The effect of dietary supplementation of cholesterol and its subsequent withdrawal on the liver lipids and serum lipoproteins of chickens

Two groups of male chickens were fed either a control diet (group N) containing a standard poultry ration admixed with 10% corn oil or a cholesterol diet (group C) in which the control diet was supplemented with 1% cholesterol. After 6 weeks on the diets, a negligible amount of very low density lipoprotein (VLDL) was found in the serum from control animals. On the other hand, the serum VLDL from the cholesterol-fed birds was the predominant lipoprotein and carried 72% of the total serum lipids. Surprisingly this lipoprotein from cholesterol-fed animals was very low in triglycrides (6%) and high in total cholesterol (77%). While the level of serum low density liporotein was unaffected by the ingestion of cholesterol, the concentration of total lipids and phospholipids in the high density lipoprotein decreased in cholesterol-fed animals. The greatest change in liver lipids from animals fed cholesterol was found in the cholesterol esters, whereas the unesterified cholesterol, triglyceride and phospholipid varied slightly or remained constant. In normal animals the distribution of cholesterol between the liver and the serum was about equal, whereas in the cholesterol-fed birds the liver accounted for 80% of the cholesterol found in the liver-serum pool. In order to determine how the hypercholesterolemic bird responds to the withdrawal of cholesterol from the ration, a diet-exchange experiment was conducted. In this study the birds that were originally fed the cholesterol diets (group C) for 6 weeks were placed on the control diet (group CN) and the birds fed the control diet (group N) for 6 weeks were given the cholesterol diet (group NC). At periodic intervals, 1, 3, 7 and 14 days following the change of diets, 3–5 animals from each group were sacrificed, and analyses performed on their serum lipoproteins and liver lipids. Within one day after the diet substitution, there was a 31-fold increase and a 46% decrease, respectively, in the serum VLDL concentration in groups NC and CN as compared with their corresponding steady state values (groups N and group C, respectively). The liver cholesterol increased 4-fold and decreased 40%, respectively, in the two groups NC and CN as compared with the values obtained before the diet substitution. It is suggested that the concentration of cholesterol in the liver is the principal factor controlling cholesterol metabolism in chickens fed a hypercholesterolemic diet. This represents a portion of a Ph.D. thesis submitted by A.W. Kruski to the University of Illinois in February 1971.     

The effect of dietary lipid on the lipoprotein status of the mongolian gerbil

The Mongolian gerbil,Meriones unguiculatus, may be a suitable animal model for the investigation of dietary lipid effects on cholesterol metabolism. The effects of dietary cholesterol, and its possible interaction with the type of dietary fat, on the lipoprotein status of this animal have not been examined previously. In the present research, the effects of adding 0.5% cholesterol to diets high in saturated (19.5% beef tallow: 0.5% safflower oil) or polyunsaturated (20% safflower oil) fats on the lipoprotein status of the gerbil were determined after 11 and 22 days of feeding. Lipoproteins (VLDL, LDL and HDL) were separated by sequential ultracentrifugation. Their cholesterol, phospholipid and protein concentrations were determined colorimetrically. In the absence of 0.5% cholesterol, safflower oil lowered the concentration (mg/100 ml) of cholesterol in each of the VLDL, LDL and HDL relative to beef tallow (BT) without greatly influencing the cholesterol distribution amongst them. The HDL carried the majority of the serum cholesterol and the VLDL transported the smallest amount. However, inclusion of 0.5% dietary cholesterol resulted in a redistribution of cholesterol amongst the lipoproteins so that the VLDL and LDL became the major and the HDL the minor carriers. Dietary cholesterol also brought about a rise in the VLDL and LDL concentrations (mg/100 ml) of cholesterol, phospholipid and protein and altered the VLDL and LDL compositions. No such changes were observed in the HDL, indicating that the HDL are relatively resistant to any of the possible effects of cholesterol feeding measured in this experiment. The specific mechanisms responsible for the changes observed in the lipoprotein status of the gerbil remain to be elucidated. Presented in part at the Triennial Joint Meeting of the AIN/ASCN/CSNS, July 1982     

The effect of neomycin on cholesterol metabolism

Oral neomycin lowers serum cholesterol in man, whereas intramuscular doses are ineffective. Probably it exerts its effect in the gastrointestinal tract. It has been suggested that neomycin specifically involves alteration of the intestinal flora. An increased excretion of bile acids and the failure of the conversion of cholic acid to deoxycholic acid has been demonstrated, which supports this hypothesis. It has also been suggested that the decrease in serum cholesterol is related to a malabsorption syndrome. Although large doses of neomycin do cause a malabsorption syndrome there is no agreement as to the occurrence or severity of a malabsorption syndrome related to therapeutic doses of neomycin.     

Effect of Castration and hormonal supplementation on cholesterol cholelithiasis in the male hamster

This study examined the effect of castration and dietary hormonal supplementation on cholesterol cholelithiasis in male hamsters. Animals fed a standard lithogenic diet developed cholesterol gallstones (17%) after 6 wk, while castrated hamsters did not form any stones. Addition of a synthetic androgen, methyltestosterone, to the lithogenic diet induced cholelithiasis in castrated animals (50%). The biles of normal and castrated-hormone supplemented hamsters had cholesterol saturation indices of 1.0 and 1.1, respectively, while the bile of the castrated animals remained unsaturated (0.6). The ratio of cholic acid/chenodeoxycholic acid in bile increased after castration, but returned to normal levels following hormonal supplementation. Biliary cholesterol carriers were separated by ultracentrifugation. Animals in the stone-forming groups (normal and castrated-hormone treated) had a significant proportion of their biliary cholesterol in vesicles (44 and 46%, respectively); castrated hamsters had less cholesterol in vesicle form (9%). The molar ratio of cholesterol/phospholipid in vesicles was reduced after castration (0.93 vs. 0.42) and increased by hormonal supplementation (1.89). In conclusion, when compared to normal male hamsters fed a standard lithogenic diet, castration reduced the cholesterol saturation of bile, lowered the vesicular/micellar ratio in bile, and inhibited cholesterol cholelithiasis. Dietary androgen supplementation increased the lithogenicity of bile, resulting in stone formation in castrated animals.     

The effect of a non-absorbable fat on the turnover of plasma cholesterol in the rat

Rats were injected with [4-¹⁴C]-cholesterol and then fed diets that contained sucrose polyester (SPE) at levels of 0 and 8% of the diet.¹⁴C was measured in neutral and acidic steroid fractions of the feces collected during days 35–39 post i.v. injection. Periodic blood samples were used to measure the specific activity of the plasma cholesterol. The plasma data were consistent with a two-pool model for the decay of the plasma specific activity. The slow component of the decay curve decreased more rapidly in animals that received SPE. The half-life corresponding to this component was approximately 20% shorter in the SPE-fed animals compared to the control group. The mass of cholesterol calculated for the first pool was similar for all groups of animals. The¹⁴C found in the feces was consistent with the more rapid removal of cholesterol from the body in the SPE-fed animals. The mass of excreted steroid was equal to the calculated rate of cholesterol production in each group of animals.     

Hydroxylation of fatty acids and alcohols by hepatic microsomal cytochrome P-450 system from the Mongolian gerbil

The liver microsomes of the Mongolian gerbilMeriones unguiculatus catalyzed the hydroxylation of various saturated fatty acids (C₈−C₁₈), alcohols (C₁₂ and C₁₆) and hydrocarbon (C₁₂) to the corresponding ω- and (ω-1)-hydroxy derivatives. Lauric acid was hydroxylated most effectively among saturated fatty acids and the order of activity as hydroxylation substrates was C₁₂>C₁₄>C₁₃>C₁₆>C₁₀>C₁₈>C₈. The specific activity of laurate hydroxylation (5.99 nmol/mg microsomal protein/min) in gerbil liver microsomes was higher than that observed in other species. 1-Dodecanol was also hydroxylated very effectively (4.58 nmol/mg microsomal protein/min) by gerbil liver microsomes, but in general the hydroxylation rates for fatty alcohols were much lower than those for the corresponding acids. It was found from both inhibitor and cofactor studies that the enzyme catalyzing the hydroxylation of fatty acids and alcohols in the liver microsomes of the Mongolian gerbil was a typical cytochrome P-450-linked monooxygenase, and at least two different cytochrome P-450 species were involved in the hydroxylation. Presented in part at the AOCS annual meeting (a joint meeting with the Japan Oil Chemists' Society), Honolulu, Hawaii, May 1986.     

Betaine supplementation affects the cholesterol but not the lipid profile of pigs

This study was undertaken to investigate the effects of long term betaine intake on the cholesterol and lipid profile of Alentejano (AL) pigs. At ?36 kg body weight (BW), castrated male and female pigs fed a commercial (C) diet, were divided into two groups: i) Group C, consuming the C diet; and ii) Group CB, consuming the C diet supplemented with 1 g/kg betaine. Pigs were slaughtered at ?100 kg BW. Fasting plasma concentrations of protein, urea, glucose, TAG, phospholipids, homocysteine, total and LDL‐ and HDL‐cholesterol were determined. Liver TAG, phospholipids, and total and free cholesterol were analyzed, as well as total lipids, cholesterol contents, and fatty acid (FA) composition of M. semimembranosus and dorsal subcutaneous fat. Betaine supplemented pigs presented significantly higher plasma concentrations of TAG, phospholipids, cholesterol, and lipoprotein cholesterol. Dorsal subcutaneous fat cholesterol concentration was also significantly higher in CB than in C pigs. No differences were detected in the most abundant FA profile (including the unsaturated to saturated FA ratio) of muscle and subcutaneous fat tissues among treatments. These data suggest that betaine induces dyslipidemia, and increases cholesterol concentration in dorsal subcutaneous fat, without affecting the FA profile of M. semimembranosus and dorsal subcutaneous fat.     

The effect of neurotensin on the concentration of cholesterol and bile acids in the guinea pig

In guinea pigs, total plasma cholesterol concentrations increased above the control values after single intravenous injections and after 3 days of continuous subcutaneous administration of neurotensin (NT). A high dose of NT (125 pmol/100 g body weight) induced tachycardia and severe respiratory distress; the lowest dose (1.25 pmol/100 g body weight) had the greatest hypercholesterolemic effect 15 min after the injections. The bulk of the total plasma cholesterol was in low density lipoprotein fractions. Cholesterol increased in the same fractions after intravenous administrations of NT. NT induced a decrease in the cholesterol content in the ileum but did not affect significantly the cholesterol content in the liver, kidneys or adrenals. In 48-hr fasted controls, plasma cholesterol concentration and cholesterol content in the liver, kidneys, adrenals and terminal ileum increased; after intravenous injections of NT, plasma cholesterol concentration further increased but cholesterol content of the liver, kidneys and ileum decreased. In fed animals, the concentration of the biliary taurochenodeoxycholic acid increased above the control values 5 and 35 min after the intravenous injections of NT. In fasted controls, the total concentration of bile acids was higher than in fed controls, but only the concentration of taurochenodeoxycholic acid further increased after the injections of NT. Proportionately more taurochenodeoxycholic acid than cholesterol was present in bile after the intravenous injections of NT. These data are consistent with the hypothesis that NT has a regulatory role in intestinal cholesterol transport.     

The effect of a histidine-excess diet on cholesterol synthesis and degradation in rats

Feeding a diet high in excess histidine (5% L-histidine) resulted in hypercholesterolemia and enlargement of the liver in rats. To clarify the mechanism of the hypercho-lesterolemia cholesterol synthesis and degradation were followed. We found that hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity in histidine-excess diet rats was significantly higher than in rats fed a basal diet. Incorporation of [³H]water into cholesterol of liver slices from rats fed the histidine-excess diet was higher than incorporation into liver slices from rats fed the basal diet (expressed per liver per 100 g body weight).In vivo incorporation of [³H]water into hepatic cholesterol was also higher, but the incorporation into cholesterol of the small intestine was lower in histidine-fed rats than in rats fed the basal diet (expressed per liver per 100 g body weight). Hepatic cholesterol 7α-hydroxylase activity was similar in both groups. The data suggest that the hypercholester-olemia caused by histidine-excess diet appears to be due to the stimulation of cholesterol synthesis in the liver.     

The effect of alfalfa-corn diets on cholesterol metabolism and gallstones in prairie dogs

Cholesterol gallstones were present in prairie dogs fed alfalfa plus corn with and without exogenous cholesterol (0.4%). The diets fed to the animals for eight weeks contained alfalfa plus corn in fixed proportions of 50∶50, 85∶15 and 15∶85 (w/w). At sacrifice, all animals were healthy but had not gained weight; no deaths occurred during the experiment. Cholesterol gallstones were present in all groups. In the absence of exogenous cholesterol, the highest stone incidence was found in the animals which received the lowest fiber (highest corn) diets (alfalfa plus corn, 50∶50, 67%; alfalfa plus corn, 15∶85, 83%). Cholesterol gallstone incidence was 100% when exogenous cholesterol was added to the alfalfa plus corn diets (50∶50 and 15∶85). No pigment gallstones were detected in any animal. Liver and plasma cholesterol concentrations were highest in the animals receiving alfalfa plus corn (15∶85) plus 0.4% cholesterol (4.29 mg/g, and 356 mg/dl, respectively). These values were lowest in animals receiving 85% alfalfa plus 15% corn without cholesterol (2.19 mg/g and 88 mg/dl, respectively). Lithogenic indices were below 1.00 in all groups. Biliary bile acids were mainly amidates of cholic acid and chenodeoxycholic acid, with the former predominating. Thus, gallstones can be formed in prairie dogs in the absence of exogenous cholesterol; gallstone incidence is reduced by dietary fiber.     

Influence of dietary cholesterol on the relative synthesis of hepatic glycerides and molecular classes of 1,2-diglycerides and phospholipids in the gerbil in vivo

The influence of dietary cholesterol on the relative rates of synthesis of hepatic lipids in the male Mongolian gerbil,Meriones unguiculatus, was studied. The semi-purified starch-based diet used lard as the dietary fat and was fed with or without a 0.5% (by wt.) cholesterol supplement. Each animal received 300 μCi [2-³H]-glycerol i.p. after 3 or 7 days on the dietary regimens. Relative rates of [2-³H]-glycerol incorporation into the major hepatic glycerides in vivo was not affected significantly by dietary cholesterol (0.5% level), suggesting that alteration in the relative biosynthesis of these lipids could not readily account for the higher triglyceride (TG) to phospholipid (PL) mass ratio in liver with cholesterol feeding. However, there was evidence for an increased formation of 1,2-diglyceride (1,2-DG). The complement of molecular species of hepatic 1,2-DG, phosphatidylcholine (PC), and phosphatidylethanolamine (PE) formed de novo, as measured using isotopic glycerol, was not influenced greatly by dietary cholesterol, although lower mean rates of synthesis of tetraenoic relative to dienoic species of phospholipids were indicated in cholesterol-fed gerbils.     

Response of free and esterified plasma cholesterol levels in the mongolian gerbil to the fatty acid composition of dietary lipid

The present study was undertaken to investigate the potential suitability of the Mongolian gerbil as a useful animal model to study the effects of dietary fats on plasma cholesterol levels. Semipurified diets containing either 20% lard, 20% safflower oil, or 19.5% beef tallow +0.5% safflower oil were equalized to contain 0.01% cholesterol and 0.05% plant sterol and were fed for a four week experimental period. The proportions of total calories contributed by fat, protein and carbohydrate (starch/sucrose ratio of 2∶1) were 40, 14 and 46%, respectively, so as to approach the distribution of calories within the average North American diet. Free, esterified, and total plasma cholesterol levels of male gerbils were determined weekly by gas liquid chromatography after drawing blood via a serial sampling technique. After 1, 2, 3, and 4 weeks of feeding the experimental diets, total cholesterol levels were lowest in the safflower oil fed animals; the corresponding values were 19–64% greater in gerbils fed lard and 68–91% greater in those consuming the beef tallow diet. Cholesterol in the free form generally responded more dramatically to the type of dietary lipid than did cholesterol in the ester form. Irrespective of the type of dietary lipid or the length of the feeding trial, 18–23% of the total plasma cholesterol was in the free form and 77–82% was present as the ester. In view of the similarity to the human of the relative proportions of free versus esterified cholesterol, the type of cholesteryl esters, and their response to dietary manipulation, the gerbil appears to be a useful animal model for studying the regulatory effect of dietary lipid on plasma cholesterol levels. Presented in part at the A.O.C.S. Annual Meeting, San Francisco, CA, May 1979.     

The effect of linoleic,arachidonic and eicosapentaenoic acid supplementation on prostacyclin production in rats

We examined the effect of dietary supplementation of linoleic acid (LA), arachidonic acid (AA) or eicosapentaenoic acid (EPA) to rats fed a diet low in linoleic acid onin vitro andin vivo production of prostacyclin. Male Sprague Dawley rats were fed a high-fat diet (50% energy as fat, 1.5% linoleic acid) for two weeks. Three of the groups were then supplemented orally with either 90 mg/d of LA, AA or EPA, all as the ethyl esters, for a further two weeks while remaining on the high-fat diet. Forty-eight hour urine samples were collected at the end of the second and fourth weeks.In vivo prostacyclin production was determined by a stable isotope dilution, gas chromatography/mass spectrometry assay for the major urinary metabolite of prostacyclins (2,3-dinor-6-keto-PGF_1α or PGI₂-M and Δ¹⁷-2-3-dinor-6-keto-PGF_1α or PGI₃-M).In vitro prostacyclin production was determined by radioimmunoassay of the stable metabolite (6-keto-PGF_1α) following incubation of arterial tissue. Oral supplementation with AA resulted in a rise in plasma and aorta 20∶4n−6, and increasedin vitro prostacyclin and urinary PGI₂-M production. EPA supplementation resulted in a rise in plasma and aorta 20∶5n−3 and 22∶5n−3, and a decline in plasma 20∶4n−6, but not in the aorta. In the EPA-supplemented group, thein vitro prostacyclin and the urinary PGI₃-M increased, but urinary PGI₂-M decreased. The increase inin vitro prostacyclin production in the EPA-supplemented rats was unexpected and without obvious explanation. Supplementation with LA had minimal effect on fatty acid composition of plasma or aorta and caused no change in prostacyclin production with either method. Thein vivo measure of prostacyclin production was positively correlated with aorta AA levels, and negatively correlated with aorta levels of EPA. There was a significant positive correlation between thein vitro production of prostacyclin and thein vivo production (as measured by the urinary prostacyclin metabolite level), despite the differences observed in the EPA-fed group. There was a high inter-animal variability in prostacyclin production using either method. These results indicate that dietary AA stimulates and dietary EPA reducesin vivo PGI₂ production in the rat. An equivalent amount of dietary LA was without effect.     

Selective effect of cholesterylphosphoserine on intracellular cholesterol transport

Cholesteryl-3β-phosphoserine (CPHS) is a synthetic steroid affecting intracellular cholesterol transport. To compare CPHS with the well-known inhibitors progesterone and U18666A, we examined cholesterol transport in three human cell lines: the monocytic U-937, the endothelial ECV-304, and the lymphoid Jurkat. Under low density lipoprotein (LDL) loading, CPHS inhibited cholesterol esterification in U-937 and ECV-304 cells but not in Jurkat cells. In contrast, CPHS inhibited the mobilization of plasma membrane cholesterol induced by 25-hydroxycholesterol, brefeldin A, or sphingomyelinase in all cell lines. In cells pulse-labeled with [³H] cholesterol, CPHS decreased incorporation of cholesterol and inhibited its esterification. In prelabeled cells, CPHS promoted cholesterol efflux and enhanced the cyclodextrin-mediated removal of plasma membrane cholesterol. CPHS did not affect endogenous cholesterol synthesis nor acylcoenzyme A: cholesterol acyltransferase activity. These data suggest that, unlike progesterone and U18666A, CPHS inhibits intracellular cholesterol transport by specifically affecting the movements of cholesterol in the plasma membrane. Owing to this restricted site of action, CPHS may help to clarify the role of the plasma membrane in cholesterol trafficking. For example, the lack of an effect of CPHS on the esterification of LDL-derived cholesterol in Jurkat cells suggests that most of the LDL-derived cholesterol in these cells is directly delivered to the endoplasmic reticulum without cycling through the plasma membrane.     

The effect of different proportions of casein in semipurified diets on the concentration of serum cholesterol and the lipoprotein composition in rabbits

The effect of different proportions of casein in semipurified diets on the concentation of serum cholesterol and the lipoprotein composition was studied in rabbits. Low-casein diets (10% w/w) resulted in serum cholesterol levels and growth rates that were lower than high-casein diets (40%). An intermediate proportion of casein (20%) produced intermediate concentrations ofserum cholesterol, but only minor differences in food intake and weight gain, compared with the high-casein group. In the animals with the highest values of total serum cholesterol (the 40% casein group), most of the serum cholesterol was transported in the very low density lipoproteins, whereas with moderate hypercholesterolemia (the 20% casein group), the low density lipoproteins were the main carriers of cholesterol. Elevation in lipoprotein cholesterol was associated in all groups with an increased ratio of cholesterol to protein, suggesting the formation of particles relatively rich in cholesterol. When the rabbits on the diet containing 10% casein were subsequently transferred to the 40% casein diet, a steep increase in the level of serum cholesterol occurred. Conversely, switching the rabbits on the 40% casein diet to the 10% casein diet resulted in a decrease in the level of serum cholesterol.     

The effect of dietary supplementation with eicosapentaenoic acid on the phospholipid and fatty acid composition of erythrocytes of marmoset

Adult male marmoset monkeys were fed eicosapentaenoic acid (20∶5n−3) as the ethyl ester in diets containing either 32% (reference diet, no added cholesterol) or 7% (atherogenic diet with 0.2% added cholesterol) linoleic acid (18∶2n−6) for 30 wk. No changes were seen in the level of phosphatidylcholine (PC) or phosphatidylethanolamine (PE) but minor changes were observed in both the sphingomyelin (SPM) and phosphatidylinositol plus phosphatidylserine (PI+PS) fractions of erythrocyte lipids. The extent of total n−3 fatty acid incorporation into membrane lipids was higher in atherogenic diets (polyunsaturated/monounsaturated/saturated (P/M/S) ratio 0.2∶0.6∶1.0) than reference diets (P/M/S ratio 1∶1∶1) and this was true for both PE (33.4±1.0%vs 24.3±1.1%) and PC (9.3±0.5%vs 4.9±0.3%). Although suitable controls for cholesterol effects were not included in the study, earlier results obtained with marmosets lead us to believe such effects were probably small. Regardless of basic diet (atherogenic, reference), 20∶5n−3 was preferentially incorporated into PE (10.8±0.2%, 6.0±0.02%) while smaller amounts were incorporated into PC (6.9±0.4%, 3.2±0.2%). The major n−3 polyunsaturated fatty acid found in PE in response to dietary 20∶5n−3 was the elongation metabolite 22∶5n−3 in both the atherogenic (17.7±0.7%) and reference (14.3±1.0%) dietary groups; 22∶6n−3 levels were less affected by diet (4.7±0.3% and 3.9±0.2%, respectively). The results can be interpreted to indicate an inverse relationship between the amount of dietary 18∶2n−6 and incorporation of 20∶5n−3 into erythrocyte membrane phospholipids regardless of whether the major dietary n−3 fatty acid was α-linolenate (18∶3n−3) or 20∶5n−3. This interpretation is supported by theoretical calculations.     

The effect of dietary n−3 polyunsaturated fatty acids on HDL cholesterol in Chukot residentsvs muscovites

Native Chukot Peninsula residents, in contrast to Muscovites, consume a diet rich in n−3 polyunsaturated fatty acids. This dietary peculiarity is reflected in differences in plasma lipid and apolipoprotein contents. The Chukot residents have lower contents of total cholesterol, triglyceride, LDL (low density lipoprotein) cholesterol and apolipoprotein B, but higher HDL (high density lipoprotein) cholesterol levels than do Muscovites. The apolipoprotein A-I levels were identical in both groups. A higher HDL cholesterol to apolipoprotein A-I ratio was determined in the coastline Chukot residents (0.52±0.01) than in Muscovites (0.43±0.01; p<0.01). In contrast to Muscovites, the coastline Chukot residents also had higher n−3 and lower n−6 polyunsaturated fatty acid percentages in plasma and erythrocyte lipids, and lower phosphatidylcholine and higher sphingomyelin or phosphatidylethanolamine levels in HDL_2b and HDL₃. The higher HDL cholesterol levels in the plasma of the coastline Chukot residents appears to reflect the higher cholesterol-scavenging capacity of their HDL. We conclude from this study that the regular consumption of dietary n−3 polyunsaturated fatty acids by the coastline Chukot residents decreased LDL cholesterol transfer from plasma to peripheral cells, and enhanced cholesterol efflux from cellular membranes toward HDL.     

Comparison of the effect of six compactin-related compounds on cholesterol synthesis in five human cell types

We have investigated the effect of six compactin-related compounds—mevinolin, compactin, ML-236A, monacolin X, monacolin L and dihydromonacolin L—on cholesterol synthesis in human umbilical vein endothelial cells, human small intestine epithelial cells, human hepatoma cell line HEP G2, normal human skin fibroblasts and in skin fibroblasts from a patient with familial homozygous hypercholesterolemia. The inhibition of cholesterol synthesis was found to depend on both the cell type and the type of compound used. The most effective compounds were mevinolin and compactin. Monacolin X, monacolin L and ML-236A were less effective, and dihydromonacolin L was the least efficacious. Endothelial and epithelial cells were sensitive to very low concentrations of inhibitors (IC₅₀=1.0–30 pg/mL), HEP G2 cells required higher concentrations (IC₅₀=0.01–66 ng/mL) and fibroblasts needed even higher concentrations (IC₅₀=0.1–200 ng/mL). Lactone and acid forms of the inhibitors were equally active. None of the inhibitors had any effect on either protein or fatty acid synthesis in any of the cell types studied. It can be concluded that different compactin-related compounds show a range of potencies as cholesterol synthesis inhibitors and a dose-dependent tissue-selectivity.