Changes In Lipoprotein Profile Research Articles

Role of Low Density Lipoprotein Receptor in the Clearance of Coagulation Factor VIII In Vivo.

Low Density Lipoprotein Receptor (LDLR) is the archetype of the family of endocytic receptors that also includes Low-density lipoprotein Receptor-related Protein (LRP), Megalin, and Very Low Density Lipoprotein Receptor (VLDLR). While most of these receptors bind a variety of ligands, LDLR has restricted specifity. Its known ligands are apolipoprotein E (apoE) and apolipoprotein B100 (apoB100). Ligand binding to the LDL-receptor family is inhibited by the Receptor-Associated Protein (RAP). We have previously reported that RAP overexpression elevates plasma levels of factor VIII (FVIII) in both normal mice and mice with hepatic LRP deficiency [Bovenschen et al. (2003) Blood 101, 3933–3939]. This implies that LRP, but also another RAP-sensitive mechanism contributes to the regulation of FVIII in vivo. This study addresses the question whether LDLR, despite its restricted ligand specificity, binds FVIII and contributes to its clearance. In vitro binding was studied using a recombinant LDLR fragment spanning the extracellular domain of complement-type repeats 1–7. The purified fragment efficiently bound to immobilized ApoE and apoB-100 containing LDL. The immobilized LDLR fragment also bound human FVIII, with half-maximal binding at 156 nM FVIII, and binding was inhibited by RAP. Human von Willebrand Factor (VWF) or non-activated factor IX did not bind to the LDLR fragment. The relevance of the FVIII-LDLR interaction was assessed in vivo employing LDLR−/− mice, cre/loxP-mediated conditional LRP-deficient mice (LRP−), and mice with the combined deficiency. Plasma FVIII levels of controls, LDLR−/− and LRP− mice were 1.1, 0.9 and 1.8 U/ml, respectively. This suggests that LRP, but not LDLR regulates FVIII in plasma. Surprisingly, however, mice that combined LDLR deficiency with hepatic LRP deficiency displayed much higher FVIII levels (median value 4.6 U/ml) than mice lacking LRP alone. This suggests that LDLR does have the potential of regulating FVIII levels. LDLR−/− LRP− mice further displayed elevated levels of VWF (median value 3.3 U/ml), but not of factor V or factor IX. The possibility was considered that FVIII levels were elevated secondary to the profound changes in lipoprotein profiles. To this end, we also examined ApoE deficient mice, which have reduced LDL, and mice that overexpress ApoC1, which is associated with elevated levels of cholesterol- and triglyceride VLDL. ApoE−/− LDLR−/−LRP− mice had a median FVIII level of 4.2 U/ml, which is close to that of LDLR−/−LRP− mice. Mice that overexpressed human ApoC1 had elevated levels of cholesterol and triglycerides, but 0.5 U/ml FVIII. This demonstrates that elevated FVIII levels were independent of lipoprotein levels. The role of LDLR and LRP in FVIII clearance were further studied by analyzing the pharmacokinetics of human FVIII. In normal mice the Mean Residence Time (MRT) was 160 min [68% confidence intervals (CI) 117–218 min]. MRT was 200 [CI 154–259] min in LDLR−/− mice, and 263 [CI 206–336] min in LRP− mice. This confirms the previously described role of LRP in FVIII clearance. Strikingly, in LDLR−/−LRP− mice the MRT of FVIII was 760 [691–826] min, which is approximately 5-fold longer than in control mice. These data demonstrate that LRP and LDLR act in concert in regulating FVIII levels in plasma. In the absence of LDLR, LRP maintains normal FVIII levels, while hepatic LRP deficiency is largely compensated by LDLR. This regulatory role of LDLR represents a novel link between LDLR and the hemostatic system.

Charge-based heterogeneity of human plasma lipoproteins at hypertriglyceridemia: capillary isotachophoresis study

To reveal the metabolic links between and within pools of pro-atherogenic triglyceride(TG)-rich lipoproteins and anti-atherogenic high density lipoproteins (HDL), the changes in lipoprotein profile at hypertriglyceridemia were analyzed by capillary isotachophoresis. Plasma samples from patients with apoE3/3 phenotype were stained with a fluorescent probe NBD-C6-ceramide and lipoproteins resolved into six H-, one (V+I) and four L-components which belong to HDL, very low and intermediate density (VLDL+IDL) and low density lipoproteins (LDL), respectively. The expected correlation between the relative size of the combined fractions and lipid and apolipoprotein values was obtained confirming the validity of the approach. The new findings were obtained as follows. (1) The fast L-component correlated inversely with HDL–cholesterol (Chol), while intermediate and slow H-components correlated inversely with plasma and LDL–Chol and apoB. (2) The content of intermediate and slow H-components increased within H-pool and decreased relative TG-rich lipoproteins as hypertriglyceridemia rose due to the impairment of triglyceride hydrolysis by lipoprotein lipase within TG-rich particles. (3) A predictive value of the ratios of fast to slow H-components as an indicator of lecithin:cholesterol acyltransferase activity was demonstrated which tended to decrease at hypertriglyceridemia. (4) The L1/L2 ratio may be considered as an indicator of the accumulation of small dense LDL, which is a feature of clinically manifested atherogenic B-pattern. The competition between H(DL) and L(DL) particles for hepatic lipase and significant contribution of apoE to functional deficiency of H(DL) particles at hypertriglyceridemia are suggested.

Lipoprotein Effects of Different Thiazolidinediones in Clinical Practice

To investigate and compare the effects of troglitazone and rosiglitazone on plasma lipoproteins in patients with type 2 diabetes mellitus and dyslipidemia. This cohort study was conducted in the Diabetes Clinic of the University of Alabama. We identified and studied 18 patients with type 2 diabetes and dyslipidemia first treated with troglitazone (600 mg/day) and then transferred to rosiglitazone therapy (8 mg/day). By lowering insulin resistance, thiazolidinediones have common effects on lipoproteins; however, these drugs may have important differences in their effects on individual lipid particles. In our patients, both troglitazone and rosiglitazone increased low-density lipoprotein (LDL) levels; however, only rosiglitazone significantly changed the LDL particle size to the larger, less atherogenic LDL particle. Similarly, both troglitazone and rosiglitazone increased high-density lipoprotein (HDL) concentrations; however, although troglitazone increased only HDL(3), rosiglitazone also significantly increased the larger, more cardioprotective HDL(2) particle. Furthermore, only troglitazone increased Lp(a) significantly. In contrast, rosiglitazone and not troglitazone significantly increased triglycerides. Small but significant differences exist in the effects of different thiazolidinediones on lipoproteins in patients with type 2 diabetes. Overall, the changes in lipoprotein profile induced by rosiglitazone therapy seem to have less atherogenic potential than those resulting from the use of troglitazone.

Statins and menopause.

During the reproductive period, women generally have lower low-density lipoprotein (LDL) cholesterol and higher high-density lipoprotein cholesterol than age- and diet-matched men. However, these possibly antiatherogenic characteristics of lipoproteins are changed to a potentially atherogenic profile after menopause. Menopause-related changes in lipoprotein profile can be corrected by the administration of hormone replacement therapy (HRT). However, the results of recent studies did not show definite benefits of HRT on coronary heart disease-related mortality rates. On the other hand, several large-scale, long-term clinical trials provide evidence for efficacy and safety of HMG-CoA reductase inhibitors (statins) in both men and women. The results of 19 short-term clinical trials using simvastatin, pravastatin, fluvastatin or lovastatin in postmenopausal women are summarised and discussed. All these investigations reported significant reductions in both total and LDL cholesterol levels. The question of whether statin therapy results in a significant decrease in cardiovascular-related mortality rates along with a better quality of life in postmenopausal women remains to be investigated in large-scale, randomised, double-blind, placebo-controlled clinical trials.

Con: Postmenopausal hormone replacement therapy does not improve outcome in women undergoing coronary artery bypass graft surgery

CARDIOVASCULAR DISEASE is the leading cause of death in the United States in men and women. Deaths from cardiovascular disease outnumber deaths from all cancers combined and include approximately 500,000 women each year.1 The prognosis for women with coronary heart disease is worse than that for men, with higher mortality for women hospitalized for acute myocardial infarction, angioplasty, and coronary artery bypass graft surgery2-4 (CABG). Although the long-term survival for men and women discharged alive after CABG surgery is similar, the incidence of graft patency and survival free of angina is lower in women than in men.5 Despite the alarming prevalence of coronary heart disease in women, the incidence of coronary artery disease is still higher in men, with women developing atherosclerotic heart disease an average of 10 years later than men.6 This apparent female advantage is thought to be due to the protective effects of estrogen in women before menopause. In the Framingham study,7 researchers showed that the incidence of cardiovascular disease was 40 times higher in women aged 75 to 84 years compared with women aged 35 to 44 years. This ratio was not seen in men and likely reflects the relatively lower incidence of coronary artery disease in premenopausal women. Many observational studies have shown a lower risk of coronary heart disease in women who are taking postmenopausal hormone replacement therapy (HRT) when compared with women who are not, providing evidence to support the influential benefit of estrogen on risk for coronary heart disease. Estrogen raises high-density lipoprotein levels and lowers levels of low-density lipoproteins.8 These changes in lipoprotein profiles account for only 25% to 50% of the reduction in cardiovascular risk, however. Studies have shown evidence for estrogen-related endothelial-dependent vasodilation,9 antioxidant effects,10 and potential influences on coagulation.11 Given this information, it may be postulated that HRT would decrease the risk for recurrent cardiac events in women who have a history of coronary artery disease, resulting in improved clinical outcome. The authors conclusively show evidence against HRT in women with coronary artery disease, however, and illustrate that there is a paucity of data to confirm that this HRT improves outcome after CABG surgery.

Effects of testosterone propionate and nandrolone decanoate on body composition and lipoprotein concentrations in the rat

AbstractAnabolic–androgenic steroids (AAS) are used illicitly by athletes, bodybuilders and polydrug users. Cardiovascular complications are associated with their use and adverse lipoprotein alterations have been implicated as a contributing factor. In this experiment male and female rats were administered testosterone propionate, nandrolone decanoate or vehicle (peanut oil), 1 mg/kg/day s.c. for 14 days. Only the testosterone‐treated females experienced a significant increase in total body weight gain compared to peanut oil controls. No changes in food and water intake or excretion were noted between these two groups. Total body water increased in the testosterone‐treated female rats. Changes in lipoprotein profiles in female testosterone rats over the treatment period indicated a significant decrease in high‐density lipoproteins (HDL) compared to peanut oil‐treated animals.This study indicates that the treatment protocol used may serve as a model to further investigate the mechanisms underlying the effects of AAS.

Changes in Physical Fitness and Physical Activity during Puberty Do Not Predict Lipoprotein Profile Changes: The Muscatine Study

To evaluate the effect of changes in aerobic fitness and physical activity on changes in lipoproteins, we measured body composition, peak V̇O2, vigorous and sedentary activity, maturation, and lipoproteins in 125 children (mean baseline age, 10.5 years) for 5 years. Change in variables was analyzed using the slopes of the regression line obtained by plotting the data for each child. No predictor variables were significant for girls. In boys, predictors of favorable changes in lipoproteins included decreases in fatness, increases in fitness, early maturation, and increases in fat-free body mass (FFM). Multivariable analysis, adjusted for baseline age, indicated that change in FFM explained 21% of the variability in change in LDL-C. Results suggest that during puberty, changes in activity and fitness do not predict changes in lipoproteins.

Tamoxifen decreases cholesterol sevenfold and abolishes lipid lesion development in apolipoprotein E knockout mice.

Apolipoprotein E (apo E) knockout mice develop severe vascular lipid lesions resembling human atherosclerotic plaques, irrespective of the fat content of their diet. Oral tamoxifen (TMX) at a dose of 1.9 mg.kg body wt-1.d-1 abolished lipid lesion development, assayed by oil red O staining, whether the mice were fed a normal diet or a diet with high fat content. The TMX-treated mice showed a sevenfold decrease in total cholesterol. However, the proportion of plasma cholesterol present in VLDL remained unchanged, whereas the proportion in LDL decreased by 37%, and that in HDL increased by 64%. Consistent with the shift from LDL to HDL cholesterol, there was a 62% decrease in total triglycerides. The concentrations of active and acid-activatable latent plus active TGF-beta in the aorta were substantially elevated by TMX (87% and 24% increase, respectively). Although the mechanism of cardiovascular protection by TMX in apo E knockout mice is unknown, the inhibition of lipid lesion formation may be attributable to the changes in lipoprotein profile and the elevated levels of TGF-beta, both of which are thought to be protective against atherosclerosis in humans and animal models.

Inhibition of cholesterol ester transfer protein by CGS 25159 and changes in lipoproteins in hamsters

As a result of screening, several isoflavans were identified to be antagonists of cholesterol ester transfer protein (CETP) activity. The present study evaluates CGS 25159, a synthetic isoflavan, as a putative inhibitor of CETP activity of human and hamster plasma. Determined by [3H]CE transfer from HDL to VLDL+LDL fraction or by fluorescent-CE transfer assay, CGS 25159 inhibited CETP in both human plasma bottom fraction (d=1.21 g/ml) and in plasma from Golden Syrian Hamsters with an IC50<10 μM. The compound also inhibited (IC50≈15 μM) the reciprocal transfer of triglycerides in the incubated whole plasma from normal and hyperlipidemic hamsters. When orally administered to normolipidemic hamsters, CGS 25159 (10 mg/kg, 4 days) reduced plasma transfer activity by 35–60%. Treatment with CGS 25159 (10 and 30 mg/kg, p.o.) resulted in dose dependent and time dependent changes in CETP activity. After two weeks of treatment at 10 mg/kg, the changes in VLDL+LDL cholesterol, total triglycerides and HDL cholesterol were −22±4.6*, −23±7.5 and +10±2.8%, respectively. The corresponding changes at 30 mg/kg were −28±5.5*, −38±6.8* and +29±4.4*%, (*, P, 0.05; mean±S.E.M., n=6). A single spin gradient density ultracentrifugation of plasma lipoproteins from treated animals showed an increase in HDL cholesterol and a redistribution to larger HDL particles. These data support the contention that pharmacological down regulation of CETP activity could result in favorable changes in lipoprotein profile.

Resveratrol Has No Effect on Lipoprotein Profile and Does Not Prevent Peroxidation of Serum Lipids in Normal Rats

Trans-resveratrol, one of the antioxidants found in red wine, has been the subject of controversial reports regarding its protective role against cardiovascular diseases. In this study we synthesized trans-resveratrol and injected it to rats (20 and 40 mg/kg body weight, once a day for 21 days, i.p.) to determine its effect on the serum lipid profile. Synthetic trans-resveratrol was an effective antioxidant in vitro against hydroxyl radical (I50 = 33 μM). Resveratrol treatment, however, did not have any effect on either the lipid profile or on Cu+2-dependent formation of thiobarbi-turic-acid-reactive substances (TBARS) from protein-associated lipids. Since the amount of resveratrol used in these experiments was orders of magnitude higher than the amounts found in wine, these results suggest that if resveratrol has any effect against coronary heart diseases, it is not related to its antioxidant role on lipids or to changes in lipoprotein profile.

Lovastatin inhibits diet induced atherosclerosis in F1B Golden Syrian hamsters

3-Hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase inhibitors are the drugs most commonly prescribed in the US to lower blood cholesterol. Previous studies have shown their efficacy in reducing plasma low density lipoprotein (LDL) cholesterol. However, little is known about their effects on preventing diet induced atherosclerosis. We have investigated the changes in lipoprotein profiles and extent of atherogenesis in hamsters (F1B strain) consuming an atherogenic diet with and without lovastatin. Thirty-six animals were randomized into 3 groups of 12 animals each, with similar plasma cholesterol levels. One group of animals received a basal chow diet, and the other two groups a basal diet plus 10% (w/w) coconut oil and 0.05% cholesterol. After 2.5 weeks, one of the groups received the latter diet supplemented with lovastatin (25 mg/kg/day). A second study was carried out in which animals received the same diets, but lovastatin was given during the 10 week period at a dose of 12.5 mg/kg/day. At the end of the experimental period, animals were sacrificed and lipoprotein cholesterol, liver enzymes, and aortic foam cell development were determined. Animals fed the high fat diet plus lovastatin had significantly lower levels of non-high density lipoprotein (HDL) cholesterol than those fed the unsupplemented high fat diet. No differences were observed in mean levels of this parameter between animals fed the low fat diet and those receiving lovastatin. The amount of aortic lipid staining was significantly less in the lovastatin and low fat groups when compared to the unsupplemented high fat groups. These results indicate that lovastatin can prevent diet induced aortic lipid deposition in this animal model.

Lipoprotein profile changes during intense training of Israeli military recruits

The effect of prolonged strenuous military training on serum lipoproteins was studied in 73 new recruits. Dietary intake, body weight, and average energy expenditure were recorded, and blood samples collected at three time periods before training began (time 0), and after 6 and 12 wk of intense physical activity (times I and II, respectively). There was a significant increase in high density lipoprotein (HDL) cholesterol and a decrease in low density lipoprotein (LDL) cholesterol accompanying an increase of duration and intensity of exercise. HDL increased from 40.5 +/- 7.7 mg.dl-1 at time 0 to 44.5 +/- 9.4 mg.dl-1 at time I and to 52.8 +/- 8.7 mg.dl-1 at time II, and each mean P-value for increases in HDL from time 0-I, I-II, and 0-II were P < 0.0001). For LDL cholesterol, the mean decreases were -1.1, -6.1, and -7.3 mg.dl-1, respectively (P = 0.003 from I-II, and 0.01 from 0-II). These changes did not correlate with weight loss, reduced energy, or fat intake. We conclude that intense physical activity is associated with beneficial changes in the lipoprotein profile in new military recruits during a training period extending over 12 wk.

Changes in lipoprotein profiles during intense military training.

The effects of intense military training on lipoprotein concentrations were monitored in a group of 44 Navy trainees. Dietary intakes and lipoprotein profiles were obtained before and after 5 weeks of physical conditioning and after 5 days of continuous, extremely intense physical and psychological stress. Body weight did not change significantly and dietary intakes were consistently high in saturated fat and cholesterol. After physical conditioning, serum total cholesterol and triglyceride concentrations were unchanged, while high-density lipoprotein (HDL) concentrations increased 31% (p less than 0.05). After 5 days of severe stress, total cholesterol and low-density lipoprotein concentrations decreased 17.2% and 30%, respectively (p less than 0.05), whereas HDL concentrations increased 12.1%. These data indicate that marked changes in lipoprotein profiles occur, not only with long-term physical conditioning, but also with strenuous training that lasts several days, despite high energy, fat, and cholesterol intakes.

Enzyme induction by eating charcoal-grilled steak with no effect on blood lipids.

1. There has been interest in the suggestion that enzyme-inducing drugs, such as anticonvulsants, may produce beneficial changes in lipoprotein levels, in particular a rise in the ratio of high density lipoprotein cholesterol to total cholesterol. 2. This controlled study observed the effects of diets of charcoal or oven-cooked beef on antipyrine clearance (a commonly used measure of drug metabolizing capacity), the apparent oral clearance of phenacetin (a measure of cytochrome P448-dependent enzyme activity) and blood lipids in 18 healthy volunteers. 3. Charcoal-cooked beef increased antipyrine clearance by an average of 20% (P less than 0.059) and increased the apparent oral clearance of phenacetin fivefold (P less than 0.01). In contrast, oven-cooked beef did not significantly alter either measure of microsomal function. Neither diet had any effects on blood lipids. 4. We conclude that the type and degree of enzyme induction achieved by this type of dietary manipulation does not produce beneficial changes in lipoprotein profiles. A previously noted rise in high density lipoprotein cholesterol levels in volunteers fed charcoal-cooked beef may have been due to the effects of charcoal formed by charring of the beef during cooking.

The effect of clomipramine treatment on plasma lipoproteins and high density lipoprotein subfractions in healthy subjects

The effect of clomipramine on plasma lipoproteins, including high density lipoprotein (HDL) subfractions in five healthy males was investigated. The concentrations of total plasma cholesterol and low density lipoprotein cholesterol decreased slightly while that of total HDL-cholesterol showed a small increase, giving a decrease ( p <0.05) in the ratio of total plasma cholesterol to HDL-cholesterol. The level of HDL 2-cholesterol increased ( p < 0.01) with clomipramine treatment while there was no significant change in the concentration of HDL 3-cholesterol. Gradient gel electrophoresis showed that administration of the drug was associated with an increase in the relative concentration of HDL 2a as well as of HDL 2b and a decrease in that of HDL 3b/3 c. The plasma concentration of apolipoprotein (Apo) A-I showed a small but insignificant increase. These changes in lipoprotein profile are characteristic of those associated with a decrease in coronary risk.

Effect of pindolol versus atenolol on lipid profile in hypertensive patients

The effect of pindolol (a beta-blocker with intrinsic sympathomimetic activity, ISA) on fasting plasma lipid profile in 30 hypertensive patients was compared with atenolol (without ISA) in a crossover single blind study. Both drugs lowered blood pressure. HDL-cholesterol increased significantly with pindolol (from 1.15 ± 0.05 to 1.34 ± 0.05 mmoi/1 at 12 weeks, P < 0.001), but not with atenolol. VLDL-cholesterol increased with atenolol (from 0.57 ± 0.09 to 0.86 ± 0.14 mmol/1 at 12 weeks, P < 0.002), while there was no change with pindolol. These changes in lipoprotein profile suggest a more favourable effect of pindolol than of atenolol on lipid profile.

Changes in plasma lipoproteins during various androgen suppression therapies in men with prostatic carcinoma: effects of orchiectomy, estrogen, and combination treatment with luteinizing hormone-releasing hormone agonist and flutamide.

Cardiovascular complications are a well recognized side-effect of antihormonal therapy in men with prostatic carcinoma. We studied changes in plasma lipoproteins in patients with prostate cancer during treatment with several androgen suppression therapies. Estrogen, orchiectomy, and a combination of LHRH agonist and antiandrogen (flutamide) reduced plasma testosterone concentrations (89-92%) and plasma estradiol decreased by 85%, 44%, and 54%, respectively. Estrogen induced hypertriglyceridemia and elevation of plasma HDL cholesterol, phospholipid, and apolipoprotein A-I and A-II concentrations. Low density lipoprotein (LDL) cholesterol decreased but LDL apolipoprotein B did not. These results suggest that the cardiovascular complications that occur during estrogen administration are not mediated through changes in lipoprotein profile, other than the hypertriglyceridemic effect. Orchiectomy caused hypercholesterolemia and an increase in both total and LDL apolipoprotein B, all of which are strong determinants of cardiovascular disease. The high density lipoprotein (HDL) concentration was not affected despite a reduction in plasma testosterone, perhaps due to a simultaneous decrease in estradiol. Combination therapy had no effect on plasma lipid and apolipoprotein B concentrations, but very low density lipoprotein (VLDL) apolipoprotein B decreased, and LDL apolipoprotein B increased. The HDL cholesterol and apolipoprotein A-I concentrations increased but A-II and phospholipids did not. These results suggest enhanced lipoprotein lipase activity, consistent with the reciprocal changes in VLDL and LDL apolipoprotein B levels, apolipoprotein B enrichment of LDL particles, and increase in HDL cholesterol. The higher apolipoprotein A-I to A-II ratio indicates an increase in HDL2 subfraction due to inhibition of endothelial hepatic lipase, increased secretion of apolipoprotein A-I, or both. These effects are attributed to estradiol, which decreased less than after orchiectomy, and to additional adrenal androgen inhibition by flutamide. We conclude that estradiol plays an important role in determining plasma lipoprotein concentrations in men, and androgens exert an antagonist effect. The lipoprotein profile resulting from the combination treatment is more beneficial than that resulting from orchiectomy or estrogen administration.

Changes in Lipoprotein Profile in Patients with Acute Alcoholic Liver Disease During Recovery

Changes in Lipoprotein Profile in Patients with Acute Alcoholic Liver Disease During Recovery

Diabetes Mellitus and Exercise

Current research shows that the response to exercise is not identical for insulin dependent and non-insulin dependent diabetic clients. Contrary to what has been practiced, exercise cannot be prescribed in a general way for these individuals. Exercise offers benefits in weight reduction, lowered blood pressure and changes in lipoprotein profile for non-insulin dependent diabetics. For the insulin-dependent person, regularity of exercise must be emphasized to achieve stable metabolic control. Depending on the severity of the pathology, exercise may provoke microvascular and neurological changes or altered absorption of insulin. Illustrative of the known risks are triggering of angina pectoris, foot damage and persistent elevation of blood glucose. Optimally designed exercise programs are based on life style and are preceded by exercise stress testing for determination of cardiovascular fitness.

Diet-induced and physiologically occurring hypercholesterolemias in the spontaneous hypothyroid European badger (Meles meles L.): a density gradient study of lipoprotein profile.

As previously shown in this laboratory (Laplaud, P. M. et al. J. Lipid Res. 1980. 21: 724-738), the European badger is, with regard to its plasma lipid transport system, an original and complex animal of great potential interest to lipoprotein research. In an effort to study the response of this animal to cholesterol feeding, we gave a diet supplemented with 1% cholesterol to six male badgers (group H) during the late fall period when spontaneous hypercholesterolemia and hypothyroidism occur. Six more male animals of similar age received the standard diet (group C) and were simultaneously used as controls. Plasma lipids were measured using enzymatic methodologies, while the use of a recently described density gradient ultracentrifugation technique allowed detailed examination of lipoprotein composition and polyacrylamide gel electrophoresis of lipoproteins and tetramethylurea-soluble apoproteins in the fractions. The results suggest the superimposition, in H badgers, of the spontaneous and diet-induced hypercholesterolemias, maximum levels being reached in December in both C and H groups. While the two groups were very similar at the beginning of the experiment, highly significant differences (P < 0.01) were subsequently observed between C and H animals in plasma cholesterol and phospholipid concentrations. Density gradient ultracentrifugation provided evidence for the following diet-induced changes in lipoprotein profile: 1) a twofold increase in cholesteryl esters in particles of d < 1.006 g/ml; 2) the occurrence of large amounts of supplementary cholesterol-rich low density lipoproteins, mainly in the 1.019-1.027 g/ml region; 3) an increase in the 1.039-1.055 g/ml low density lipoproteins; and 4) a change in the ratio of the concentrations of high density lipoproteins of d 1.065-1.100 g/ml and d 1.100-1.162 g/ml, to the benefit of the former. Electrophoresis of the density gradient fractions revealed marked heterogeneity, especially in the low density part of the spectrum. Electrophoresis of the low molecular weight, tetramethylurea-soluble apoproteins failed to show marked differences between C and H badgers. However, chromatographic determination of the proportion of apoB in the protein moiety of the two main low density components showed that 1) it was consistently low, 2) its contribution to the higher density fraction (d 1.039-1.046 g/ml) was unaffected by the hypercholesterolemic diet (being about 25% in both C and H animals), and 3) its contribution to the lower density fraction (d 1.019-1.027 g/ml) decreased under the same nutritional conditions, representing about 20% in C as compared to about 10% in H badgers.-Laplaud, P. M., Beaubatie, and D. Maurel. Dietinduced and physiologically occurring hypercholesterolemias in the spontaneous hypothyroid European badger (Meles meles L.): a density gradient study of lipoprotein profile.