Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging.

OBJECTIVE: Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort. METHODS: We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ε4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D). RESULTS: Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2-4) had lower total brain and greater white matter hyperintensity volumes (for model A: ß ± SE = -0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs. Q2-4) also had lower scores on tests of visual memory (ß ± SE = -0.47 ± 0.18; p = 0.008), executive function (ß ± SE = -0.07 ± 0.03; p = 0.004), and abstract thinking (ß ± SE = -0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models. CONCLUSION: Lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia.

Safety and tolerability of esterified phytosterols administered in reduced-fat spread and salad dressing to healthy adult men and women.

OBJECTIVE/DESIGN: The safety and tolerability of three levels of plant sterol-esters administered in reduced-fat spread and salad dressing vs. control products were evaluated in this randomized, double-blind, four-arm parallel study. METHODS: Eighty-four free-living men and women consumed reduced-fat spread and salad dressing providing 0.0 g/day (n = 21), 3.0 g/day (n = 21), 6.0 g/day (n = 19) or 9.0 g/day (n = 23) of phytosterols as esters for an eight-week treatment period. RESULTS: Side effects did not differ among the groups during the study, and there were no study product-related serious adverse events. There were no changes in clinical laboratory values in response to phytosterol intake. Blood concentrations of all fat-soluble vitamins remained within normal reference ranges, and there were no differences in serum vitamin responses among the four groups. Alpha- and trans-beta-carotene levels were reduced in the 9.0 g/day group vs. control (p < 0.05), but all carotenoid values remained within normal ranges throughout the study. All groups receiving phytosterols had significant increases in serum campesterol vs. control (p < 0.001), but beta-sitosterol responses did not differ from control. Total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol responses did not differ significantly among the groups. The total:HDL cholesterol response in the 9.0 g/day group was significantly different from the control group response (-9.6% vs. 2.6%, p < 0.05). A median increase of 7.8% in serum triglycerides was observed in the control group, which differed significantly from the response in the 3.0 g/day arm (-13.3%, p < 0.05). DISCUSSION: The results of this study indicate that phytosterol esters are well tolerated and show no evidence of adverse effects at a daily intake of up to 9.0 g of phytosterols for eight weeks.

Lipid responses to plant-sterol-enriched reduced-fat spreads incorporated into a National Cholesterol Education Program Step I diet.

BACKGROUND: Plant sterol esters reduce cholesterol absorption and lower circulating blood cholesterol concentrations when incorporated into the habitual diet. OBJECTIVE: This randomized, double-blind, 3-group parallel, controlled study evaluated the influence of esterified plant sterols on serum lipid concentrations in adults with mild-to-moderate primary hypercholesterolemia. DESIGN: Subjects incorporated a conventional 50%-fat spread into a National Cholesterol Education Program Step I diet for a 4-wk lead-in period, followed by a 5-wk intervention period of the diet plus either a control reduced-fat spread (40% fat; n = 92) or a reduced-fat spread enriched with plant sterol esters to achieve intakes of 1.1 g/d (n = 92; low-sterol group) or 2.2 g/d (n = 40; high-sterol group). RESULTS: Subjects in the low- and high-sterol groups who consumed > or = 80% of the scheduled servings (per-protocol analyses) had total cholesterol values that were 5.2% and 6.6% lower, LDL-cholesterol values that were 7.6% and 8.1% lower, apolipoprotein B values that were 6.2% and 8.4% lower, and ratios of total to HDL cholesterol that were 5.9% and 8.1% lower, respectively, than values for the control group (P < 0.001 for all). Additionally, triacylglycerol concentrations decreased by 10.4% in the high-sterol group. Serum concentrations of fat-soluble vitamins and carotenoids were generally within reference ranges at baseline and postintervention. Serum plant sterol concentrations increased from baseline (0.48% of total sterol by wt) to 0.64% and 0.71% by wt for the low- and high-sterol groups, respectively (P < 0.05 compared with control). CONCLUSION: A reduced-fat spread containing plant sterol esters incorporated into a low-fat diet is a beneficial adjunct in the dietary management of hypercholesterolemia.

Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT).

BACKGROUND: A low level of HDL cholesterol has been identified as a risk factor for stroke in observational studies. METHODS AND RESULTS: Our objective was to determine whether treatment aimed at raising HDL cholesterol and lowering triglycerides reduces stroke in men with coronary heart disease and low levels of both HDL and LDL cholesterol. The study was a placebo-controlled, randomized trial conducted in 20 Veterans Affairs medical centers. A total of 2531 men with coronary heart disease, with mean HDL cholesterol 0.82 mmol/L (31.5 mg/dL) and mean LDL cholesterol 2.9 mmol/L (111 mg/dL), were randomized to gemfibrozil 1200 mg/d or placebo and were followed up for 5 years. Strokes were confirmed by a blinded adjudication committee. Relative risks were derived from Cox proportional hazards models. There were 134 confirmed strokes, 90% of which were ischemic. Seventy-six occurred in the placebo group (9 fatal) and 58 in the gemfibrozil group (3 fatal), for a relative risk reduction, adjusted for baseline variables, of 31% (95% CI, 2% to 52%, P=0.036). The reduction in risk was evident after 6 to 12 months. Patients with baseline HDL cholesterol below the median may have been more likely to benefit from treatment than those with higher HDL cholesterol. CONCLUSIONS: In men with coronary heart disease, low HDL cholesterol, and low LDL cholesterol, gemfibrozil reduces stroke incidence.

Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial.

CONTEXT: A low plasma level of high-density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary heart disease (CHD). A secondary prevention study, the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), demonstrated that CHD events were significantly reduced during a median follow-up of 5.1 years by treating patients with the fibric acid derivative gemfibrozil when the predominant lipid abnormality was low HDL-C. OBJECTIVE: To determine if the reduction in major CHD events with gemfibrozil in VA-HIT could be attributed to changes in major plasma lipid levels. DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial conducted from September 1991 to August 1998. SETTING: The Department of Veterans Affairs Cooperative Studies Program, in which 20 VA medical centers were participating sites. PARTICIPANTS: A total of 2531 men with a history of CHD who had low HDL-C levels (mean, 32 mg/dL [0.83 mmol/L] ) and low low-density lipoprotein cholesterol (LDL-C) levels (mean, 111 mg/dL [2.88 mmol/L]). INTERVENTION: Participants were randomly assigned to receive gemfibrozil, 1200 mg/d (n = 1264), or matching placebo (n = 1267). MAIN OUTCOME MEASURE: Relation of lipid levels at baseline and averaged during the first 18 months of gemfibrozil treatment with the combined incidence of nonfatal myocardial infarction and CHD death. RESULTS: Concentrations of HDL-C were inversely related to CHD events. Multivariable Cox proportional hazards analysis showed that CHD events were reduced by 11% with gemfibrozil for every 5-mg/dL (0.13-mmol/L) increase in HDL-C (P =.02). Events were reduced even further with gemfibrozil beyond that explained by increases in HDL-C values, particularly in the second through fourth quintiles of HDL-C values during treatment. During gemfibrozil treatment, only the increase in HDL-C significantly predicted a lower risk of CHD events; by multivariable analysis, neither triglyceride nor LDL-C levels at baseline or during the trial predicted CHD events. CONCLUSIONS: Concentrations of HDL-C achieved with gemfibrozil treatment predicted a significant reduction in CHD events in patients with low HDL-C levels. However, the change in HDL-C levels only partially explained the beneficial effect of gemfibrozil.

Common variants in the gene encoding ATP-binding cassette transporter 1 in men with low HDL cholesterol levels and coronary heart disease.

HDL cholesterol (HDL-C) deficiency is the most common lipid abnormality observed in patients with premature coronary heart disease (CHD). Recently, our laboratory and others demonstrated that mutations in the ATP-binding cassette transporter 1 (ABCA1) gene are responsible for Tangier disease, a rare genetic disorder characterized by severely diminished plasma HDL-C concentrations and a predisposition for CHD. To address the question of whether common variants within the coding sequence of ABCA1 may affect plasma HDL-C levels and CHD risk in the general population, we determined the frequencies of three common ABCA1 variants (G596A, A2589G and G3456C) in men participating in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a study designed to examine the benefits of HDL raising in men having low HDL-C (< or =40 mg/dl) and established CHD, as well as in CHD-free men from the Framingham Offspring Study (FOS). Allele frequencies (%) in VA-HIT were 31, 16, and 4 for the G596A, A2589G, and G3456C variants, respectively, versus 27, 12, and 2 in FOS (P<0.03). None of the variants were significantly associated with plasma HDL-C concentrations in either population; however, in VA-HIT, the G3456C variant was associated with a significantly increased risk for CHD end points, suggesting a role for this variant in the premature CHD observed in this population.

Targeting low high-density lipoprotein cholesterol for therapy: lessons from the Veterans Affairs High-density Lipoprotein Intervention Trial.

Results of the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) showed that therapy with the fibric acid gemfibrozil significantly reduced the incidence of coronary artery disease events in men with known coronary artery disease and a low level of high-density lipoprotein cholesterol (HDL-C). Coronary artery disease event reduction was inversely related to levels of HDL-C achieved with gemfibrozil and, even at relatively low concentrations of HDL-C, coronary artery disease event reduction with gemfibrozil was significantly greater than with placebo. Subjects with a low HDL-C level who were recruited for VA-HIT had a high prevalence of features of the metabolic syndrome with obesity, type 2 diabetes, and hyperinsulinemia. These individuals especially benefited from gemfibrozil, and thus, fibrate therapy may have an increasing role in reducing coronary artery disease risk in a setting of an increasing worldwide prevalence of obesity and diabetes.

Effect of ursodeoxycholic acid on hepatic LDL binding and uptake in dietary hypercholesterolemic hamsters.

Administration of ursodeoxycholic acid (UDCA) has been shown to decrease serum total and low density lipoprotein (LDL) cholesterol in hypercholesterolemic patients with primary biliary cirrhosis. Results of previous studies prompted us to postulate that the cholesterol-lowering effect of UDCA may be due, at least in part, to a direct increment in hepatic LDL receptor binding [Bouscarel et al., Biochem J, 1991;280:589; Bouscarel et al., Lipids 1995;30:607]. The aim of the present investigation was to determine the ability of UDCA to enhance hepatocellular LDL receptor recruitment, as determined by its effect in vivo on LDL uptake, and its effect in vitro on LDL binding, under conditions of moderately elevated serum cholesterol. Study groups consisted of male golden Syrian hamsters fed either a standard chow diet (control), a 0.15% cholesterol-containing diet, or a 0.15% cholesterol-containing diet supplemented with either 0.1% UDCA, or 0.1% chenodeoxycholic acid (CDCA). Cholesterol feeding increased (P<0.01) total serum cholesterol by 44%, and was associated with a 10-fold accumulation of cholesteryl esters in the liver (P<0.01). In vivo, hepatic uptake of [U-(14)C]sucrose-labeled hamster LDL was increased (P<0.05) to a level of 454+/-101 microl in animals fed a cholesterol-containing diet supplemented with UDCA, compared to that either without UDCA (337+/-56 microl), or with CDCA (240+/-49 microl). The hepatic uptake of [U-(14)C]sucrose-labeled methylated human LDL, a marker of LDL receptor-independent LDL uptake, was unaffected by bile acid feeding. In vitro, specific binding of [125I]hamster LDL to isolated hepatocytes was determined at 4 degrees C, in presence and absence of 700 micromol/l UDCA. The K(D) ranged from 25 to 31 microg/ml, and was not affected by either cholesterol feeding or UDCA. In the presence of UDCA, the B(max) was increased by 19% (P<0.05) in cells isolated from control animals and by 29% (P<0.01) in cells isolated from hamsters fed a cholesterol-supplemented diet. In conclusion, in dietary hypercholesterolemic hamsters, both chronic in-vivo and acute in-vitro treatments with UDCA resulted in restoration of hepatic LDL binding and uptake to levels observed in control hamsters.

Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.

BACKGROUND: Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary heart disease is beneficial, there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein (HDL) cholesterol. METHODS: We conducted a double-blind trial comparing gemfibrozil (1200 mg per day) with placebo in 2531 men with coronary heart disease, an HDL cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or less, and an LDL cholesterol level of 140 mg per deciliter (3.6 mmol per liter) or less. The primary study outcome was nonfatal myocardial infarction or death from coronary causes. RESULTS: The median follow-up was 5.1 years. At one year, the mean HDL cholesterol level was 6 percent higher, the mean triglyceride level was 31 percent lower, and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group. LDL cholesterol levels did not differ significantly between the groups. A primary event occurred in 275 of the 1267 patients assigned to placebo (21.7 percent) and in 219 of the 1264 patients assigned to gemfibrozil (17.3 percent). The overall reduction in the risk of an event was 4.4 percentage points, and the reduction in relative risk was 22 percent (95 percent confidence interval, 7 to 35 percent; P=0.006). We observed a 24 percent reduction in the combined outcome of death from coronary heart disease, nonfatal myocardial infarction, and stroke (P< 0.001). There were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer. CONCLUSIONS: Gemfibrozil therapy resulted in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level. The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.

Delineation of a novel hepatic route for the selective transfer of unesterified sterols from high-density lipoproteins to bile: studies using the perfused rat liver.

Cholesterol is principally excreted from the body in bile as unesterified cholesterol (UC). Using the unesterified plant sterol, sitostanol (SIT), as a nonexchangeable analog for UC, we have found that high-density lipoproteins (HDL), but not low-density lipoproteins, provide a vehicle for the direct delivery of cholesterol to bile. To determine the mechanism for preferential cholesterol transport from HDL to bile, isolated rat livers were perfused with a reconstituted HDL, made with radiolabeled unesterified SIT, UC, and cholesteryl esters (CE). Total biliary sterol secretion was independent of the concentration of HDL added to perfusions, but with increasing HDL-SIT perfused, the proportion of SIT to cholesterol in bile was linearly increased. Biliary SIT secretion was rapid (detected within 2 to 4 minutes after reconstituted HDL was added to perfusions) and was dependent on the immediate presence of SIT in the perfusate, but independent of the amount of SIT that had accumulated in the liver. The ratio of SIT to UC was seven- to ninefold greater in bile than in the liver, consistent with preferential mobilization of membrane sterols delivered from HDL. Although radiolabeled UC as well as SIT was taken up from HDL by the liver and secreted in bile, net UC uptake could not be quantitated because of both UC exchange and a sizable enrichment of HDL with UC mass that approximated the SIT removed during the passage of HDL through the liver. These results are consistent with sterol transport to bile from HDL by a direct plasma membrane pathway and by a mechanism that appears to involve substitution of unesterified (exogenous) sterol from HDL for plasma membrane UC during transport. By this process, HDL can promote reverse cholesterol transport from peripheral tissues to bile, even without an increase in biliary cholesterol secretion.

Carotid atherosclerosis in men with low levels of HDL cholesterol.

BACKGROUND AND PURPOSE: A low HDL cholesterol (HDL-C) frequently occurs in conjunction with a desirable LDL cholesterol (LDL-C) and is a risk factor for coronary heart disease (CHD). Additionally, the presence of carotid atherosclerosis is a strong and independent predictor of morbidity and mortality in patients with CHD. This article describes the prevalence and correlates of sonographically detected carotid atherosclerosis in men with low levels of HDL-C and CHD but without elevated levels of LDL-C or total cholesterol. METHODS: High-resolution B-mode ultrasonography was used to quantify intima-media wall thickness (IMT) in the common and internal carotid arteries and at the carotid artery bifurcation in 202 randomly selected male veterans with CHD and low levels of HDL-C who are participating in the VA HDL Intervention Trial. Ultrasonographic measurement of carotid artery wall stiffness was determined in a subset of 94 of these individuals. RESULTS: The mean maximum and single greatest carotid artery IMT measurements were 1.41 and 2.58 mm, respectively. The prevalence of ultrasound-detected carotid atherosclerosis as defined by a mean maximum IMT > or = 1.3 mm was 58.9% and by single maximum IMT > or = 1.5 mm was 87.1%. IMT was associated with increased age, lower extremity arterial disease, systolic blood pressure, and ultrasonographically measured carotid artery stiffness. CONCLUSIONS: Men with low levels of HDL-C and CHD but without elevated LDL-C or total cholesterol have a very high prevalence of ultrasound-detected carotid artery atherosclerosis.

High density lipoproteins, but not other lipoproteins, provide a vehicle for sterol transport to bile.

Unesterified cholesterol (UC) that is taken up by the liver from lipoproteins is rapidly mixed by exchange with liver UC. Thus, it is not possible to quantitate the transport of UC from different lipoproteins into bile using radiolabeled UC. However, plant sterols do not exchange with UC and are secreted in bile with the same kinetics as UC. To compare the contribution to bile of sterols from different lipoproteins, we perfused isolated rat livers with VLDL, LDL, and HDL that were obtained from patients with hereditary phytosterolemia and were rich in plant sterols. After 30-min recirculating perfusions, hepatic concentrations of plant sterols were not different after different lipoproteins were perfused. However, biliary plant sterol secretion was markedly different: with the perfusion of either VLDL or LDL there was no increase in plant sterols in bile, but with perfusion of HDL, the secretion of plant sterols was increased two- to threefold (P = 0.0005). The increase in biliary plant sterols was detected 5-10 min after HDL was added to perfusates and was similarly large for each of three individual plant sterols that was tracked. Results show that when sterol transport from lipoproteins into bile can be determined, only HDL provides a vehicle for UC elimination in bile that is consistent with its putative function in reverse cholesterol transport.

The Veterans Affairs High-Density Lipoprotein Intervention Trial: baseline characteristics of normocholesterolemic men with coronary artery disease and low levels of high-density lipoprotein cholesterol. Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Intervention Trial Study Group.

This report describes the baseline characteristics of the 2,531 patients with coronary artery disease enrolled in the Veterans Affairs Cooperative Studies Program High Density Lipoprotein Intervention Trial. The population is characterized by a large percentage of elderly patients, diabetic patients, and patients with the clinical characteristics of the insulin-resistance syndrome.

Correlates and consequences of diffuse atherosclerosis in men with coronary heart disease. Veterans Affairs High-Density Lipoprotein Intervention Trial Study Group.

BACKGROUND: Peripheral atherosclerosis is a strong and independent predictor of mortality even in patients with known coronary heart disease. However, the prevalence, correlates, and potential adverse effects on quality of life associated with combined coronary heart disease and clinically evident cerebrovascular or lower-extremity atherosclerosis are not known. Identification of patients with "diffuse atherosclerosis" may enhance treatment of modifiable risk factors and alter therapeutic strategies. METHODS: We conducted a cross-sectional analysis of 2531 men younger than 73 years with coronary heart disease, low-density lipoprotein cholesterol levels of 3.62 mmol/L (140 mg/dL) or less, and high-density lipoprotein cholesterol level of 1.03 mmol/L (40 mg/dL) or less who were participating in Department of Veterans Affairs Cooperative Study 363 (the Veterans Affairs High-Density Lipo-protein Intervention Trial. Baseline demographic, medication, comorbidity, and atherosclerotic risk factor data were assessed by means of a standardized questionnaire. All plasma lipid levels were determined after a 12-hour fast by a central standardized lipid laboratory. Health status was determined by baseline reported symptoms, medical comorbidities, and the Psychological General Well-being Index. Clinically evident diffuse atherosclerosis was defined as a documented history of lower-extremity atherosclerosis or cerebrovascular disease. RESULTS: The mean age of all participants was 63.5 years. The mean plasma lipid values were as follows: total cholesterol, 4,52 mmol/L (174.6 mg/dL); high-density lipo-protein cholesterol, 0.81 mmol/L (31.5 mg/dL); low-density lipoprotein cholesterol, 2.88 mmol/L (111.2 mg/dL); and triglycerides, 1.81 mmol/L (160.6 mg/dL). Diffuse atherosclerosis was present in 525 (21%). Lower-extremity atherosclerosis was reported in 10%, while cerebrovascular disease was present in 13%. After controlling for other variables, the following factors were associated with the presence of diffuse atherosclerosis: increased age, being unmarried, being retired, having less than a high school education, increased alcohol use, hypertension, cigarette smoking, and diabetes. There was no association between lipid levels and the presence of diffuse atherosclerosis. After adjustment for age, race, and comorbidities, men with diffuse disease still had a reduced quality of life compared with men without diffuse atherosclerosis, as defined by having a greater number of clinical symptoms, lower psychological well-being scores, and more advanced or complicated coronary heart disease. CONCLUSIONS: Clinically evident diffuse atherosclerosis is common in men with coronary heart disease and low levels of high-density lipoprotein cholesterol. Because diffuse atherosclerosis is associated with a reduced quality of life and several modifiable risk factors, early detection and aggressive risk factor intervention appear justified.

Hepatic transport and secretion of unesterified cholesterol in the rat is traced by the plant sterol, sitostanol.

The hepatic uptake, transport, and secretion into bile of unesterified cholesterol cannot be directly quantitated because of extensive exchange and equilibration between different pools of unesterified cholesterol. Plant sterols are structurally similar to cholesterol but because of poor intestinal absorption are ordinarily not present in the liver. To quantitate hepatic sterol uptake and transport in the absence of exchange with endogenous sterols, isolated rat livers were perfused with the plant sterol, sitostanol, incorporated in phosphatidylcholine liposomes. Appreciable amounts of sitostanol were taken up by the liver and uptake was independent of the presence of bile salt. In contrast, like unesterified cholesterol, the secretion of sitostanol in bile required bile salt. Sitostanol was detected in bile within 5 min after a perfusion was begun and reached a plateau by about 20 min. The rate of appearance of sitostanol in bile was precisely the same as unesterified cholesterol when both sterols were perfused together. Furthermore, the output of sitostanol in bile was directly proportional to the output of cholesterol. At the peak of biliary sitostanol secretion, the amount of sitostanol relative to unesterified cholesterol was much greater in bile (40-50% of sterols) than in the whole liver (11% of sterols). Selective biliary secretion of sitostanol was associated with much greater concentrations of sitostanol in canalicular membranes than in the interior membranes of the hepatocyte and in newly secreted high density lipoproteins compared to newly secreted very low density lipoproteins. These results indicate that sitostanol parallels the secretion from and distribution of unesterified cholesterol in the liver and suggest that sitostanol can be used as a physiologic analog of unesterified cholesterol to trace the transport of sterols through the liver.

Diurnal changes and adaptation by the liver of hamsters to an atherogenic diet.

Studies were performed in freely feeding, male (F1B) Syrian hamsters fed a high-fat diet to determine the extent and manner of adaptation of the liver to diurnal changes in eating patterns and an increase in serum lipids. Serum cholesterol and triglycerides strongly paralleled changes in food consumption and were 40-50% greater during the 12-h dark period than the 12-h light period of the diurnal cycle. Hepatic cholesterol changes closely approximated changes in serum cholesterol (r = 0.916) due principally to changes in hepatic cholesteryl esters that were on average about 10-fold greater with the high-fat diet than with a chow diet. With the high-fat diet, hepatic cholesteryl esters were, however, extremely variable and were 40% greater at the mid-dark than at the mid-light period. With high fat there was also a marked increase in the secretion of very low density lipoproteins (VLDL) from the liver that were cholesteryl ester rich and closely paralleled the diurnal changes in hepatic cholesteryl esters (r = 0.911). In contrast, although with a high-fat diet biliary cholesterol secretion was increased, the increase in cholesterol in bile exhibited no diurnal pattern and with the high-fat diet was far less in magnitude than the increase of cholesterol in VLDL. Biliary cholesterol secretion is dependent on bile acid secretion. However, with the high-fat diet, neither the bile acid pool size nor bile acid secretion was increased compared with chow-fed controls. Moreover, with high fat at mid-dark period, bile acid secretion was significantly less than controls at mid-dark period. Thus in these hamsters a high-fat diet produced a marked increase in serum cholesterol that was distinctly diurnal and was compensated for by a diurnal increase in hepatic cholesteryl ester stores and the secretion of cholesteryl esters in VLDL. In contrast, cholesterol secretion in bile did not correspond to the fluctuating changes of cholesterol in the liver and was far less in magnitude than would be necessary to reduce a greatly expanded pool of hepatic cholesterol.