ApoB (XbaI) polymorphism and lipid variation in Teharnian population

This study examines the association of XbaI apolipoprotein B polymorphism with lipid related variables in Tehran lipid and glucose study. 809 subjects from the TLGS population were selected, anthropometrical and biochemical factors were measured. A segment of the apo B gene in exon 26 was amplified by PCR and the polymorphism was revealed by RFLP using XbaI restriction enzyme. Allele frequencies obtained for X⁺ and X^? were 27.6 and 72.4%, respectively. Presence of the X⁺ allele was significantly associated with increased levels of total cholesterol (p 0.048), apolipoprotein B (p 0.018), and low‐density lipoprotein (p 0.022). The associations were significant even after adjustment for age, BMI, smoking, and history of diabetes. There are some relationships between the presence of different alleles of XbaI polymorphism with serum cholesterol, apoB, and LDL‐C concentration. These findings highlight the importance of variation in this gene on some lipid related factors levels.     

Effect of nicotine on lipoprotein metabolism in rats

Nicotine, a major component of cigarette smoke, plays an important role in the development of cardiovascular disease and lung cancer in smokers. The effect of nicotine on lipoprotein metabolism was studied using rats as the experimental animal. There was a significant increase in the total cholesterol, phospholipids, and triglycerides as well as the amount of lipids associated with very low density lipoprotein (VLDL) and low density lipoprotein (LDL) in sera of nicotine-treated rats. The incorporation of ³H labeled leucine into the apo B was found to be increased both in the medium and associated cells in the hepatocytes isolated from nicotine-treated rats indicating an increased synthesis and secretion of the apo B containing lipoproteins. This was further confirmed by the higher incorporation of ¹⁴C acetate into total and individual lipids of LDL and VLDL secreted into the medium as well as that associated with different lipids in the cell layer. The activity of lipoprotein lipase in extrahepatic tissues and plasma lecithin cholesterol acyltransferase activity were significantly lower in nicotine-treated rats. These results indicate that nicotine exerts hyperlipidemic effects particularly by increasing the synthesis and secretion of triglyceride-rich lipoproteins. Since nicotine is one of the major hazardous components present in cigarette smoke and tobacco, one can extrapolate that the deleterious effect exerted by nicotine on rats extends to cigarette smokers and those who use other forms of tobacco.     

Very low density lipoprotein secretion by cultured hepatocytes of rabbits fed purified or autoxidized cholesterol

The main objectives of this study were to compare the effects of dietary commercial cholesterol (containing 5% of oxidized cholesterol derivatives) and purified cholesterol on the secretion rate of very low density lipoprotein apolipoproteins and lipids by cultured rabbit hepatocytes and to verify the hypothesis that products of cholesterol autoxidation stimulate the rapid development of hypercholesterolemia. Rabbits fed dietary (old) commercial cholesterol for six weeks showed a fivefold increase in the serum concentration of cholesterol compared with that in purified cholesterol-fed rabbits. The secretion rates of very low density lipoprotein total protein and very low density lipoprotein [³H]apolipoproteins were similar for the hepatocytes of these two cholesterol-fed groups of animals and were two- and threefold greater, respectively, than for cells from control rabbits. Cholesteryl ester content of the hepatocytes from dietary (old) commercial cholesterol-fed rabbits was dramatically increased in comparison with hepatocytes from control and purified cholesterol-fed rabbits. The elevated intracellular cholesteryl ester content is assumed to account for such an increase of very low density lipoprotein-cholesteryl ester secretion by cells prepared from dietary (old) commercial cholesterol-fed rabbits. These effects appear to be caused by activation of cholesterol esterification by oxidized cholesterol derivatives. The rapid development of hypercholesterolemia induced by dietary (old) commercial cholesterol is associated, at least in part, with the stimulated production of hepatic very low density lipoprotein apolipoproteins and cholesteryl esters.     

Lipid peroxidation in low density lipoproteins from human plasma and egg yolk promotes accumulation of 1-acyl analogues of platelet-activating factor-like lipids

Oxidative modification of low density lipoprotein (LDL) is known to be a key event for induction of atherosclerosis. However, there has been little progress in structural elucidation of oxidized lipids, especially oxidatively fragmented phospholipids retaining a glycerol backbone. In this study, we found that LDL derived from egg yolk has no platelet-activating factor (PAF) acetylhydrolase activity, and that prolonged incubation of egg yolk LDL with Cu²⁺ resulted in the formation of various PAF-like lipids: 1-acyl type phosphatidylcholines with ansn-2-short-chain dicarboxylate or monocarboxylate group. Only a very small amount of the PAF-like lipid having ansn-2-short-chain monocarboxylate group was detected by gas chromatography-mass spectrometry in Cu²⁺-oxidized LDL from human plasma with high PAF-acetylhydrolase activity, which has been reported to hydrolyze PAF-like lipids to lysophosphatidylcholines. Preincubation of plasma LDL with diisopropyl fluorophosphate dose-dependently inhibited PAF-acetylhydrolase activity, resulting in accumulation of the PAF-like lipids when the LDL was oxidized with Cu²⁺. As well as PAF and lysophosphatidylcholines, several PAF-like lipids were found to inhibit [³H]thymidine incorporation into cultured vascular smooth muscle cells derived from rat aorta. The possible formation of PAF-like lipids by lipid peroxidation in LDL is discussed as well as its possible significance for induction of atherosclerosis.     

Genetic variations in serum lipid levels of inbred mice and response to hypercholesterolemic diet

The serum lipid contents of a number of inbred and congenic strains of mice were measured. There were interstrain variations in each of the lipid fractions in mice fed a normal diet. Male and female C3H mice had the highest total cholesterol level; AKR mice showed the lowest values. Serum phospholipids were correlated well with cholesterolemia. The greatest variations between strains were in the triglyceride levels. There also was significant variation in the high density lipoprotein cholesterol serum levels (from 73–88% of the total cholesterol). The response to a hypercholesterolemic diet (1% cholesterol) was tested in seven inbred strains. All strains showed changes in serum cholesterol and in the proportions of the lipoproteins fractions. There was a large increase in the low density lipoprotein+very low density lipoprotein fractions. Feeding the diet revealed marked interstrain differences in the responses of the serum cholesterol and electrophoretic lipoprotein profiles. The C57BL/6 and B10.D2 strains were hyperresponders to the hypercholesterolemic diet with 71% and 63% of their serum cholesterol in the low density lipoprotein plus very low density lipoprotein fractions, respectively.     

Effects of dietary triglyceride on the properties and lipid composition of plasma lipoproteins: Acute experiments in rats fed safflower oil

Male rats were administered 1.5 ml safflower oil by gastric intubation 0, 4, and 8 hr after a 16 hr fast. Plasma, liver, and adipose tissue were collected 16 hr after the last fatty meal. Rats fasted for 16 hr served as controls. Following fat feeding, the fatty acid composition of the very low density lipoprotein, triglyceride, and hepatic triglyceride were similar, as were the percentages of 18:2 in the very low density lipoprotein and hepatic cholesteryl esters. The phospholipids of liver and plasma lipoproteins were similar in the control groups, except that more 16:0 was present in the plasma lipoproteins. After fat feeding, the plasma lipoproein phospholipids were enriched with 18:2 more than were the hepatic phospholipids. Furthermore, the percentage of 18:2 in phospholipid was much less than in triglyceride or cholesteryl esters. Clearly, esterified lipids of liver and plasma lipoproteins (very low density lipoprotein, low density lipoprotein, and high density lipoprotein), and to a lesser extent, adipose tissue, were enriched with 18:2 derived from dietary triglyceride fatty acid even 16 hr after the terminal meal. A major proportion of the very low density lipoprotein isolated by ultracentrifugation in zonal rotors from plasma of fat fed animals had a faster rate-zonal mobility than did the very low density lipoprotein isolated from plasma of control animals. The very low density lipoprotein isolated from plasma of fat fed rats contained fewer moles of phospholipids, cholesterol, and cholesteryl esters, relative to triglyceride than did the very low density lipoprotein from plasma of animals not receiving safflower oil. The molar ratio triglyceride:phospholipid:cholesterol:cholesterol esters in the very low denity lipoprotein was 100:42.0:22.1:44.5 in the control group and 100:35.4:17.8:19.5 in the fat fed animals. It is postulated that an important biochemical mechanism by which dietary triglyceride fatty acids consumed by the animal over a long period of time alter plasma concentrations of triglyceride, phospholipids, and cholesterol esters is the directive influence of plasma free fatty acid, derived from dietary triglyceride, on the secretion of very low density lipoprotein lipids by the liver.     

Inhibition of rat hepatic sterol formation from squalene by plasma lipoproteins

The conversion of³H-squalene to sterols by rat liver microsomes and cytosol was inhibited by individual rat and human plasma lipoproteins at various concentrations. This inhibition was also observed with added human high density apolipoprotein, but triglycerides, cholesterol or cholesteryl esters had no inhibitory effects. Lipoproteins and apo high density lipoprotein (HDL) were demonstrated to bind³H-squalene in vitro. The binding of³H-squalene by apo HDL could be reversed by increasing concentration of liver cytosol containing sterol carrier protein.     

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.     

Evidence for the lipoprotein heterogeneity of human plasma high density lipoproteins isolated by three different procedures

Quantitative electroimmunoassays of apolipoproteins in ultracentrifugally isolated high density lipoproteins (HDL) of normolipidemic subjects showed that A-I and A-II are the major (80–85% of total HDL protein) and B, C-III, E, D and F are the minor protein constituents of this density class. A comparison between the apolipoprotein composition of ultracentrifugally isolated HDL and heparin-Mn⁺⁺ supernates showed no significant difference in the levels of A-I and C-III. However, the concentration of ApoE in the heparin-Mn⁺⁺ supernates was almost twice as high as that in the ultracentrifugally isolated HDL; ApoB was only detectable in trace amounts in the heparin-Mn⁺⁺ supernates. To establish whether these apolipoproteins are parts of a single macromolecular complex or form separate, discrete lipoprotein particles, the high density lipoproteins were isolated by three different procedures including ultracentrifugation, heparin-Mn⁺⁺ precipitation and agarose column chromatography. The double diffusion analyses of each of these HDL preparations with antisera to A-I, A-II, ApoB, C-III, ApoD, ApoE, and ApoF showed nonidentity reactions between each possible combination of these antisera. The only exception was a reaction of partial identity between antisera to A-I and A-II polypeptides indicating the occurrence of two types of lipoprotein particles, a major one (LP-A) containing both polypeptides and a minor one (LP-A-I) containing A-I as the sole protein constituent. These findings indicate that high density lipoproteins, regardless of the manner of isolation, do not consist of a single macromolecular complex, but represent a mixture of several, discrete lipoprotein families. Presented at the AOCS Meeting, St. Louis, May 1978.     

Low fat-monounsaturated rich diets containing high-oleic peanuts improve serum lipoprotein profiles

Postmenopausal hypercholesterolemic women are at risk for cardiovascular disease and are encouraged to follow low-fat (LF) (≤30% energy) diets. However, these diets may have undesirable effects on high density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apo A-I) and triglycerides, whereas diets high in monounsaturated fats do not. Twenty postmenopausal hypercholesterolemic women previously consuming high-fat diets (34% energy) were placed on a low fat-monounsaturated rich diet (LFMR: 26%, 14% energy, respectively) for 6 mon. Sixteen women already eating LF diets (24% energy) were also followed to monitor variations in serum lipids due to seasonal variations. Twenty-five women successfully completed the study (LFMR=12, LF=13). Serum cholesterol decreased 10% (264 to 238 mg/dL, P≤0.01) and low density lipoprotein cholesterol (LDL-C) decreased 12% (182 to 161 mg/dL, P≤0.01) in the LFMR group, but did not change in the LF group. The reduction in serum cholesterol in the LFMR group was greater than estimated by predictive formulas. Serum triglycerides and apo A-I did not change in the LFMR group. A modest decrease in HDL-C, HDL₃-C, and apolipoprotein B (apo B) occurred in both groups, but only the LFMR group showed a trend toward beneficial changes in LDL-C/HDL-C and apo A-I/apo B ratios. Overall, the LFMR diet was well tolerated and resulted in an improved serum lipid and apolipoprotein profile. A portion of this material was presented earlier at the annual meeting of the American Oil Chemists’ Society and in abstract from (O’Byrne, D.J., Shireman, R.B., and Knauft, D., 1993. The effects of a low-fat/high-oleic acid diet on lipoproteins in postmenopausal hypercholesterolemic women. INFORM 4(4), 553, #SS7).     

Lipoproteins of fetal and newborn calves and adult steer: A study of developmental changes

Serum lipoproteins in fetal and newborn calves were characterized and compared with those of adult animals. Fetal calf serum contains only low density (LDL) and high density (HDL) lipoproteins; the LDL is the major lipoprotein class. Fetal LDL are ca. 26.0 nm diameter and are morphologically unusual in that particles form linear aggregates or “chains” in which LDL have flattened, parallel sides. These particles contain only apolipoprotein B and are high in polar lipids. Fetal HDL consist of 8.2-nm, round particles which contain large amounts of chlesteryl ester thus suggesting an active lecithin: cholesterol acyltransferase system in the fetal state. The major protein in fetal HDL is apolipoprotein A−I (80%); however, another component with a molecular weight (MW) of ca. 9,000 is also present. Newborn calves show a 5-fold increase in HDL concentration. These particles are 9.0 nm spherical particles and they contain mainly apolipoprotein A−I although C-apolipoproteins are also present; the lipid and apolipoprotein composition of newborn HDL is similar to that of adults. Newborn calves possess very low density (VLDL) lipoproteins which have a mean diameter of 61 nm and are similar in size and composition to those of adult animals; their apolipoprotein composition is principally apolipoprotein B, although C-apolipoproteins and apolipoprotein A−I are also present. The LDL of neonatal and adult animals are similar in morphology, chemical composition and apolipoprotein content. In both instances, LDL are round particles ca. 19.0 nm diameter which contain less polar lipids than the fetal animal. Apolipoprotein B is the major protein in newborn LDL, but adult LDL additionally contains a protein of 27,000 MW which probably represents apolipoprotein A−I from overlapping α-migrating particles in this region. The altered morphology and composition of fetal LDL, together with the lack of VLDL, suggest that the LDL particles may be synthesized de novo. Preliminary data was presented at the American Oil Chemists' Society Meeting, 1979.     

Characterization of in Vitro Modified Human Very Low-Density Lipoprotein Particles and Phospholipids by Capillary Electrophoresis

A simple capillary zone electrophoresis (CZE) method was used to characterize human very low-density lipoprotein (VLDL) particles for four healthy donors. One major peak was observed for native, in vitro oxidized and glycated VLDL particles. The effective mobilities and peak areas of the capillary electrophoresis (CE) profiles showed good reproducibility and precision. The mobility of the oxidized VLDL peak was higher than that of the native VLDL. The mobility of the glycated VLDL peak was similar to that of the native VLDL. Phospholipids isolated from VLDL particles were analyzed by our recently developed micellar electrokinetic chromatography (MEKC) with a high-salt stacking method. At absorbance 200 nm, the native VLDL phospholipids showed a major peak and a minor peak for each donor. For oxidized VLDL phospholipids, the area of the major peak reduced for three donors, possibly due to phospholipid decomposition. For glycated VLDL phospholipids, the peak mobilities were more positive than native VLDL phospholipids for two donors, possibly due to phospholipid-linked advanced glycation end products (AGEs). Very interestingly, at absorbance 234 nm, the major peak of oxidized VLDL phospholipids was resolved as two peaks for each donor, possibly due to conjugated dienes formed upon oxidation.     

LDL-Oxidation - Results and Relevance for Atherogenesis and Possible Clinical Consequences

Increasing evidence exists that oxidative modification of low density lipoprotein (LDL) plays an important role in the pathogenesis of atherosclerosis. Lipid peroxidation processes degrade polyunsaturated fatty acids of the LDL-lipids to hydroperoxyacids and further breakdown products, which themselves modify the apolipoprotein B. These oxidized LDL-particles are taken up via the scavenger receptor of tissue-macrophages in an uncontrolled manner and lead to the formation of lipid laden foam cells, which are present in fatty streaks. Oxidized LDL (oxLDL) is detectable in atherosclerotic plagues immunochemically. Autoantibodies against oxLDL are detectable in serum and their titers correlate with the progression of atherosclerosis. The oxidation resistance of LDL is in part dependent of its antioxidant content (vitamin E, carotenoids, ubiquinol-10). Oral supplementation of vitamin E increases significantly the oxidation resistance of LDL while β-carotene supplementation seems to increase the oxidation resistance only of certain individuals. A clinical trial has demonstrated an inverse correlation of severity of myocardial infarction and oxidation resistance of LDL.     

Hypolipidemic effects in monkeys of ML-236B,a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase

The fungal metabolite ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, has been shown to be significantly effective in lowering serum cholesterol levels in cynomolgus monkeys at doses of 20–50 mg/kg per day. Levels of serum phospholipids and triglycerides were, however, not significantly changed by the administration of the drug. Of the serum lipoprotein fractions, a β-lipoprotein corresponding to low density lipoprotein was preferentially reduced by the drug treatment. Fecal excretion of neutral sterols was unaffected but that of bile acids was slightly elevated by the administration of ML-236B.     

Influence of dietary egg and soybean phospholipids and triacylglycerols on human serum lipoproteins

Human serum lipid and lipoprotein concentrations and compositions were compared in ten healthy middle-aged men consuming phospholipids from egg or from soybean or triacylglycerol mixtures with fatty acid compositions similar to those of the phospholipids. All subjects followed each of the four treatments: egg phospholipids (EP), soybean phospholipids (SP), an oil of fatty acid composition similar to that of EP, and an oil similar in fatty acid composition to SP for six weeks with “wash-out” periods of similar duration between treatment periods. The phospholipids, 15 g/d, and the oils, 12 g/d, which contained approximately equivalent quantities of fatty acids were provided to the subjects in gelatin capsules and were taken before meals. Diet intake was monitored by three-day food records. Serum lipoproteins (L_p) were separated by ultracentrifugation into very low density lipoproteins, low density lipoproteins (LDL), high density lipoproteins (HDL)₂ and HDL₃. L_p fractions and whole serum were analyzed for triacylglycerols, cholesterol (CH), phospholipids (PL), and protein. HDL cholesterol was determined in while serum. Cholesteryl esters were determined in some L_p fractions. Lipid compositions of L_p were expressed in mmol/g protein. Apoprotein B was measured in whole serum and in LDL; apoprotein A-I in whole serum and in HDL₃. In whole serum, CH and PL were significantly lower after the SP compared to EP treatment periods. CH, but not PL, was lower after SPTG compared to EP. CH in HDL₂ was significantly higher after SP compared to SPTG. Also, PL in HDL₂ were significantly higher after SP compared to all other treatments and to baseline. Although human serum lipid responses to dietary phospholipids were generally the same as responses to ingested oils of comparable fatty acid composition, the data suggest the possibility that SP selectively increase HDL₂ cholesterol and phospholipids.     

The effect of exercise on plasma high density lipoproteins

The influence of vigorous activity in man on plasma lipids and lipoproteins is reviewed, with particular emphasis on high density lipoproteins. Both cross sectional and longitudinal (or training) studies have been reported, many of them of less than ideal design. Nonetheless, a consistent pattern emerges in which increased exercise levels lead to lower plasma concentrations of triglycerides and very low density lipoproteins, and of low density lipoproteins. High density lipoprotein levels increase. Sometimes, but not uniformly, plasma total cholesterol level falls as the result of these changes. The increase in plasma high density lipoprotein appears to be the result largely of an increase in the less dense HDL₂ subfraction. Plasma apolipoprotein A-I levels (but not apo-A-II levels) seem to increase concomitantly. The precise biochemical mechanism responsible for these changes has not been elucidated; but the recent finding of increased lipoprotein lipase activity in adipose tissue and muscle of endurance runners suggests that increased lipolytic rate of trigly ceride-rich lipoproteins may be an initial step in a sequence of events leading to higher plasma levels of HDL₂.     

Lipid transfers to HDL are diminished in long-term bedridden patients: association with low HDL-cholesterol and increased inflammatory markers

Plasma lipids have been extensively studied in sedentary and in subjects practicing exercise training, but not in extreme inactivity as occurs in bedridden patients. This is important for the care of bedridden patients and understanding the overall plasma lipid regulation. Here, we investigated plasma lipids, lipid transfers to HDL and inflammatory markers in bedridden patients. Fasting blood samples were collected from 23 clinically stable bedridden patients under long‐term care (>90 days) and 26 normolipidemic sedentary subjects, paired for age and gender. In vitro transfer of four lipids to HDL was performed by incubating plasma with donor nanoparticles containing radioactive lipids. Total (193 ± 36 vs 160 ± 43, p = 0.005), LDL (124 ± 3 vs 96 ± 33 p = 0.003) and HDL‐cholesterol (45 ± 10 vs 36 ± 13, p = 0.008), apolipoprotein A‐I (134 ± 20 vs 111 ± 24, p = 0.001) and oxidized LDL (53 ± 13 vs 43 ± 12, p = 0.011) were lower in bedridden patients, whereas triglycerides, apolipoprotein B, CETP and LCAT were equal in both groups. Transfers of all lipids, namely unesterified cholesterol, cholesterol esters, triglycerides and phospholipids, to HDL were lower in bedridden patients, probably due to their lower HDL‐cholesterol levels. Concentrations of IL‐1β, IL‐6, IL‐8, HGF and NGF were higher in bedridden patients compared to sedentary subjects. In conclusion, inactivity had great impact on HDL, by lowering HDL‐cholesterol, apolipoprotein A‐I and thereby cholesterol transfers to the lipoprotein, which suggests that inactivity may deteriorate HDL protection beyond the ordinary sedentary condition.     

p-Chlorophenoxyisobutyrate enhanced retention of homologous lipoproteins by human aortic smooth muscle cells

Human aortic smooth muscle cells (SMC) specifically bind and take up indiscriminately both the lipid and protein moietics of homologous²⁵I-very low density lipoproteins (VLDL) and¹²⁵I-low density lipoproteins LDL). Sixty-five to 80% of absorbed lipids are incorporated into the cell lipids, preferentially into the phospholipid fraction. Twenty to 35% of the lipid bound and the protein moiety are eliminated from the cells. Half of the eliminated protein label is recovered as TCA soluble products. Five mM of p-chlorophenoxyisobutyrate (CPIB) raise the level of intracellular radioactivity derived from the lipid moieties of VLDL and LDL by about 40% via a reduced elimination. The processing of the protein moiety and lipoprotein binding to the cell surface are not affected by 5.0 mM of CPIB. CPIB lowers the incorporation of¹⁴C-acetate,¹⁴C-pyruvate, and³²phosphate radioactivity into fatty acids and phospholipids of aortic SMC. Five mM of CPIB reduce the overall palmitic acid synthesis by shifting from de novo synthesis to the mechanism of chain elongation, although the further elongation to saturated C₁₈–C₂₄ fatty acids is also depressed. The CPIB-enhanced retention of the lipid-derived lipoprotein radio-activity is interpreted as a compensatory mechanism providing cellular fatty acids which are deficient as a result of the CPIB inhibited synthetic processes.     

Increased amounts of cholesterol precursors in lipoproteins after ileal exclusion

Serum cholesterol precursor sterols reflect the activity of cholesterol synthesis. In this study, squalene, methyl sterol and lathosterol contents were studied in very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) of heterozygous familial hypercholesterolemia patients without and with ileal bypass. The contents of lathosterol and all methyl sterols (lanosterol, Δ^8,24-dimethylsterol, Δ⁸-dimetylsterol, Δ⁸-methostenol and methostenol), but not of squalene were increased in all lipoproteins by ileal bypass. The increase in the free methyl sterols was more marked than that in the esterified ones. The percentage esterification of the methyl sterols was highest in HDL and lowest in VLDL. Lipoprotein methyl sterol contents were positively correlated with each other and with cholesterol synthesis. The methyl sterols were slightly concentrated in LDL, and squalene strongly concentrated in VLDL. It is concluded that long-term stimulation of cholesterol synthesis increases the methyl sterols in all lipoproteins.