Regulation of plasma plant sterol levels in patients with gut resections

The role of cholesterol and bile acid malabsorption in the regulation of plasma plant sterol levels was studied in 30 patients with an ileal resection (seven without any malabsorption, eight with bile acid malabsorption alone and 15 with bile acid, fat and cholesterol malabsorption) and nine with jejunoileal bypass (modest bile acid, and severe cholesterol and fat malabsorption). In contrast to cholesterol, plant sterols are not synthesized by the body, and so the plasma levels are regulated by their intestinal absorption and biliary secretion. In fact, the plant sterol, especially campesterol, levels were low in patients with cholesterol and fat malabsorption. Cholesterol absorption efficiency was a significant determinant of the plant sterol levels, suggesting that it reflects overall sterol absorption efficiency and that the plasma plant sterol levels, in turn, reflect cholesterol absorption. Bile acid malabsorption, though it appeared to promote biliary plant sterol secretion, had little direct effect on the plasma plant sterol contents. The results indicate that plasma campesterol levels can be used to evaluate cholesterol absorption efficiency in general and may reveal clinically significant steatorrhoea in patients with gut exclusion.     

High density lipoproteins, but not other lipoproteins, provide a vehicle for sterol transport to bile.

Unesterified cholesterol (UC) that is taken up by the liver from lipoproteins is rapidly mixed by exchange with liver UC. Thus, it is not possible to quantitate the transport of UC from different lipoproteins into bile using radiolabeled UC. However, plant sterols do not exchange with UC and are secreted in bile with the same kinetics as UC. To compare the contribution to bile of sterols from different lipoproteins, we perfused isolated rat livers with VLDL, LDL, and HDL that were obtained from patients with hereditary phytosterolemia and were rich in plant sterols. After 30-min recirculating perfusions, hepatic concentrations of plant sterols were not different after different lipoproteins were perfused. However, biliary plant sterol secretion was markedly different: with the perfusion of either VLDL or LDL there was no increase in plant sterols in bile, but with perfusion of HDL, the secretion of plant sterols was increased two- to threefold (P = 0.0005). The increase in biliary plant sterols was detected 5-10 min after HDL was added to perfusates and was similarly large for each of three individual plant sterols that was tracked. Results show that when sterol transport from lipoproteins into bile can be determined, only HDL provides a vehicle for UC elimination in bile that is consistent with its putative function in reverse cholesterol transport.     

Effects of lovastatin and dietary cholesterol on sterol homeostasis in healthy human subjects.

We measured biliary and fecal sterol outputs in 12 human subjects on a metabolic ward in four randomly allocated, 6-7 wk periods: (a) lovastatin (40 mg b.i.d.) + low cholesterol diet (mean 246 mg/d), (b) lovastatin + high cholesterol diet (mean 1,071 mg/d), (c) low cholesterol diet alone, (d) high cholesterol diet alone. In addition to lowering serum LDL cholesterol, lovastatin significantly lowered biliary secretion of cholesterol, fecal output of endogenous neutral sterols, cholesterol balance, and systemic cholesterol input (the sum of cholesterol synthesis and absorbed dietary cholesterol). The high cholesterol diet significantly lowered cholesterol balance, but significantly increased systemic cholesterol input and fecal output of acidic sterols. There was no significant interaction between lovastatin and dietary cholesterol for any parameter measured. Judging from these data, the primary action of lovastatin is to lower cholesterol synthesis and systemic cholesterol input, the main compensatory response being reduced biliary cholesterol secretion. Conversely, increased dietary cholesterol appears to increase systemic cholesterol input, the major compensatory response being increased bile acid synthesis. There appears to be no interaction between these two perturbations of systemic cholesterol input.     

Serum noncholesterol sterols during inhibition of cholesterol synthesis by statins

We studied changes in serum cholestanol and plant sterols (indexes of cholesterol absorption) and cholesterol precursors (indexes of cholesterol synthesis) in response to cholesterol reduction by way of 1 year's treatment with atorvastatin (n = 102) and simvastatin (n = 105) treatments in patients with coronary heart disease. Serum cholesterol levels and ratios of the precursor sterols to cholesterol after 1 year of treatment were reduced in proportion to the pretreatment values (33% +/- 1% by simvastatin and 36% +/- 1% by atorvastatin; P <.01 for difference between groups) for cholesterol; the respective reductions in the precursor sterol:cholesterol ratios were also higher with atorvastatin (50% +/- 2% for lathosterol) than with simvastatin (42% +/- 1%; P <.01 between groups), but the ratio of squalene to cholesterol was increased (17% +/- 5%, P <.001) by atorvastatin. Plant sterol concentrations were gradually increased by atorvastatin but decreased initially by simvastatin. However, their ratios with respect to cholesterol were increased by as much as 82% with atorvastatin and by as much as 39% with simvastatin. In conclusion, effective inhibition of cholesterol synthesis and subsequent reduction in serum cholesterol levels by statins lead to increases in serum plant-sterol levels, probably as a result of reduced biliary secretion and enhanced absorption of these sterols. Because serum plant sterols have been claimed to be involved in the early development of atherosclerosis, the question arises whether continuously increasing serum plant sterols during long-term statin treatment should be prevented by cholesterol malabsorption (eg, by plant stanol ester consumption), especially in subjects with high baseline plant sterol values and effective sterol absorption.     

Effects of plant stanol and sterol esters on serum phytosterols in a family with familial hypercholesterolemia including a homozygous subject

We studied the concentrations and ratios to cholesterol of noncholesterol sterols reflecting absorption (eg, campesterol) or synthesis (eg, lathosterol) of cholesterol off and on plant sterol and stanol ester spreads in serum and in different lipoproteins of a family with familial hypercholesterolemia, including heterozygous parents receiving no treatment and their homozygous offspring undergoing long-term treatment with statins and apheresis. Serum cholesterol levels were similar in the homozygous and heterozygous individuals, but the concentrations of sterols reflecting cholesterol absorption were as much as 10 times greater in the homozygous child than in the heterozygous parents, whereas the respective markers of cholesterol synthesis only tended to be higher. About 70% of squalene in the homozygous individual (60% in the heterozygous family members) and 85% to 90% of noncholesterol sterols (60%-80% in the heterozygous subjects) were transported by low-density lipoprotein. The ratios of absorption sterols to cholesterol were higher in high-density lipoprotein (HDL) than in very low-density lipoprotein (VLDL), whereas those of synthesis markers and plant stanols were highest in VLDL. The ratios of absorption sterols in serum were mostly lower than those in HDL but higher than in VLDL, whereas the ratios of synthesis sterols in serum were lower than they were in VLDL. Both spreads reduced serum total cholesterol by about 14% in the heterozygous family members and 9% in the homozygous individual. The sterol ester spread increased serum plant sterol concentrations (eg, campesterol in the homozygous family member increased from 5 to 9 mg/dL) and the ratios to cholesterol, but the stanol ester spread decreased them. Plant sterol esters seemed to similarly decrease serum cholesterol in this family with familial hypercholesterolemia, but the clinical role of increased plant sterol concentrations, almost doubled in the LDL of homozygous individuals, is not known.     

Lipid metabolism in bile acid malabsorption

Malabsorption of bile acid increases cholesterol synthesis and activates hepatic LDL receptors which leads to enhanced elimination of cholesterol from the body. Interruption of enterohepatic circulation of bile acids may lead to a smaller bile acid pool, which, in turn, impairs cholesterol and fat absorption by reduced micellar solubilization. Together with reduced cholesterol absorption, the increased cholesterol loss as bile acids also reduces plasma cholesterol concentrations and the biliary cholesterol excretion, too. Diminished biliary cholesterol in bile acid malabsorption may contribute to the increased incidence of gallstones associated with ileal dysfunction. Malabsorption of bile acid leads to a fall in LDL-cholesterol concentration, and an increase of HDL-cholesterol concentration has been reported. VLDL-triglyceride concentrations are almost invariably raised. Enhanced cholesterol and bile acid synthesis in ileal dysfunction is reflected by raised concentrations of plasma cholesterol precursors, especially lathosterols, which can be used as an indicator of increased bile acid loss to faeces. Cholesterol absorption, in turn, correlates positively with plasma plant sterol concentrations levels and the ratio of lathosterols to campesterols can be used as a screening measurement for ileal dysfunction. Plasma fatty acid composition is also altered as a response to fat malabsorption associated with ileal dysfunction. The proportion of essential fatty acids is inversely correlated with faecal fat excretion and endogenous fatty acid synthesis is activated.     

Inappropriate hepatic cholesterol synthesis expands the cellular pool of sterol available for recruitment by bile acids in the rat.

These studies test the hypothesis that a major determinant of excessive biliary cholesterol secretion is a level of hepatic sterol synthesis that is inappropriately high relative to the needs of the liver cell for preserving cholesterol balance. Biliary cholesterol secretion was measured in vivo in two models after loading the hepatocyte with sterol by two different mechanisms. In the first model, cholesterol was delivered physiologically to the liver in chylomicron remnants. This resulted in a sixfold increase in cholesteryl ester content and marked suppression of cholesterol synthesis, but biliary cholesterol secretion remained essentially constant. In the second model, 3-hydroxy-3-methyl-glutaryl CoA reductase levels in the liver were markedly increased by chronic mevinolin (lovastatin) administration. Withdrawal of the inhibitor resulted in a sudden fivefold increase in the rate of sterol synthesis in the liver of the experimental animals that was inappropriately high for cellular needs. This excessive synthesis, in turn, was accompanied by a fivefold increase in the cholesteryl ester content, enrichment of microsomal membranes with cholesterol and, most importantly, by a threefold increase in the rate of biliary sterol secretion. As the rate of sterol synthesis gradually returned to normal over 48 h, the cholesterol ester content, the lipid composition of the microsomal membranes, and rate of cholesterol secretion into bile also returned to baseline values. These results further support the concept of functional compartmentalization of cholesterol in the hepatocyte. Derangements that cause an inappropriately high rate of sterol synthesis in the endoplasmic reticulum may lead to an expansion of that pool of cholesterol that is recruitable by bile acids and, hence, to greater situation of the bile.     

Serum plant sterols and lathosterol related to cholesterol absorption in coeliac disease

The concentrations of the plant sterols, campesterol and beta-sitosterol in serum, normally correlate with the efficiency of cholesterol absorption, whereas the concentration of lathosterol, a cholesterol precursor sterol, closely parallels changes in cholesterol synthesis. In this study we explored whether the plant sterol concentrations in serum in coeliac disease are determined by cholesterol absorption and whether they alone or with the serum lathosterol concentration, could be used for screening the activity of coeliac disease. In six patients the plant sterol concentrations in serum were significantly lower than in 17 control subjects, the reduction being more marked for campesterol than for beta-sitosterol: the serum lathosterol concentration was significantly higher than in the control subjects. The opposite changes in serum plant sterols and lathosterol were recorded in patients on a gluten-free diet. The plant sterol concentrations in serum (nmol/mg of cholesterol) were positively correlated with each other, and with the percentage absorption of cholesterol and with xylose absorption; they were negatively correlated with faecal fat, but not with faecal plant sterols. Thus, the low plant sterol concentrations in serum in coeliac disease were attributable to their impaired absorption, which in turn was closely associated with the absorption of cholesterol. The serum campesterol concentration clearly distinguished the untreated patients from the controls, whereas the use of serum beta-sitosterol, and the serum ratios of lathosterol/plant sterol resulted in some overlapping with the controls. It is suggested that the plant sterols in serum might be worth of determining when screening patients for coeliac disease and especially when testing their adherence to the gluten-free diet.     

Non-cholesterol sterols in serum, lipoproteins, and red cells in statin-treated FH subjects off and on plant stanol and sterol ester spreads

BACKGROUND: Serum plant sterol levels are increased by consumption of statins and dietary plant sterols, and decreased by dietary plant stanols, but little is known about combination therapy of statin and plant sterols. METHODS: We measured plant sterols in serum, lipoproteins, and red cells in subjects with familial hypercholesterolemia (FH) (n=18) treated with variable doses of statins off and on plant stanol (STA) and sterol ester (STE) spreads. RESULTS: STA and STE spreads lowered LDL cholesterol approximately 15%. Plant sterols were decreased in serum, lipoproteins, and red cells by approximately 25% with STA and increased from 37% to 80% with STE, especially with high statin doses. The changes in serum were related to those in red cells. The baseline levels of serum plant sterols were negatively (r-range -0.639 to -0.935) and positively (r-range 0.526 to 0.598) correlated with the respective changes evoked by the STA and STE spreads. CONCLUSIONS: STE reduces LDL cholesterol, but increases serum, lipoprotein, and red cell plant sterol levels in statin-treated FH subjects, while all the respective values are decreased with STA. Recent predictions that elevated serum plant sterols pose an increased coronary risk suggest that increases of serum plant sterol levels should be avoided, especially in atherosclerosis-prone individuals, such as subjects with FH.     

Plant stanol and sterol esters in prevention of cardiovascular diseases

Statin trials have indicated that effective reduction of serum cholesterol should last up to one year before reduced risk of cardiovascular diseases can be detected. This observation can be applied most probably also to the use of plant stanol/sterol ester spreads for the treatment of hypercholesterolemia. However, despite the fact that the two spreads lower serum cholesterol similarly in short term studies, a comparison of one year results reveals an inconsistent effect of plant sterol spread as compared with that of plant stanol spread on cholesterol concentration in both men and women. This favors the use of plant stanol ester spread for long-term lowering of serum cholesterol. Doses of about 2 g/day of plant stanols as fatty acid ester spread enhances fecal elimination of cholesterol, but not of bile acids, through inhibition of cholesterol absorption by about 40%. This lowers serum total and low density lipoprotein (LDL) cholesterol despite enhanced compensatory increase in cholesterol synthesis by about 10% and 15% as compared with control spread, respectively, and by up to 20% as compared with the baseline diet. About one-third of mildly hypercholesterolemic subjects reach an accepted cholesterol level. A small dose of statin should be added to treatment in individuals resistant to monotherapy with plant stanol ester spread. A life-long consumption of plant stanol ester spread has been predicted to lower coronary events by about 20%.