Origin of cholesterol transported in intestinal lymph: studies in patients with filarial chyluria

In subjects fed a cholesterol-free diet there are three possible sources of intestinal lymph cholesterol: a) mucosal synthesis; b) absorption of endogenous (biliary) cholesterol; and c) transudation of plasma lipoproteins into the lacteals of the intestinal wall. To test these possibilities, the extent of transudation was measured by means of [3H]beta-sitosterol administered intravenously as a marker. Absorption of biliary cholesterol was reduced by oral administration of beta-sitosterol (9 g/day), and mucosal synthesis of cholesterol was evaluated by comparisons of plasma/lymph [14C]cholesterol specific activity ratios after intravenous administration of a single dose of labeled cholesterol. Studies were carried out on six patients with filarial chyluria. In five patients fed a cholesterol-free diet the results indicated that lymph cholesterol was largely derived by transudation of plasma lipoproteins into the lacteals from the intestinal blood supply, without contribution from de novo mucosal synthesis or from absorption of endogenous cholesterol. The intestinal lymph of one patient fed cholesterol (2 g/day) contained cholesterol originating mostly from plasma transudation and from dietary absorption, with little contribution from absorbed endogenous cholesterol. In all experiments the larger part of the cholesterol transported away from the intestine in the lymph was carried in chylomicrons, even though it had its origin in plasma lipoproteins.     

Sources of error in the isotopic cholesterol balance method in African green monkeys consuming a cholesterol-free diet

Six African green monkeys were labeled intravenously with [1,2-(3)H]cholesterol while consuming a cholesterol-free liquid formula diet. The plasma cholesterol specific activity was compared with the specific activity of the biliary cholesterol and bile acids and with the fecal neutral steroids in order to determine whether the traditional isotopic balance method was valid for the calculation of endogenous cholesterol excretion. The specific activity of biliary cholesterol and bile acids averaged 10-15% lower than plasma cholesterol specific activity. Fecal cholesterol and coprostanone specific activities were similar to that of the biliary cholesterol, but the specific activity of fecal coprostanol was approximately 25% lower. This suggests that biliary cholesterol and bile acids were derived from a pool of hepatic cholesterol that did not completely equilibrate with the whole body exchangeable cholesterol pool. In addition, there was further reduction in the specific activity of coprostanol, the major fecal neutral steroid, presumably by cholesterol synthesized in the lower intestine and preferentially converted to coprostanol. As a result, the traditional isotopic balance procedure underestimated endogenous neutral steroid excretion by 46% and bile acid excretion by 31% in African green monkeys fed the cholesterol-free diet. Within 7 days after the addition of 1 mg cholesterol/kcal to the diet, the specific activities of plasma and biliary cholesterol and biliary bile acids were identical and there was no difference in the specific activities of the individual fecal neutral steroids. Thus, the traditional isotopic balance procedure (DPM fecal neutral steroids + bile acids/specific activity [DPM/mg] plasma cholesterol) can be used for calculation of endogenous cholesterol excretion in cholesterol-fed animals during the nonsteady state when plasma cholesterol concentrations are rapidly increasing, as well as after a new steady state has been achieved.-Henderson, G. R., and R. W. St. Clair. Sources of error in the isotopic cholesterol balance method in African green monkeys consuming a cholesterol-free diet.     

Identification and origins of neutral fecal sterols in adult Large White sows: occurrence of externally-secreted intestinal cholesterol

Cholesterol, the main neutral fecal sterol (54-84 p. 100) in adult Large White sows fed a controlled semi-purified diet containing 0.08 p. 100 cholesterol (500 g twice a day; 3 510 kcal/day), was partially converted into coprostanol (10-44 p. 100). Exceptionally, epicoprostanol was present, indicating a second pathway of bacterial cholesterol degradation. In this paper, the term "fecal cholesterol" is restricted to the sum of cholesterol + coprostanol. The contribution of fecal cholesterol to the bulk of neutral fecal sterols eliminated daily, averaged 97 +/- 1 p. 100. For a given dietary cholesterol intake of 80 mg per day, eliminated fecal cholesterol was estimated to be 392 +/- 47 mg/day and mean fecal cholesterol concentration 1.88 +/- 0.12 mg/g of stools. The various sources of fecal cholesterol were unabsorbed ingested cholesterol, cholesterol excreted from the plasma, and externally-secreted intestinal cholesterol, synthesized by the digestive tract, discharged into the lumen and not absorbed. The respective contributions of these different sources were as follows: unabsorbed dietary cholesterol 34 +/- 2 mg/day, excreted cholesterol 234 +/- 28 mg/day and externally-secreted cholesterol 125 +/- 23 mg/day.     

Cholesterol absorption and transport in thoracic duct lymph lipoproteins of nonhuman primates. Effect of dietary cholesterol level

The effect of dietary cholesterol level on cholesterol absorption and its subsequent transport in thoracic duct lymph lipoproteins was studied in two species of nonhuman primates, namely the African green monkey (Cercopithecus aethiops) and the cynomolgus macaque (Macaca fascicularis). Each animal served as its own control because each received sequential, intraduodenal infusions of two fat-rich liquid diets that differed only in the amounts of cholesterol. The percentage of dietary cholesterol absorbed was calculated by dividing the rate of appearance of exogenous cholesterol radioactivity in lymph by the rate of infusion of dietary cholesterol radioactivity at a time when lymph cholesterol specific activity was constant relative to that of diet. The percentage of dietary cholesterol absorbed was similar during both diet infusions in African green monkeys but was significantly decreased during the high cholesterol diet infusion in cynomolgus macaques. Rates of appearance of lymph total cholesterol mass were significantly increased during infusion of high cholesterol diets due to a statistically significant increase in cholesteryl ester transport rates. This increase was due in large part to the preferential esterification of exogenous cholesterol that was incorporated into lymph chylomicrons and VLDL. The rate of appearance in lymph of exogenous cholesterol significantly increased during the high cholesterol diet infusion while that of endogenous cholesterol decreased. This decrease or compensation in endogenous cholesterol transport occurred during absorption of increased levels of dietary cholesterol and apparently was due to an approximate 50% decrease in the absorption of lumenal cholesterol. Our data demonstrated that there was not a simple one-to-one relationship between the amount of isotopic dietary cholesterol absorbed from the intestinal lumen and the mass of cholesterol moved into lymph via the intestine. Rather, the amount of sterol transported into the body depends on the degree of the decrease in endogenous cholesterol transport and probably on the efficiency of cholesterol esterification during absorption.     

Cholesterol-free diet with a high ratio of polyunsaturated to saturated fatty acids in heterozygous familial hypercholesterolemia: significant lowering effect on plasma cholesterol

We have studied the effect of diet therapy on plasma lipoprotein metabolism in heterozygous familial hypercholesterolemia. Seven patients with a mean plasma cholesterol concentration of 323 +/- 67 mg/dl were hospitalized and kept on a cholesterol-free diet for as long as 11 days without any medication. The content of dietary cholesterol was approximately 1.4 mg a day, and dietary fat, carbohydrate and protein comprised 18.0, 69.2 and 12.8% of calories, respectively. The ratio of polyunsaturated to saturated fatty acids (P/S) was 3.1. At the end of the study period, plasma cholesterol was lowered by 14.2%, from 323 to 277 mg/dl, and low density lipoprotein (LDL) cholesterol by 17.5% from 229 to 189 mg/dl. Using density gradient ultracentrifugation, the major change in LDL cholesterol was found to be in those fractions with a mean density between 1.034 and 1.042, where cholesterol concentrations decreased from 132 to 87 mg/dl (34%). These results indicate that diet therapy with free-cholesterol and a high ratio of P/S is highly effective in controlling plasma cholesterol levels in heterozygous familial hypercholesterolemia.     

The lipid-lowering effect of ezetimibe in pure vegetarians

Results of previous studies have shown that ezetimibe (10 mg/day) reduces LDL cholesterol in patients with mild hypercholesterolemia on a normal-cholesterol diet (dietary intake of 200-500 mg/day) by 16-22%. However, the LDL cholesterol-lowering effect of ezetimibe in subjects with an extremely low dietary cholesterol intake (vegetarians) has not been studied. We conducted a randomized, double-blind, placebo-controlled, two-phase crossover study in 18 healthy pure vegetarians to assess the effect of ezetimibe (10 mg/day) on plasma lipids, cholesterol absorption, and its synthesis. Treatment periods lasted 2 weeks each, with an intervening 2 week washout period. Fractional cholesterol absorption was determined using the continuous dual stable isotope feeding method. Mean dietary cholesterol intake in the pure vegetarians was extremely low and averaged 29.4 +/- 16.8 and 31.4 +/- 14.4 mg/day during the placebo and ezetimibe administration phases, respectively. Fractional cholesterol absorption during the placebo phase was 48.2 +/- 8.2% and was decreased by 58% during ezetimibe treatment to 20.2 +/- 6.2% (P < 0.001). This change in intestinal cholesterol absorption was followed by a significant reduction in LDL cholesterol of 17.3%. In individuals with extremely low dietary cholesterol intake, treatment with ezetimibe (10 mg/day) leads to a significant reduction of cholesterol absorption and a clinically relevant decrease of plasma LDL cholesterol, comparable to that of subjects with a normal dietary cholesterol intake. Thus, the lipid-lowering effect of ezetimibe is mediated mainly through a reduction of the absorption of endogenous (biliary) cholesterol.     

Effects of synthetic glycosides on steroid balance in Macaca fascicularis

The predominantly beta-anomer of diosgenin glucoside (DG) was synthesized and its effects on cholesterol homeostasis were tested in monkeys. Cynomolgus macaques (Macaca fascicularis) were fed, during two 3-week periods, a semipurified diet with 0.1% cholesterol and a similar ration containing 1% DG, respectively. A Chow diet was given for 5 weeks between the experimental periods. Cholesterol and bile acid balance were analyzed during the last week of each semipurified diet. Diosgenin glucoside reduced cholesterolemia from 292 mg/dl to 172 mg/dl, decreased intestinal absorption of exogenous cholesterol from 62.4% to 26.0%, and increased secretion of endogenous cholesterol from -0.8 to 93.5 mg/day. The fecal excretion of neutral steroids rose from 40.7 to 157.3 mg/day; that of bile acids changed, nonsignificantly, from 23.1 to 16.0 mg/day. The cholesterol balance was -44 mg/day in the control period, and 88 mg/day in the DG-fed animals. No toxic signs were observed. Thus, when long-term studies demonstrate that the glucoside is well tolerated, DG and other synthetic glycosides with similar activities may be of use in the management of hypercholesterolemia and atherosclerosis.     

Validation of a dual-isotope plasma ratio method for measurement of cholesterol absorption in rats

Several methods for measuring cholesterol absorption in the rat have been compared. After administration of an oral dose of labeled cholesterol ((14)C or (3)H) and an intravenous dose of colloidal labeled cholesterol ((3)H or (14)C) the ratio of the two labels in plasma or whole blood 48 hr or more after dosing compared closely to the ratio of areas under the respective specific activity-time curves. The area ratio method is independent of a time lag between the appearance of oral and intravenous label in the bloodstream. Both measures of cholesterol absorption agree fairly well with a method based on measuring the unabsorbed dietary cholesterol in a pooled fecal sample. The plasma isotope ratio method gave more reproducible results than the fecal collection method when the measurement was repeated in the same animals 5 days after the first measurement. Cholesterol absorption was overestimated by the use of Tween 20-solubilized labeled cholesterol for the intravenous dose. The plasma disappearance curves of injected labeled colloidal cholesterol and cholesterol-labeled chylomicrons infused intravenously over a 3.5-hr period in the same animal coincided within experimental error from the first day until 75 days after injection. The plasma isotope ratio method for cholesterol absorption gave the same results in rats practicing coprophagy as in those in which this practice was prevented. The addition of sulfaguanidine to the diet lowered cholesterol absorption as measured by the plasma isotope ratio to the same degree as that measured by the fecal collection method.     

Sterol balance studies in the rat. Effects of dietary cholesterol and beta-sitosterol on sterol balance and rate-limiting enzymes of sterol metabolism.

Sterol balance measurements using isotopic and chromatographic techniques were carried out in rats fed diets containing beta-sitosterol (0.8%) and cholesterol (1.2%). The activities of the rate-limiting enzymes of cholesterol synthesis (beta-hydroxy-beta-methylglutaryl-CoA reductase, EC 1.1.1.34) and bile acid synthesis (cholesterol 7 alpha-hydroxylase) were determined in the same animals. Cholesterol feeding increased cholesterol absorption from 1.2 to 70 mg/day. The increased absorption was compensated for by inhibition of hepatic cholesterol synthesis, enhanced conversion of cholesterol to bile acids (from 13.7 to 27.3 mg/day) and a slight increase in the excretion of endogenous neutral steroids (from 7.7 to 11.2 mg/day). Despite the adaptation there was accumulation of cholesterol in the liver (from 2.2 to 9.2 mg/g). Beta-Sitosterol feeding inhibited cholesterol absorption (calculated absorption was zero). In these rats there was enhanced cholesterol synthesis (from 20.0 to 28.8 mg/day, but no change in the rates of bile acid formation. Measurements of the activities of the rate-limiting enzymes showed fair correlation with cholesterol-bile acid balance. In cholesterol fed animals, beta-hydroxy-beta-methylglutaryl-CoA reductase was inhibited 80% and cholesterol 7 alpha-hydroxylase was enhanced 61%. In beta-sitosterol-fed animals, the reductase was increased 2-fold and cholesterol 7 alpha-hydroxylase was not significantly different from controls.     

The interaction of cholesterol absorption and cholesterol synthesis in man

The total miscible pool of cholesterol in the body is determined largely by the interaction of cholesterol absorption and synthesis. In the present study we have examined the net effects of this interplay in one normal and five hypercholesteremic subjects when various amounts of cholesterol were made available for absorption. Feeding large amounts of cholesterol to the normocholesteremic patient caused an expansion of body pools by as much as 20 g before the amount of cholesterol re-excreted as fecal neutral steroids each day came into balance with the cholesterol absorbed from the diet. There was no detectable decrease in total body synthesis of cholesterol nor any increase in conversion of cholesterol into bile acids. However, feedback control of cholesterol synthesis was demonstrable when large quantities of plant sterols were fed: in the hypercholesteremic patients thus studied, the absorption of both endogenous and exogenous cholesterol was then greatly reduced, and a compensatory increase in synthesis occurred. Thus, the plant sterol experiments, but not the cholesterol feeding experiment, demonstrated that feedback control by dietary cholesterol does occur in man. That feedback control by dietary cholesterol is relatively unimportant in man seems to be due to the fact that in the metabolic "steady state" the absorption mechanism is essentially saturated by the large amounts of endogenous cholesterol available for reabsorption. These findings demonstrate that there are important differences between man and various laboratory animals in regard to the interaction of absorption and synthesis as factors controlling the size of tissue pools of cholesterol.     

Cholesterol catabolism in the rabbit in fasted and fed states.

Urinary and fecal endogenous steroid excretion of fed or fasted New Zealand white rabbits was determined by the isotopic steady state method after subcutaneous implantation of radioactive cholesterol. While plasma cholesterol was increasing during a 9-day fast, fecal steroid excretion decreased to 10% of the excretion rates in the fed state. Refeeding the fasted rabbits led to a decrease in plasma cholesterol and an increase in fecal endogenous steroid excretion. Urinary steroid excretion, which represented 18% of total endogenous steroid excretion for fed animals, decreased during fasting and increased during refeeding, but these changes were relatively small. The small intestine, cecum, and colon of fed or fasted rabbits had similar endogenous steroid was acidic steroid. During attempts to alter the circulating bile acid concentration by supplying deoxycholate (200 mg/day) to fed rabbits or cholestyramine (2 g/day) to fasted rabbits, plasma cholesterol concentration did not change to the same extent as during fasting or refeeding, respectively. The decreased cholesterol catabolism and the hypercholesterolemia that are seen in the fasting rabbit may result from decreased clearance of plasma cholesterol.     

Dietary cholesterol absorption, and sterol and bile acid excretion in hypercholesterolemia-resistant white rabbits

The New Zealand white (NZW) rabbit fed a 0.1% cholesterol-enriched diet (CD) typically responds (normoresponsive, NR) by quickly developing hypercholesterolemia. To study the underlying mechanisms responsible for the widespread phenomenon of inter-individual variability of response to dietary cholesterol, a unique hypercholesterolemia-resistant (RT) rabbit model was developed. These animals were utilized to investigate selected potential mechanisms that might enable the RT animal to compensate for dietary cholesterol overload. When rabbits were fed the low-cholesterol stock diet, there was no significant difference in the plasma cholesterol concentrations of the NR and the RT animals. However, a significant rise was observed in the NR rabbits within 1 month of their being placed on the cholesterol-enriched diet; the plasma cholesterol concentration of the RT animals was not affected. During consumption of the cholesterol diet the cholesterol absorption rate was somewhat greater in the NR rabbits (P less than 0.05), whereas intestinal transit times and the fecal excretion of neutral steroids were substantially the same in both groups. In contrast, the fecal bile acid excretion of the RT animals was more than twice as great (P less than 0.0001) as that of the NR animals. We conclude that the response to dietary cholesterol is a heritable trait in these rabbits and that, although less dietary cholesterol was absorbed by the RT animals, it appears that a major mechanism controlling plasma cholesterol levels involves the rate of conversion of cholesterol to bile acids and their subsequent excretion.     

Cholesterol metabolism in rhesus monkey, squirrel monkey, and baboon

The metabolism of cholesterol was studied in baboons, rhesus monkeys, and squirrel monkeys while they were being fed either a low fat, low cholesterol (basal) diet or the basal diet supplemented with saturated fat and cholesterol (atherogenic diet). When the diet was changed from basal to atherogenic, the mean total serum cholesterol concentration increased from 70 to 180 mg/dl in the baboon, from 168 to 283 mg/dl in the squirrel monkey, and from 144 to 608 mg/dl in the rhesus monkey. In animals fed the atherogenic diet, the percentage of dietary cholesterol absorbed was greatest in the rhesus monkey and least in the baboon. The fraction of the total body pool of cholesterol that was derived from the diet was greatest in the squirrel monkey and least in the baboon. The turnover of the body pool of cholesterol was several times faster in the squirrel monkey than in the baboon or the rhesus monkey when either dict was fed. The mean total fecal excretion of endogenous cholesterol and bile acid increased in all species on transition to the atherogenic diet; however, the relative contributions of the neutral and acidic fractions to the increase in total excretion differed among species. The difference in percentage of dietary cholesterol absorbed may, in part, account for the large differences in serum cholesterol during the atherogenic diet period. Comparison with other published results indicates that of these species cholesterol metabolism in the baboon is most like that in the human.     

A cholesterol-free, high-fat diet suppresses gene expression of cholesterol transporters in murine small intestine

Transporters present in the epithelium of the small intestine determine the efficiency by which dietary and biliary cholesterol are taken up into the body and thus control whole-body cholesterol balance. Niemann-Pick C1 Like Protein 1 (Npc1l1) transports cholesterol into the enterocyte, whereas ATP-binding cassette transporters Abca1 and Abcg5/Abcg8 are presumed to be involved in cholesterol efflux from the enterocyte toward plasma HDL and back into the intestinal lumen, respectively. Abca1, Abcg5, and Abcg8 are well-established liver X receptor (LXR) target genes. We examined the effects of a high-fat diet on expression and function of cholesterol transporters in the small intestine in mice. Npc1l1, Abca1, Abcg5, and Abcg8 were all downregulated after 2, 4, and 8 wk on a cholesterol-free, high-fat diet. The high-fat diet did not affect biliary cholesterol secretion but diminished fractional cholesterol absorption from 61 to 42% (P < 0.05). In an acute experiment in which triacylglycerols of unsaturated fatty acids were given by gavage, we found that this downregulation occurs within a 6-h time frame. Studies in LXRalpha-null mice, confirmed by in vitro data, showed that fatty acid-induced downregulation of cholesterol transporters is LXRalpha independent and associated with a posttranslational increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity that reflects induction of cholesterol biosynthesis as well as with a doubling of neutral fecal sterol loss. This study highlights the induction of adaptive changes in small intestinal cholesterol metabolism during exposure to dietary fat.     

Comparison of synthetic saponin cholesterol absorption inhibitors in rabbits: evidence for a non-stoichiometric, intestinal mechanism of action

The hypocholesterolemic activities of pamaqueside and tiqueside, two structurally similar saponins, were evaluated in cholesterol-fed rabbits. The pharmacological profiles of the saponins were virtually identical: both dose-dependently decreased the intestinal absorption of labeled cholesterol 25-75%, increased fecal neutral sterol excretion up to 2.5-fold, and decreased hepatic cholesterol content 10-55%. High doses of pamaqueside (>5 mg/kg) or tiqueside (>125 mg/kg) completely prevented hypercholesterolemia. Decreases in plasma and hepatic cholesterol levels were strongly correlated with increased neutral sterol excretion. Ratios of neutral sterol excreted to pamaqueside administered were greater than 1:1 at all doses, in opposition to the formation of a stoichiometric complex previously suggested for tiqueside and other saponins. Ratios in tiqueside-treated rabbits were less than unity, a reflection of its lower potency. Pamaqueside-treated rabbits exhibited a more rapid decline in plasma cholesterol concentrations than control animals fed a cholesterol-free diet, indicating that the compound also inhibited the absorption of biliary cholesterol. Intravenous administration of pamaqueside had no effect on plasma cholesterol levels despite plasma levels twice those observed in rabbits given pamaqueside orally.These data indicate that pamaqueside and tiqueside induce hypocholesterolemia by blocking lumenal cholesterol absorption via a mechanism that apparently differs from the stoichiometric complexation of cholesterol hypothesized for other saponins.     

Evaluation of the contribution of dietary cholesterol to hypercholesterolemia in diabetic rats and of sitosterol as a recovery standard for cholesterol absorption

The contribution of dietary cholesterol to hypercholesterolemia in diabetic rats fed chow ad libitum was evaluated. Diabetes was induced with streptozotocin, and the intake, absorption, and subsequent tissue distribution of dietary cholesterol were measured. Absorption was measured as the difference between [3H]cholesterol intake and fecal 3H-labeled neutral sterol excretion, using both [14C]sitosterol (added to diet) and [14C]cholesterol (added to feces) as recovery markers. [3H]Cholesterol absorption was underestimated by 1-3% using [14C]sitosterol as a recovery standard, due to the 7-8% absorption of sitosterol. After 3 weeks of diabetes, rats were hyperphagic, thereby increasing dietary cholesterol intake 2-fold. [3H]Cholesterol absorption was significantly increased from 69% in controls to 78% in diabetics, whereas [14C]sitosterol absorption was unaffected. With increased dietary cholesterol intake and decreased whole body cholesterol synthesis (Diabetes. 1983. 32: 811-819), influx from diet equaled for exceeded influx from synthesis. The amounts of 3H-labeled neutral sterol recovered from the small intestine, periphery, and plasma were increased 3- to 4-fold in the diabetic rats. Furthermore, the degree of hypercholesterolemia in diabetic rats was directly related to the fraction of plasma cholesterol derived from the diet. We conclude that the 2.3-fold increase in absorbed dietary cholesterol resulting from hyperphagia and, to a lesser extent, from increased fractional absorption, contributes to the hypercholesterolemia of diabetic rats fed chow ad libitum.     

Stronger Suppression of Plasma Cholesterol and Enhancement of the Fecal Excretion of Steroids by a Buckwheat Protein Product than by a Soy Protein Isolate in Rats Fed on a Cholesterol-free Diet

We investigated the effects of a buckwheat protein product (BWP), soy protein isolate (SPI) and casein on the plasma cholesterol level and fecal steroid excretion in rats fed on a cholesterol-free diet. The consumption of BWP suppressed plasma cholesterol by enhancing the fecal excretion of both neutral and acidic steroids. These effects of BWP were stronger than those of SPI.     

Stronger suppression of plasma cholesterol and enhancement of the fecal excretion of steroids by a buckwheat protein product than by a soy protein isolate in rats fed on a cholesterol-free diet

We investigated the effects of a buckwheat protein product (BWP), soy protein isolate (SPI) and casein on the plasma cholesterol level and fecal steroid excretion in rats fed on a cholesterol-free diet. The consumption of BWP suppressed plasma cholesterol by enhancing the fecal excretion of both neutral and acidic steroids. These effects of BWP were stronger than those of SPI.     

Delineation of molecular changes in intrahepatic cholesterol metabolism resulting from diminished cholesterol absorption

The absorption of cholesterol by the small intestine is a major route for the net entry of cholesterol into the body and can therefore affect the plasma low density lipoprotein-cholesterol (LDL-C) concentration. These studies used ezetimibe, a potent inhibitor of cholesterol absorption, to delineate the biochemical and molecular changes in intrahepatic metabolism and biliary lipid secretion when there is a major reduction in chylomicron cholesterol delivery to the liver. In female LDL receptor (LDLR)-deficient (LDLR-/-) mice fed a basal diet containing ezetimibe (0-10 mg/day/kg body weight), cholesterol absorption was reduced up to 91%, fecal neutral sterol excretion was increased up to 4.7-fold, and plasma total cholesterol concentrations decreased by up to 18%. Blocking cholesterol absorption prevented the accumulation of very low density lipoproteins and LDL in the circulation of LDLR-/- mice fed a lipid-rich diet. In female LDLR+/+ mice fed the lipid-rich diet with ezetimibe, the relative mRNA level for the LDLR in the liver was 2-fold greater than in matching mice given the lipid-rich diet alone. We conclude that in the mouse the reduction in plasma LDL-C levels induced by blocking cholesterol absorption reflects both a diminished rate of LDL-C production and a modest increase in hepatic LDLR expression.     

Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men

This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks. Ezetimibe and ezetimibe/simvastatin decreased fractional cholesterol absorption by 65% and 59%, respectively (P < 0.001 for both relative to placebo). Simvastatin did not significantly affect cholesterol absorption. Ezetimibe and ezetimibe/simvastatin increased fecal sterol excretion (corrected for dietary cholesterol), which also represents net steady state cholesterol synthesis, by 109% and 79%, respectively (P < 0.001). Ezetimibe, simvastatin, and ezetimibe/simvastatin decreased plasma LDL-cholesterol by 20, 38, and 55%, respectively. The coadministered therapy was well tolerated. The decreases in net cholesterol synthesis and increased fecal sterol excretion yielded nearly additive reductions in LDL-cholesterol for the coadministration of ezetimibe and simvastatin.