Promoter methylation of serotonin transporter gene is associated with obesity measures: a monozygotic twin study.

OBJECTIVE: Epigenetic mechanisms are increasingly being recognized as an important factor for obesity. The serotonin transporter gene (SLC6A4) has a critical role in regulating food intake, body weight and energy balance. This study examines the potential association between SLC6A4 promoter methylation and obesity measures in a monozygotic (MZ) twin sample. METHODS: We studied 84 MZ twin pairs drawn from the Vietnam Era Twin Registry. Obesity measures include body mass index (BMI), body weight, waist circumference (WC) and waist-hip ratio (WHR). The SLC6A4 promoter methylation profile in peripheral blood leukocytes was quantified by bisulfite pyrosequencing. The association between methylation variation and obesity parameters was examined by mixed-model regression and matched pair analysis, adjusting for age, smoking, alcohol consumption, physical activity and total daily energy intake. Multiple testing was controlled using the adjusted false discovery rate (q-value). RESULTS: Mean methylation level was positively correlated with BMI (r=0.29; P=0.0002), body weight (r=0.31; P<0.0001) and WC (r=0.20; P=0.009), but not WHR. Intra-pair differences in mean methylation were significantly correlated with intra-pair differences in BMI, body weight and WC, but not WHR. On average, a 1% increase in mean methylation was associated with 0.33 kg m(-2) increase in BMI (95% CI: 0.02-0.65; P=0.03), 1.16 kg increase in body weight (95% CI, 0.16-2.16; P=0.02) and 0.78 cm increase in WC (95% CI, 0.05-1.50; P=0.03) after controlling for potential confounders. CONCLUSIONS: SLC6A4 promoter hypermethylation is significantly associated with an increased prevalence of obesity within a MZ twin study.

Glucose challenge test screening for prediabetes and undiagnosed diabetes.

AIMS/HYPOTHESIS: Diabetes prevention and care are limited by lack of screening. We hypothesised that screening could be done with a strategy similar to that used near-universally for gestational diabetes, i.e. a 50 g oral glucose challenge test (GCT) performed at any time of day, regardless of meal status, with one 1 h sample. METHODS: At a first visit, participants had random plasma and capillary glucose measured, followed by the GCT with plasma and capillary glucose (GCTplasma and GCTcap, respectively). At a second visit, participants had HbA(1c) measured and a diagnostic 75 g OGTT. RESULTS: The 1,573 participants had mean age of 48 years, BMI 30.3 kg/m(2) and 58% were women and 58% were black. Diabetes (defined by WHO) was present in 4.6% and prediabetes (defined as impaired glucose tolerance [2 h glucose 7.8-11.1 (140-199 mg/dl) with fasting glucose

Unrecognized glucose intolerance is not associated with depression. Screening for Impaired Glucose Tolerance study 3 (SIGT 3).

AIMS: To understand the metabolic and temporal links in the relationship between diabetes and depression, we determined the association between depressive symptoms and unrecognized glucose intolerance. METHODS: In a cross-sectional study, 1047 subjects without known diabetes were screened for diabetes or pre-diabetes using the oral glucose tolerance test and for depressive symptoms using the Patient Health Questionnaire (PHQ). RESULTS: Mean age was 48 years, body mass index 30 kg/m(2); 63% were female, 54% black, 11% previously treated for depression and 10% currently treated; 5% had diabetes and 34% pre-diabetes. Median PHQ score was 2 (interquartile range 0-5). Depressive symptoms did not increase with worsening glucose tolerance, after adjusting for age, sex, ethnicity, body mass index, family history, exercise, education and depression treatment. CONCLUSIONS: There is no association between depressive symptoms and unrecognized glucose intolerance. However, it remains possible that diagnosed diabetes, with its attendant health concerns, management issues, and/or biological changes, may be a risk for subsequent development of depression. Thus, patients with newly diagnosed diabetes should be counselled appropriately and monitored for the development of depression.

Coronary heart disease in women: update 2008.

Coronary heart disease (CHD) remains the leading cause of mortality for US women, responsible for almost 250,000 deaths annually. Preventive heart-health behavioral changes by women and aggressive coronary risk reduction can decrease the number of women disabled and killed by CHD. Angina is the predominant initial and subsequent presentation of CHD in women; categorization of chest pain and risk stratification of women assume pivotal roles. A robust evidence-based algorithm can guide cardiovascular imaging techniques to evaluate women with suspected myocardial ischemia to detect those with worsened survival. Restricted functional capacity (<5 METs) is a consistent marker of worsened prognosis. Younger women have substantially higher mortality rates than men following myocardial infarction and coronary bypass surgery. Although these women have more comorbidity and risk factors, other issues including biological differences, treatment differences, and psychosocial factors require management strategies tailored to the unique needs of women.

Depression and risk of heart failure among older persons with isolated systolic hypertension.

BACKGROUND: Investigators have shown that depression is associated with an increased risk of coronary heart disease in general and myocardial infarction in particular. However, it is unknown whether depression, independent of its association with myocardial infarction, is a risk factor for heart failure. METHODS: This study examined whether depression was a predictor of incident heart failure among 4538 persons aged 60 years and older with isolated systolic hypertension who were enrolled in the Systolic Hypertension in the Elderly Program (SHEP). Depression was defined as a score of 16 or more at baseline on the Center for Epidemiological Studies Depression Scale (CES-D). The relationship between depression and heart failure was assessed using Cox proportional hazards regression. RESULTS: The average follow-up was 4.5 years. Heart failure developed in 138 (3.2%) of 4317 nondepressed persons and in 18 (8.1%) of 221 depressed persons. After controlling for age; sex; race; history of myocardial infarction, diabetes, or angina; blood pressure; cholesterol levels; electrocardiographic abnormalities; smoking; disability; and SHEP treatment group, depressed persons had more than a 2-fold higher risk of developing heart failure compared with nondepressed persons (hazard ratio, 2.59; 95% confidence interval, 1.57-4.27; P<.001). After additional adjustment for the occurrence of myocardial infarction during follow-up, depressed persons remained at elevated risk of heart failure (hazard ratio, 2.82; 95% confidence interval, 1.71-4.67; P<.001). CONCLUSIONS: Depression is independently associated with a substantial increase in the risk of heart failure among older persons with isolated systolic hypertension. This association does not appear to be mediated by myocardial infarction.

An evidence-based assessment of federal guidelines for overweight and obesity as they apply to elderly persons.

BACKGROUND: The US Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults set the body mass index (BMI; weight in kilograms divided by the square of height in meters) of 25 as the upper limit of ideal weight for all adults regardless of age. However, the prognostic importance of overweight and obesity in elderly persons (>/=65 years) is controversial. We sought to analyze the guidelines in the context of currently available evidence that is relevant to older adults. METHODS: We searched MEDLINE for all English-language studies of the association between BMI and all-cause or cardiovascular mortality or coronary heart disease events from January 1966 through October 1999. Additional pertinent articles were identified through bibliographies of the MEDLINE articles. We selected studies for detailed review if they reported on the association between BMI and mortality for nonhospitalized subjects who were 65 years or older and had been followed up for at least 3 years. We controlled for age, smoking, and baseline health status. Of the 444 screened articles, 13 were selected to assess the guidelines. We extracted information regarding publication year, study design, population, recruitment period, follow-up duration, number of subjects, sex, age range, inclusion and exclusion criteria, and statistical models, including variables and end points. RESULTS: These data do not support the BMI range of 25 to 27 as a risk factor for all-cause and cardiovascular mortality among elderly persons. The results were not substantially different for men and women. Most studies showed a negative or no association between BMI and all-cause mortality. Three studies indicated overweight (BMI >/=27) as a significant prognostic factor for all-cause and cardiovascular mortality among 65- to 74-year-olds, and one study showed a significant positive association between overweight (BMI >/=28) and all-cause mortality among those 75 years or older. Higher BMI values were consistent with a smaller relative mortality risk in elderly persons compared with young and middle-aged populations. CONCLUSIONS: Federal guideline standards for ideal weight (BMI 18.7 to <25) may be overly restrictive as they apply to the elderly. Studies do not support overweight, as opposed to obesity, as conferring an excess mortality risk. Future guidelines should consider the evidence for specific age groups when establishing standards for healthy weight.

Moderate alcohol consumption and risk of heart failure among older persons.

CONTEXT: Heavy consumption of alcohol can lead to heart failure, but the relationship between moderate alcohol consumption and risk of heart failure is largely unknown. OBJECTIVE: To determine whether moderate alcohol consumption predicts heart failure risk among older persons, independent of the association of moderate alcohol consumption with lower risk of myocardial infarction (MI). DESIGN: Prospective cohort study conducted from 1982 through 1996, with a maximum follow-up of 14 years. SETTING AND PARTICIPANTS: Population-based sample of 2235 noninstitutionalized elderly persons (mean age, 73.7 years; 41.2% male; 21.3% nonwhite) residing in New Haven, Conn, who were free of heart failure at baseline. Persons who reported alcohol consumption of more than 70 oz in the month prior to baseline were excluded. MAIN OUTCOME MEASURE: Time to first fatal or nonfatal heart failure event, according to the amount of alcohol consumed in the month prior to baseline. RESULTS: Increasing alcohol consumption in the moderate range was associated with decreasing heart failure rates. For persons consuming no alcohol (50.0%), 1 to 20 oz (40.2%), and 21 to 70 oz (9.8%) in the month prior to baseline, crude heart failure rates per 1000 years of follow-up were 16.1, 12.2, and 9.2, respectively. After adjustment for age, sex, race, education, angina, history of MI and diabetes, MI during follow-up, hypertension, pulse pressure, body mass index, and current smoking, the relative risks of heart failure for those consuming no alcohol, 1 to 20 oz, and 21 to 70 oz in the month prior to baseline were 1.00 (referent), 0.79 (95% confidence interval [CI], 0.60-1.02), and 0.53 (95% CI, 0.32-0.88) (P for trend =.02). CONCLUSIONS: Increasing levels of moderate alcohol consumption are associated with a decreasing risk of heart failure among older persons. This association is independent of a number of confounding factors and does not appear to be entirely mediated by a reduction in MI risk.

The association between depression and coronary heart disease incidence.

The evidence from research studies linking depression to excess risk for coronary heart disease (CHD) is strong and consistent. Depression is a risk factor for new cardiovascular events in individuals initially free of CHD, as well as for recurrent events and mortality among cardiac patients. The risk is not only limited to individuals who meet the criteria for a clinical diagnosis of major depression. Increasing levels of depressive symptoms, even in the absence of a major depressive episode, also carry higher CHD risk. What is less established, however, is the mechanism (or mechanisms) responsible for the effect of depression on CHD risk. Depression might increase CHD incidence by promoting or worsening coronary atherosclerosis (through effects on lipid profile, platelets and inflammatory factors), directly inducing cardiac ischemia, increasing the risk for cardiac arrhythmias and sudden death, and inducing unhealthy behaviors (cigarette smoking, decreased adherence to medications and other lifestyle factors). Depression is common in the U.S. and its prevalence is rising. It is important that individuals with depression are promptly identified and treated. This is likely to result in a reduction of CHD and related disability as well as health care costs among Americans.

Thrombolytic therapy for eligible elderly patients with acute myocardial infarction.

OBJECTIVE: To determine the correlates of thrombolytic therapy use in a population-based sample of elderly patients hospitalized with acute myocardial infarction who were eligible for the therapy on presentation. DESIGN: Retrospective cohort study using data from medical charts and administrative files. SETTING: All acute care, nongovernmental hospitals in Connecticut. PATIENTS: A cohort of 3093 patients aged 65 years and older with a discharge diagnosis of acute myocardial infarction covered by Medicare from May 1992 to May 1993. RESULTS: Among the 753 patients with ST-segment elevation of 1 mm or more in at least 2 contiguous leads, left bundle branch block not known to be old, and no absolute contraindications to thrombolytic therapy who were not referred for direct angioplasty or bypass surgery, 419 patients (56%) did not receive thrombolytic therapy. The strongest predictors of not receiving thrombolytic therapy included advanced age, absence of chest pain, presentation more than 6 hours after the onset of symptoms, left bundle branch block, total ST-segment elevation of 6 mm or less, presence of Q waves, ST-segment elevation in only 2 leads, and altered mental status. Physicians documented why they did not administer thrombolytic therapy in 19% of the charts. Delay in presentation and increased age were the most common reasons cited. Among the subset of 261 patients who presented with chest pain and within 6 hours of symptoms, 197 (75%) received thrombolytic therapy. CONCLUSIONS: Many eligible and ideal patients for thrombolytic therapy are not treated. Physicians are less likely to use thrombolytic therapy in eligible patients with characteristics associated with an increased risk of bleeding, lower-risk infarction, less certain diagnosis, less certain efficacy, or altered mental status. These findings suggest that the lack of treatment represents a clinical judgment rather than an inadvertent omission. In some cases, such as the lower use of thrombolytic therapy with older age, these judgments are not consistent with the published literature and may represent opportunities to improve care.

Prevalence of coronary heart disease risk factors in northern-Italian male and female employees.

A cross-sectional study of 2650 male and 751 female employees of the IBM company in the Milan area was conducted in 1987 to compare risk profiles for coronary heart disease between men and women and to analyse the awareness of risk status of people at risk. After age adjustment, the rate of cigarette smoking was higher in women (35%) than in men (25%). Other coronary heart disease risk factors were more common in men than in women. After controlling for age, 38% of the men and 19% of the women met the study criteria for hypertension, and 22% of the men and 17% of the women had high blood cholesterol. However, an analysis by age groups showed that, although in the younger age groups women had lower levels of cardiovascular risk factors, except smoking, compared to men, in the age brackets 50 or older women had similar or more adverse risk factor profiles than men. Of the people with hypertension, only 22% of the men and 19% of the women were aware of their hypertension, and only 2% of the men and 4% of the women had successful control by drugs. Even when subjects with mild hypertension were excluded, high proportions of undiagnosed and uncontrolled hypertension were found in both sexes. Of the individuals with serum cholesterol > or = 240 mg.dl-1, less than half of the men and less than 20% of the women were aware of their high blood cholesterol levels. Multiple risk factors were frequently present in the same individuals, especially among males and older women.(ABSTRACT TRUNCATED AT 250 WORDS)

Activity profile of gemfibrozil on the major plasma lipoprotein parameters.

Gemfibrozil (G) is a widely used and highly effective fibric acid derivative. It acts both on lipoprotein disorders characterized by hypertriglyceridemia, as well as in hyperchlolesterolemia. The results of two separate studies are summarized, in order to elucidate the differential activity profile of the drug on the major plasma lipoprotein parameters. In a group of hypertriglyceridemic patients (Study I) the major activity of G was on the VLDL cholesterol (C) and triglyceride levels (respectively -40.4 and -35.7%), associated with a marked increase of the HDL-C levels, in particular in the HDL3 subfraction. In addition, apolipoprotein B levels were significantly reduced (-12%) in all treated patients. In Study II, treatment with G in severe hypercholesterolemia was compared to that with pravastatin, a major hydroxymethylglutaryl coenzyme A reductase inhibitor. G, in these patients, markedly reduced both total (-21.6%) and LDL-cholesterol (-24.4%) levels. The increase of HDL-C was less marked than in type IV patients but G, similarly to pravastatin, induced a significant reduction of apolipoprotein B, together with an increase (+19.2%) of apolipoprotein AII levels. These findings indicate that the activity profile of G is wider than expected and that it may include a reduction of LDL levels in severely hypercholesterolemic patients. The mechanism of this latter change is difficult to establish, although it may also be related to an improved delipidation of LDL, resulting in a more efficient interaction with peripheral high affinity receptors.

Aortic and coronary atheromatosis in a woman with severe hypercholesterolaemia without LDL receptor alterations.

Familial hypercholesterolaemia (FH) is a monogenic disorder, with a strong family history, characterized by a deficiency in functional receptors for low density lipoproteins (LDL). The case of a patient with all the clinical traits of FH, including elevated cholesterol, xanthomas and early coronary and peripheral arterial lesions, but with a normal LDL receptor function, is described. In the patient the molecular weight and immunological properties of apolipoprotein (apo) B were normal; furthermore, autoantibodies to either LDL or to their receptor were also absent. The increased apo B/cholesterol ratio in LDL was compatible with the diagnosis of hyperapobetalipoproteinaemia. With the help of a turnover study using 131I homologous and 125I autologous LDL, it could be established that the patient had an almost three-fold increase in LDL-apo B biosynthesis, with, however, a fractional catabolic rate within normal limits. These findings pointed to the possibility of a genomic alteration in the region responsible for the control of apo B biosynthesis. However, extensive studies both at the cDNA level and in the 5' region of the apo B gene, failed to detect any significant alteration vs published nucleotide sequences. Although the exact mechanism for this unusual clinical presentation of an FH-like syndrome could not be uncovered, this case provides an extreme example of hypercholesterolaemia, with early and severe arterial disease, solely explained by an increased LDL biosynthesis.

Plasma lipoprotein changes after treatment with pravastatin and gemfibrozil in patients with familial hypercholesterolemia.

The ability of pravastatin, a new hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, to lower plasma lipid levels and modify lipoprotein patterns was compared with that of gemfibrozil in 18 patients with familial hypercholesterolemia who participated in a 16-week, double-blind, parallel trial. Pravastatin proved better than gemfibrozil in lowering total and low-density lipoprotein (LDL) cholesterolemia: -23.6% and -28.2% versus -18.1% and -21.4%, respectively. A significant positive correlation was found between the starting level of serum cholesterol (both total and LDL) and the gemfibrozil-induced reduction (r = 0.72 and 0.69), whereas the hypocholesterolemic effect of pravastatin was apparently independent from pretreatment levels (r = 0.32 and 0.10). Apolipoprotein B concentrations were lowered by 25.4% (pravastatin) and 22.0% (gemfibrozil). Pravastatin and gemfibrozil reduced triglyceride levels by 13.9% and 49.4%, respectively. Both drugs increased the level of high density lipoprotein (HDL) cholesterol, but this change was significant only with gemfibrozil (p less than 0.05). The HDL subfraction structure and distribution were not modified by pravastatin treatment. Gemfibrozil, in contrast, increased HDL3 cholesterol level by 9% because of an enrichment of HDL3 particles in both free cholesterol and cholesteryl esters and lowered the flotation rate of HDL3 (p less than 0.05). LDL particles became smaller after gemfibrozil treatment (diameter: 25.4 +/- 0.3 nm vs 26.1 +/- 0.4 nm, p less than 0.01) and were not modified by pravastatin. This comparison shows a more pronounced efficacy of the HMG CoA reductase inhibitor on total and LDL cholesterol levels, also indicating that pravastatin acts by a single major mechanism, reducing the number of circulating LDL particles. Gemfibrozil may exert additional activities, possibly consequent to the stimulation of very low density lipoprotein catabolism.

Mechanisms of HDL reduction after probucol. Changes in HDL subfractions and increased reverse cholesteryl ester transfer.

Treatment with probucol, a widely used lipid-lowering agent, is associated with a significant reduction of high density lipoprotein (HDL) cholesterol levels, but with an apparently improved removal of cholesteryl esters from tissues (e.g., from tendon xanthomas). The effects of probucol (500 mg twice daily) on HDL subfraction distribution and cholesteryl ester transfer activity were tested in 12 patients with stable type II hyperlipidemia [low density lipoprotein (LDL) cholesterol greater than 180 mg/dl] after a placebo-controlled cross-over trial. Probucol significantly lowered total cholesterol (-13.8%), LDL cholesterol (-9.1%), and HDL cholesterol (-30%). By rate zonal ultracentrifugation, a marked reduction of HDL2 cholesterol (-68%) was shown, whereas changes in HDL3 were less significant (-21%). These findings were confirmed by polyacrylamide gradient gel electrophoresis, typically showing a reduction or disappearance of HDL2b particles and the prevalence of particles in the HDL3a range. Cholesteryl ester transfer from HDL to lower density lipoproteins was significantly increased (30%) in all patients. These findings suggest that, in addition to the well-documented in vitro changes (prevention of LDL peroxidation and macrophage uptake), probucol characteristically modifies HDL particle distribution in vivo, and is associated with a significant increase of cholesteryl ester transfer activity.

Apheretic treatment of severe familial hypercholesterolemia: comparison of dextran sulfate cellulose and double membrane filtration methods for low density lipoprotein removal.

The two more widely available techniques for the extracorporeal removal of low density lipoproteins (LDL), dextran sulfate cellulose column and double membrane filtration, were comparatively tested in severe familial hypercholesterolemic patients, both acutely and during a continued 3-month treatment. The selective dextran sulfate procedure removed close to 60% of LDL and 16% of high density lipoproteins (HDL) upon each apheresis, vs. 42% and 32%, respectively, in the case of the semi-selective double membrane filtration. Upon long term biweekly treatments, LDL-cholesterol (LDL-C) decreased, with the selective procedure, from a pre-treatment level of 406.0 +/- 40.7 mg/dl to a value fluctuating between 295.4 +/- 33.8 mg/dl and 116.9 +/- 22.0 mg/dl (highest vs. lowest levels) whereas, in the case of double membrane filtration, LDL-C levels ranged between 334.8 +/- 39.8 mg/dl and 192.3 +/- 49.9 mg/dl. HDL-cholesterol levels were somewhat raised, to a higher extent with dextran sulfate apheresis. The LDL/HDL-cholesterol "atherogenic ratio", decreased from a pre-treatment value of 10.27 +/- 3.04 to values ranging between 3.61 and 6.82 with dextran sulfate and between 6.70 and 7.68 with double membrane plasmapheresis.

Alterations in the HDL system after rapid plasma cholesterol reduction by LDL-apheresis.

Changes in high density lipoprotein (HDL) subfraction structure and composition were analyzed during and after extracorporeal removal of apo B containing lipoproteins in seven familial hypercholesterolemic (FH) patients. After the apheretic procedure, carried out with dextran-sulfate-cellulose columns, the plasma levels of very low density lipoproteins (VLDL), low density lipoproteins (LDL), and HDL decreased by 72%, 50%, and 19%, respectively. The free cholesterol to esterified cholesterol ratio in plasma increased, with a 26% drop in the lecithin:cholesterol acyl transferase (LCAT) activity. In the ensuing 24 hours, VLDL, HDL, and LCAT activity approached the pretreatment levels. During this phase, possibly as a consequence of increased cholesterol esterification and exchange of cholesteryl esters for triglycerides between HDL and VLDL, HDL2a particles were detected in plasma. However, these metabolic changes did not result in clearcut modifications in the HDL2-HDL3 subfraction distribution. These findings clearly demonstrate that rapid changes in the plasma VLDL-LDL levels affect several processes involved in the HDL metabolism, but confirm that the HDL system, in spite of a considerable plasticity, displays a marked stability of the HDL2-HDL3 subfraction distribution.

Selective and semiselective low-density lipoprotein apheresis in familial hypercholesterolemia.

Seven patients with familial hypercholesterolemia were treated fortnightly for 3 months by selective low-density lipoprotein apheresis with dextran-sulfate cellulose column (DSC). Subsequently, 4 of them were treated with semiselective double filtration. No cholesterol-lowering drugs were given. Plasma processed ranged from 39 to 58 ml/kg body weight/procedure. Fractional removals from plasma filtrate at the secondary treatment (adsorption or fractionation) for total cholesterol, high-density lipoprotein cholesterol, and albumin, respectively, were 0.84, 0.06, and 0.03 with DSC and 0.74, 0.47 and 0.35 with double filtration. Postapheresis reductions of total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were 57, 15, and 59% with DSC and 47,35, and 48% with double filtration. Both methods are suitable for clinical use, but with a 15-day treatment schedule, lowering circulating lipid fraction levels are maintained with DSC.

Soybean protein diet increases low density lipoprotein receptor activity in mononuclear cells from hypercholesterolemic patients.

The effect of two diets containing different protein sources (animal vs. soybean) on the low density lipoprotein (LDL) receptor activity was tested in freshly isolated mononuclear cells from 12 individuals with severe type II hyperlipoproteinemia. The two diets, both taken for 4 wk in a crossover design were of otherwise identical composition. During the soybean protein diet period, total cholesterol was reduced by 15.9% and LDL-cholesterol by 16.4%. The diet containing animal proteins exerted no significant change in plasma lipid levels vs. the baseline findings. The soybean diet regimen dramatically affected the degradation of LDL by mononuclear cells. Degradation was increased 16-fold vs. the basal activity and 8-fold compared with the standard low lipid diet with animal proteins. There was, however, no clear relationship between the reduction of total and LDL-cholesterolemia and the increased LDL degradation. These findings confirm similar data previously obtained in cholesterol-fed rats and suggest that some factor/s, most likely of a protein nature, may regulate the expression of lipoprotein receptors in peripheral cells, particularly when receptor activity is suppressed by experimental diets and/or spontaneous hypercholesterolemia.