The storage lipids in Tangier disease. A physical chemical study.

The physical states and phase behavior of the lipids of the spleen, liver, and splenic artery from a 38-yr-old man with Tangier disease were studied. Many intracellular lipid droplets in the smectic liquid crystalline state were identified by polarizing microscopy in macrophages in both the spleen and liver, but not in the splenic artery. The droplets within individual cells melted sharply over a narrow temperature range, indicating a uniform lipid composition of the droplets of each cell. However different cells melted over a wide range, 20-53 degrees C indicating heterogeneity of lipid droplet composition between cells. Furthermore, most of the cells (81%) had droplets in the liquid crystalline state at 37 degrees C. X-ray diffraction studies of splenic tissue at 37 degrees C revealed a diffraction pattern typical of cholesterol esters in the smectic liquid crystalline state. Differential scanning calorimetry of spleen showed a broad reversible transition from 29-52 degrees C, with a maximum mean transition temperature at 42 degrees C, correlating closely with the polarizing microscopy observations. The enthalpy of the transition, 0.86+/-0.07 cal/g of cholesterol ester, was quantitatively similar to that of the liquid crystalline to liquid transition of pure cholesterol esters indicating that nearly all of the cholesterol esters in the tissue were free to undergo the smectic-isotropic phase transition. Lipid compositions of spleen and liver were determined, and when plotted on the cholesterol-phospholipid-cholesterol ester phase diagram, fell within the two phase zone. The two phases, cholesterol ester droplets and phospholipid bilayers were isolated by ultracentrifugation of tissue homogenates. Lipid compositions of the separated phases approximated those predicted by the phase diagram. Extracted lipids from the spleen, when dispersed in water and ultracentrifuged, underwent phase separation in a similar way. Thus (a) most of the storage lipids in the liver and spleen of this patient were in the liquid crystalline state at body temperature, (b) the phase behavior of the storage lipids conformed to that predicted by lipid model systems indicating lipid-lipid interactions predominate in affected cells, (c) lipid droplets within individual cells have similar compositions, whereas droplet composition varies from cell to cell, and (d) cholesterol ester does not accumulate in the splenic artery. Since Tangier patients lack high density lipoprotein, we conclude that high density lipoprotein-mediated cholesterol removal from cells is essential only for those cells which have an obligate intake of cholesterol (macrophages).

Platelet interaction with high and low density lipoproteins.

Gel-filtered platelets (GFP) from normal human subjects bound both low density lipoproteins (LDL) and high density lipoproteins (HDL). This binding was saturable and 125I-labelled lipoprotein uptake was inhibited by plasma. Platelets are also able to degrade lipoproteins but only to a limited extent. LDL appeared to compete with 125I-labelled HDL for platelet uptake, whereas the ability of HDL to displace 125I-LDL was limited. Cyclohexanedione-treated LDL (CHD-LDL), unlike CHD-HDL, did not compete with [125I]LDL for platelet accumulation, suggesting that arginine residues are necessary for LDL but not HDL binding. Addition of HDL or LDL to GFP did not alter platelet aggregation. However, in the presence of thrombin (0.5 U/ml), 1 mg/ml LDL incubated for 1 h at 23 degrees C enhanced platelet aggregation (215% increase) whereas HDL under similar conditions decreased aggregation by 53%. LDL also shortened the time of maximal aggregation whereas HDL had the opposite effect.

Platelet function in a case with abetalipoproteinemia.

Platelet aggregation, [14C]serotonin release and platelet malondialdehyde production were determined in a patient with abetalipoproteinemia (ABL) and found to be normal. The patient demonstrated complete absence of apolipoprotein (apo) B and decreased apo A-I concentration in plasma. The high density lipoprotein (HDL) composition of plasma was abnormal, with an increased cholesterol/protein ratio, increased apo E levels and reduced apo C concentration. The patient's platelets, like platelets derived from a normolipidemic control, possessed receptors capable of binding lipoproteins. On incubating washed platelets derived from a control subject with HDL obtained from the ABL patient, an enhancement in platelet function was observed. A similar concentration of HDL derived from the control had the opposite effect, a depression of platelet function. Lipoprotein-deficient plasma (LPDP) derived from the patient, on the other hand, decreased platelet aggregation and [14C]serotonin release in comparison to the LPDP obtained from the control. The normal platelet function observed in the patient appears to be the result of the platelet-enhancing effect of an abnormal HDL, thus compensating for the absence of low and very low density lipoproteins from the patient's plasma which, when present, stimulate platelet function.

Chylomicrons from patients with type V hyperlipoproteinemia inhibit platelet function.

Platelet aggregation and [14C]serotonin release induced by collagen and also by ADP and thrombin were significantly decreased in patients with primary Type V hyperlipoproteinemia. Platelets derived from these patients lost their hyporesponsiveness to thrombin and ADP (but not to collagen) after washings and isolation from their plasma environment. On incubation of platelets derived from normolipidemic controls with plasma derived from patients, platelet aggregation and [14C]serotonin release were lowered by 20% and 30%, respectively. On incubation of these platelets with 100 mg/dl of chylomicron triglyceride, a 40% reduction in both platelet aggregation and [14C]serotonin release was observed. The inhibition of platelet activity was positively correlated with chylomicron concentration up to a concentration of 225 mg/dl by chylomicron triglyceride. In 2 patients, bezafibrate administration (600 mg/day) resulted in marked reduction of plasma triglyceride concentration and a parallel improvement in platelet function. The platelet hyporesponsiveness in patients with Type V hyperlipoproteinemia appears to be a consequence of platelet-chylomicron interaction. This depressed platelet function may be responsible for the absence of overt atherosclerosis noted in these patients.

Increased concentration of high density lipoprotein in plasma and decreased platelet aggregation in primary biliary cirrhosis.

Plasma lipoprotein concentration and composition were studied in 7 female patients with primary biliary cirrhosis and compared with 6 normal, age-matched controls. The effect of the lipoproteins derived from these patients on the function of normal platelets was also tested. High levels of plasma cholesterol and phospholipids and a raised free/esterified cholesterol ratio were found. In 4 of the patients, both HDL cholesterol and HDL protein were increased, and high levels of plasma apoprotein A-I and A-II were evident. This abnormal HDL did not contain excess apolipoprotein E. The VLDL and LDL fractions were also abnormal, as evidenced by a high cholesterol/protein ratio. Little correlation between lipoprotein disorders and clinical condition was found. Platelet function was reduced in all patients. LDL from the patients reduced aggregation of normal platelets, whereas HDL had a minimal effect. The abnormal lipoproteins in these patients may contribute to their abnormal in vitro platelet aggregation.

Effect of plasma lipoproteins on cholesterol accumulation in macrophages: comparison of lipoproteins from normal and homozygous familial hypercholesterolemic subjects.

Total cholesterol (TC) content of mouse peritoneal macrophages (MPM) increased when incubated with increasing concentrations of normal low density (N-LDL) or very low density (N-VLDL) lipoprotein. Incubation with increasing concentrations of normal high density lipoprotein (N-HDL) caused a decrement in cellular mass of TC in MPM. Incubation of MPM with serum from normal subjects as well as from subjects with homozygous familial hypercholesterolemia (HFH) resulted in a 25% increment in cellular mass of TC, due to an increment in both free cholesterol (FC) and cholesteryl ester (CE) fractions. Accumulation of TC in MPM, due mainly to elevation of CE, was observed when the macrophages were incubated in the presence of LDL or VLDL derived from either group of subjects. N-LDL caused a higher increment in cellular CE compared to HFH-LDL. However, the presence of HFH-VLDL in the medium caused elevation in the cellular TC and CE content to a higher level than did N-VLDL. The presence of N-HDL as well as of HFH-HDL in the medium resulted in a similar decrement in the cholesterol content of MPM. The decrement was expressed in both FC and CE fractions. The present study shows different abilities of normal and HFH plasma lipoproteins to cause cholesterol accumulation in MPM.

Intralipid infusion in patients with familial hypercholesterolemia. Effect of serum and plasma lipoproteins on platelet aggregation and on macrophage cholesterol metabolism.

Intralipid infusion into normal volunteers was recently shown to possess anti-atherogenic properties. We studied the effect of intralipid infusion in patients with severe Familial Hypercholesterolemia (FH) refractory to conventional therapy. FH patients and normal subjects, who served as controls, were given an intravenous infusion of intralipid for 6 h. Serum samples taken from both groups before, during and after intralipid infusion were studied for their ability to inhibit cellular cholesterol accumulation by macrophages. A significantly lower rate of cellular cholesterol esterification (of 46%, P less than 0.005 and 44%, P less than 0.005 in patients and normals, respectively) was demonstrated in macrophages incubated with serum obtained during intralipid infusion compared to those incubated with preinfusion serum. The maximal effect was demonstrated with serum samples taken at the end of the infusion, but the inhibitory effect persisted even at 24 h post-infusion. It was found that chylomicron like particles could induce the above-mentioned effects on macrophage cholesterol esterification. A significant decrement of 50% (P less than 0.005) in aggregation of platelets isolated from plasma samples taken during and after intralipid infusion from both groups was demonstrated, when compared to platelets isolated in the preinfusion state. This effect persisted 18 h subsequent to infusion. We conclude that intralipid infusion abolishes serum ability to stimulate cholesterol esterification in cultured macrophages, and exhibits inhibitory effects upon platelet aggregation. If similar events occur in the arterial wall, intralipid might inhibit foam cell formation.

Low density lipoprotein isolated from patients with essential hypertension exhibits increased propensity for oxidation and enhanced uptake by macrophages: a possible role for angiotensin II.

In patients with essential hypertension, the increased risk for atherosclerosis is related not only to the blood pressure levels per se, but also to other, unknown, factors. Recent observations have indicated that oxidation of low density lipoprotein (LDL) and macrophage uptake of oxidized LDL are implicated in human atherosclerosis. We tested both the susceptibility of LDL, derived from hypertensive patients, to lipid peroxidation as well as its uptake by macrophages, in comparison with control LDL obtained from healthy subjects. The LDL that was derived from 25 patients with essential hypertension demonstrated increased propensity for lipid peroxidation with a 63%, 91% and 69% elevation in the content of the lipoprotein malondialdehyde, peroxides and conjugated dienes, respectively, in comparison with control LDL. Minimally modified LDL (MM-LDL) (prepared by 6 months' storage of the LDL at 4 degrees C) derived from the hypertensive patients also demonstrated increased lipid peroxidation with a 94%, 130% and 96% elevation in lipoprotein malondialdehyde, peroxides and conjugated dienes, respectively, compared with the control LDL. The susceptibility of the patients' LDL to lipid peroxidation decreased by 32% and 44% (measured as malondialdehyde) after 3 weeks of therapy with the angiotensin converting enzyme inhibitors captopril and enalapril, respectively, with no parallel reduction in the patients' blood pressure. The patients' LDL was shown to contain increased content of lipid peroxides and unsaturated fatty acids, which may explain its increased susceptibility to lipid peroxidation. In vitro experiments revealed that LDL can bind angiotensin II, and that angiotensin II has a stimulatory effect on copper-mediated oxidation of LDL, as well as on LDL degradation by macrophages. These results were secondary to cell-mediated oxidation of the LDL and to its cellular uptake via the scavenger receptor. We conclude that LDL derived from patients with essential hypertension is more susceptible to lipid peroxidation than control LDL, and this may be secondary to angiotensin II stimulation of LDL lipid peroxidation in these patients. Furthermore, this LDL demonstrates enhanced cellular uptake by macrophages in comparison with normal LDL which can also be related to angiotensin II-mediated LDL oxidation. Both these phenomena have been shown to be associated with accelerated atherosclerosis, and thus suggest a new mechanism for increased atherogenecity in hypertensive patients.

The concentration of high density lipoprotein in patients with type IV hyperlipoproteinemia and the effect of clofibrate.

Lipid and lipoprotein concentrations, including high density lipoproteins (HDL) and its subfractions, were contrasted in subjects with Type IV hyperlipoproteinemia, before and after therapy with clofibrate. Very low density lipoprotein (VLDL) levels were raised, whereas both low density lipoprotein (LDL) and HDL values were reduced in the patient group. Clofibrate reversed this trend and VLDL cholesterol and protein levels fell to approximate control values. LDL and HDL cholesterol increased but remained significantly lower than in normal controls. However, LDL and HDL protein did approach control values. Of the HDL subfractions, HDL-3 was significantly reduced in the group with Type IV hyperlipoproteinemia. Clofibrate resulted in a significant increase in the HDL-2: HDL-3 cholesterol ratio, but had only a modest effect on HDL-3 concentrations. HDL-3 may be the critical HDL subfraction responsible for the inverse correlation between levels of HDL and the development of ischemic heart disease.

Accumulation of lipoprotein remnants in patients with chronic renal failure.

The composition and concentration of remnant lipoprotein particles accumulating in the plasma of patients with chronic renal failure (CRF) was determined. Ten patients on chronic hemodialysis were compared with 8 controls. The patients' very low density lipoproteins (VLDL) were abnormal and contained more of the dense VLDL subfraction (VLDL3). The concentration of intermediate density lipoproteins (IDL) was increased 3-fold in CRF plasma, whereas the amount of low density lipoprotein (LDL) was decreased by 25%. On electrophoresis of plasma lipoproteins the beta-band from the patients' samples demonstrated increased anodal mobility, indicating an abnormality in composition of the patients' LDL. These abnormalities were present regardless of whether patients were hyperlipidemic or not. These findings suggest defective conversion of VLDL to LDL in CRF, allowing for the accumulation of lipoprotein particles usually absent from plasma. The latter may account for the accelerated atherosclerosis reported in patients with CRF.

The D allele of the angiotensin-converting enzyme gene contributes towards blood LDL-cholesterol levels and the presence of hypertension.

Coronary artery disease is a polygenic disease whose phenotypic manifestation depends on the interaction of the genetic background with a number of environmental factors. Recently, the gene coding for the angiotensin-converting enzyme (ACE) has been characterized and a deletion/insertion (D/I) polymorphism was defined. The prevalence of the three genotypes and their association with coronary artery disease (CAD) differ in different population groups. Mostly, the D allele was found as a significant risk factor for CAD, independently from other risk factors. In the present study, we determined the distribution of ACE alleles (D or I) in a cohort of healthy Israeli men and examined the correlation of the different genotypes with various CAD risk factors. We found LDL cholesterol levels to be highest in the DD genotype group, intermediate in the DI genotype group and lowest in the II genotype group. We also found higher blood pressure levels in subjects bearing the D allele compared to II homozygous subjects. In conclusion, it appears that the genetic influence of the D/I polymorphism on CAD manifests primarily through traditional risk factors.

Complete heart block following therapeutic irradiation of the left side of the chest.

Two female patients had received therapeutic irradiation of the left side of the chest for adenocarcinoma of the left breast and 18 and 23 years later, respectively, developed atrioventricular block. Both patients had early and late cutaneous reactions, as well as fibrosis of the left lung, lymphedema of the left arm, and pathologic rib fractures but had no signs of recurrence of the carcinoma. One patient developed signs of congestive heart failure while the electrocardiogram revealed second and third degree atrioventricular block; subsequent pacemaker implantation relieved the congestive heart failure. In the second patient, fatigue was the only symptom leading to the diagnosis of transient second and third degree atrioventricular block; this symptom subsided after pacemaker implantation. Based on reports of radiation-induced cardiac damage, it is assumed that the heart block in these two patients might have been due to postirradiation fibrosis of the atrioventricular node, either direct or mediated by fibro-occlusive changes in the coronary vessels.

Plasma lipoproteins and platelet aggregation during alimentary lipemia. Decreased atherogenic pattern in the elderly.

Ten healthy women in their tenth decade of life were compared with ten healthy women in their fourth decade of life regarding the response of plasma lipoproteins and platelet aggregation to one meal rich in saturated fats. In the elderly group, plasma cholesterol decreased in the postprandial state three hours after the meal in comparison to no significant changes in the younger group. This resulted from reduction in plasma lipoprotein cholesterol levels, except for the high-density lipoprotein (HDL) cholesterol, which was enhanced. A similar pattern was found for plasma lipoprotein levels. The increase in plasma triglyceride concentration in the elderly women was less than in the younger women, as fewer changes in their plasma triglyceride-rich lipoproteins (chylomicrons and very-low-density lipoprotein) were observed. Platelet aggregation in response to collagen was reduced in the elderly women, whereas in the younger group, increased platelet aggregation in the postprandial state was found. Our study thus demonstrates a clear advantage of the elderly women in comparison to the younger ones in reducing atherosclerosis and thrombotic risks. The elderly group responded to the saturated fat-rich meal by minimal plasma triglyceride elevation, an increase in HDL cholesterol concentration, and reduced platelet aggregation.

Secretory products from human monocyte-derived macrophages enhance platelet aggregation.

Both macrophages and platelets play an important role in atherogenesis. We studied the effect of conditioned medium obtained from human monocyte-derived macrophages on in vitro platelet aggregation. Incubation of macrophage-conditioned medium (MCM) with platelets resulted in enhanced platelet aggregation (up to 35% difference between basal and MCM-stimulated activity), which was time dependent. This MCM effect on platelet function was increased both with time of mononuclear cell culturing (up to 10 days) and with the time of macrophage incubation in serum-free medium (up to 24 hours) prior to MCM collection. MCM from either cholesterol-loaded macrophages or from macrophages obtained from patients with familial hypercholesterolemia demonstrated a 37% and 20% increased effect, respectively, in comparison to MCM derived from normal subjects. Macrophage activation with lipopolysaccharide resulted in the harvesting of a MCM that enhanced platelet activity 60% more than MCM obtained from nonactivated cells. The active component of MCM was inhibited fivefold following heating at 100 degrees C for 10 minutes or after treatment with trypsin or protease, but was not affected by antioxidants. MCM activation of blood platelets may be of importance in atherogenesis. Understanding the mechanisms involved may contribute to an improved appreciation of the role of both platelets and macrophages in atherosclerosis.

Lovastatin decreases plasma and platelet cholesterol levels and normalizes elevated platelet fluidity and aggregation in hypercholesterolemic patients.

The lipid composition of whole platelets and the fluidity of platelet membranes, as well as the sensitivity of the cell to aggregation, were studied in type IIA hypercholesterolemic human subjects before and after treatment with lovastatin. Fourteen patients with primary hypercholesterolemia having initial cholesterol levels of 383 +/- 52 mg/dL (mean +/- standard deviation) were studied and compared with 21 control subjects having cholesterol levels of 187 +/- 32 mg/dL. Lovastatin was administered orally at a starting dose of 40 mg daily. The dose was increased to 80 mg daily for eight patients who did not achieve the target cholesterol level of 200 mg/dL at 6 weeks. Serum cholesterol level was decreased by 37% following 20 weeks' administration of the drug. The fluidity of platelet membranes expressed in terms of the fluorescence anisotropy parameter was determined using the probe 1,6-diphenyl-1,3,5-hexatriene (DPH). When compared with platelets obtained from normocholesterolemic controls, platelets from hypercholesterolemic patients had a higher molar ratio of cholesterol to phospholipids ([C/PL] 0.86 +/- 0.15 v 0.57 +/- 0.06 for controls) and of phosphatidylcholine to sphingomyelin ([PC/SM] 2.64 +/- 0.87 v 2.00 +/- 0.15 for controls), enhanced fluidity (anisotropy parameter at 37 degrees C of 0.892 +/- 0.066 v 0.977 +/- 0.065 for controls), and a greater tendency to aggregate (aggregation of 84.2% +/- 6.3% v 78.5% +/- 7.6% for controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Lovastatin inhibits low-density lipoprotein oxidation and alters its fluidity and uptake by macrophages: in vitro and in vivo studies.

Under experimental conditions, oxidized low-density lipoprotein (Ox-LDL) may possess atherogenic properties, as is evidenced by its contribution to cholesterol accumulation in macrophages. LDL was oxidized in a cell-free system by predialysis of the lipoprotein against EDTA-free buffer and the addition of copper ions. Oxidation of LDL in the presence of lovastatin (10 to 1,000 mumol/L) resulted in a time- and dose-dependent reduction in thiobarbituric-acid-reactive substances (TBARS) concentration that was accompanied by increased LDL lysine-amino-group reactivity, in comparison with Ox-LDL produced in the absence of lovastatin. At 100 mumol/L, the drug reduced malondialdehyde concentration and increased amino-group reactivity by 24% and 42%, respectively. However, lovastatin's antioxidant effect was limited relative to other antioxidants, such as probucol and vitamin E. The fluidity of Ox-LDL was substantially reduced in comparison with native LDL. However, lovastatin inhibited this reduction in fluidity by 20%. Upon incubation of J-774 macrophage-like cell line with Ox-LDL, the lovastatin-treated Ox-LDL induced a reduction in the cellular cholesterol esterification rate in comparison with the effect of Ox-LDL that was produced in the absence of the drug. In four patients with hypercholesterolemia, the effect of lovastatin therapy (20 mg/d) on the sensitivity of their LDL to in vitro oxidation was studied. In all patients, Ox-LDL prepared from LDL obtained during lovastatin treatment demonstrated a reduced TBARS content, an increased trinitrobenzenesulfonic acid (TNBS) reactivity, an increased fluidity, and an impaired uptake by macrophages. These results were similar to those obtained by adding lovastatin in vitro.

Low density lipoprotein metabolism in type IV and type V hyperlipoproteinemia.

Low density lipoproteins (LDL) are thought to arise largely from degradation of triglyceride-rich very-low-density lipoproteins (VLDL). LDL kinetics in patients with Type IV and Type V hyperlipoproteinmia were studied and compared with normal subjects. LDL labeled in the protein moiety with 125I was used as a tracer. There was no significant difference in LDL turnover between the three groups, suggesting that a catabolic defect in VLDL degradation to LDL may exist in both Type IV and Type V hyperlipoproteinemia.

Lipid and lipoprotein pattern in thyroid dysfunction and the effect of therapy.

Lipid and lipoprotein concentrations were studied in 12 hypothyroid and 11 hyperthyroid female subjects, both before and after therapy, and in 27 age matched female controls. Recognized clinical and laboratory criteria established the diagnosis. Lipoproteins, including the sub-fractions of the high density lipoproteins (HDL), were isolated by preparative ultracentrifugation, and the cholesterol (c) and protein (p) contents of each were determined. Total cholesterol, and in particular HDL-c, were elevated in the hypothyroid patients. The low density lipoprotein (LDL) -c/HDL-c ratio was 1.9 in this group, compared to 2.2 in the control group and 1.35 in the hyperthyroid patients. The HDL-2/HDL-3 ratio in the hypothyroid group was 3.75, as compared to 1.75 in the controls and 4.2 in the hyperthyroid group. Plasma triglycerides were moderately elevated in the hypothyroid patients and were significantly reduced in the hyperthyroid group. Total cholesterol was significantly lower in the hyperthyroid group as compared to the control group. Very low density (VLDL) cholesterol and protein were significantly increased and LDL and HDL cholesterol were reduced in the hyperthyroid patients. On rendering the patients euthyroid, most of these changes were reversed. Thyroid function profoundly affects lipoprotein concentration and composition. The change in the plasma HDL concentrations of the hypothyroid group questions the relationship of this group to arteriosclerosis. Therapy partially corrects the abnormalities, but complete correction may be related to duration of therapy.

The effect of oestrogen implants on high density lipoproteins and its subfractions in women in their pre-mature menopause.

Oestrogen is recognized as having profound effects on lipid and lipoprotein levels. It is also considered as the agent protecting the pre-menopausal woman from arteriosclerotic cardiovascular disease. High density lipoprotein (HDL) has also been ascribed a protective role against the development of arteriosclerosis. The effect of natural oestrogen (17 beta-oestradiol) administered in the form of a subcutaneous pellet on concentrations of lipids and lipoproteins, particularly high density lipoproteins and its subfractions were determined in three young women with premature menopause. Plasma cholesterol, low density lipoprotein and very low density lipoprotein and very low density lipoprotein levels decreased following oestrogen implantation. High density lipoproteins and in particular subfraction 2 (density cut 1.063-1.125 gm/ml) and subfraction 3 (density cut 1.125-1.21 gm/ml) increased profoundly but there was a slight fall in the HDL 2/HDL 3 cholesterol ratio. The HDL/LDL cholesterol ratio increased from 0.21 to 0.46. A decrease in the urinary FSH levels paralleled these changes in the lipoprotein concentrations. Oestrogen administered in this form, unlike other oestrogen or mixed oestrogen--progestogen compounds is a definite modifier of arteriosclerotic risk, and as such could be given therapeutically in menopausal hypercholesterolemic females.

Increased low-density lipoprotein levels after splenectomy: a role for the spleen in cholesterol metabolism in myeloproliferative disorders.

Patients with myeloproliferative disorders demonstrate decreased plasma cholesterol and apolipoprotein B concentrations, and this has been related to the presence of a large spleen. Patients that underwent splenectomy in the past demonstrated normal plasma cholesterol levels. Plasma high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I were also reduced in these patients, but were normal after splenectomy. To study the immediate effect of splenectomy on the plasma lipid pattern, three patients with myeloproliferative disease and a large spleen who were undergoing splenectomy were compared with two control groups, one undergoing orthopedic operations and the second, cholecystectomy. In the control groups, plasma lipids tended to decrease for the first 2 days after surgery and then returned to preoperative levels. After splenectomy, however, plasma cholesterol, low-density lipoprotein (LDL), and apolipoprotein B significantly increased, reaching maximum levels after 4 days. Plasma HDL as well as apolipoprotein A-I decreased 1 day after splenectomy, but then increased over and above their preoperative concentrations. These results suggest an important role for the spleen in cholesterol metabolism in these patients. The spleen appears to be an important site for LDL catabolism in these patients.