathosterol concentration was 30% lower (P less than 0.02) and plasma betasitosterol concentration was 33% higher (P less than 0.02) in the runners compared to the sedentary men. Plasma concentrations of lathosterol and plant sterols were inversely and significantly (P less than 0.05) correlated in both the runners and the sedentary men. Plasma plant sterol concentrations were correlated positively and significantly (P less than 0.01) with plasma high density lipoprotein cholesterol (HDL-C) concentrations in the runners and sedentary men combined. These findings suggest that more efficient cholesterol absorption may lead to higher plasma plant sterol concentrations and may contribute to lower cholesterol synthesis rates, reduced concentrations of plasma lathosterol and higher plasma HDL-C concentration in distance runners.

Gas-liquid chromatographic determination of fecal neutral sterols using a capillary column

Because the plasma campesterol/cholesterol ratio does not differ between groups that absorb different amounts of cholesterol, the authors investigated whether the plasma Phytosterols (PS) relate to the body's cholesterol synthesis rate measured as non-cholesterol sterol precursors (lathosterol).The authors studied 38 non-obese volunteers (58±12 years; Low-Density Lipoprotein Cholesterol ‒ LDL-C ≥ 130 mg/dL) randomly assigned to consume 400 mL/day of soy milk (Control phase) or soy milk + PS (1.6 g/day) for four weeks in a double-blind, cross-over study. PS and lathosterol were measured in plasma by gas chromatography coupled to mass spectrophotometry.PS treatment reduced plasma total cholesterol concentration (-5.5%, p < 0.001), LDL-C (-7.6%, p < 0.001), triglycerides (-13.6%, p < 0.0085), and apolipoprotein B (apo B) (-6.3%, p < 0.008), without changing high density lipoprotein cholesterol (HDL-C concentration), but plasma lathosterol, campesterol and sitosterol expressed per plasma cholesterol increased.The lathosterol-to-cholesterol plasma ratio predicted the plasma cholesterol response to PS feeding. The highest plasma lathosterol concentration during the control phase was associated with a lack of response of plasma cholesterol during the PS treatment period. Consequently, cholesterol synthesis in non-responders to dietary PS being elevated in the control phase indicates these cases resist to further synthesis rise, whereas responders to dietary PS, having in the control phase synthesis values lower than non-responders, expand synthesis on alimentary PS. Responders absorb more PS than non-responders, likely resulting from responders delivering into the intestinal lumen less endogenous cholesterol than non-responders do, thus facilitating greater intestinal absorption of PS shown as increased plasma PS concentration.