A short-term increase in dietary cholesterol and fat intake affects high-density lipoprotein composition in healthy subjects

Background and Aims

High-cholesterol and high-fat diets alter biochemical composition and anti-oxidant properties of high-density lipoproteins (HDL) in animals. Whether this occurs in humans is unknown. Therefore, we examined the effect of a short-term elevation in dietary cholesterol and fat intake on HDL composition in healthy subjects.

Effect of low-dose niacin on high-density lipoprotein cholesterol and total cholesterol/high-density lipoprotein cholesterol ratio

Niacin significantly alters blood lipid concentrations but its use has been limited because of clinically disturbing side effects. In an attempt to circumvent these drawbacks, 55 patients with cardiovascular disease were given low-dose long-acting niacin, 1 g/d. Treatment was continued for a mean of 6.7 months and lipid values were compared with a non-treated group of 17 patients followed for a mean of 6.3 months. Lipid values did not change in the nontreated group. In the niacin-treated group total cholesterol and triglyceride levels also did not significantly change. High-density lipoprotein (HDL) cholesterol level rose 31% from 1.01 +/- 0.31 mmol/L to 1.32 +/- 0.31 mmol/L and total cholesterol/HDL cholesterol ratio was reduced 27% from 6.4 +/- 1.9 to 4.7 +/- 1.3. Despite these results, 40% of the patients left the study mainly because of side effects. Apart from one patient who developed overt diabetes, of questionable relationship to niacin, no patient developed serious side effects such as jaundice or peptic ulcer as seen with much higher doses of the drug. Although often difficult to administer to patients, niacin, particularly in low dose, deserves consideration as an inexpensive agent especially useful for elevating HDL cholesterol level and altering the total cholesterol/HDL cholesterol ratio.     

Comparison of low-density lipoprotein cholesterol/high-density lipoprotein cholesterol and total cholesterol/high-density lipoprotein cholesterol for the prediction of thin-cap fibroatheroma determined by intravascular optical coherence tomography

BackgroundThe correlation among the ratios of low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/ HDL-C), total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) and thin-cap fibroatheroma has not yet been established.MethodsIt was a single center, retrospective observational study. In total, we recruited 421 patients (82.4% men; mean age 65.73 ± 10.44 years) with one culprit vessel which determined by intravascular optical coherence tomography (OCT). The thinnest-capped fibroatheroma (TCFA) group was defined as lipid contents in > 2 quadrants, with the thinnest fibrous cap measuring less than 65 μm. Univariate and multivariate logistic regression were carried out to explore the relationship between lipoprotein ratios, TCFA and other characteristics of plaque. To compare different ratios, the area under curve (AUC) of receiver-operating characteristic (ROC) curve was assessed.ResultsOCT was performed in 421 patients (TCFA group (n = 109), non-TCFA group (n = 312)). LDL-C/HDL-C in the TCFA group was significantly higher than in the non-TCFA group (2.95 ± 1.20 vs. 2.43 ± 0.92, P < 0.05), as was TC/LDL in TCFA and non-TCFA group (4.57 ± 1.58 vs. 4.04 ± 1.13, P < 0.05). Both LDL-C/HDL-C (OR: 1.002 (1.002-1.003), P < 0.05) and TC/HDL-C (OR: 1.001 (1.001-1.004), P < 0.05) were considered independent factors for the prediction of TCFA according to the logistic regression. Based on the AUC comparison, LDL-C/ HDL-C and TC/HDL-C had no significant difference statistically (LDL-C/HDL-C AUC: 0.63; TC/HDL-C AUC: 0.61; P = 0.10) for the prediction of TCFA.ConclusionsLDL-C/HDL-C and TC/HDL-C could be the independent factors for predicting the presence of TCFA, indicating coronary plaque vulnerability in CAD patients. Moreover, TC/HDL-C also showed a comparative performance for the prediction of TCFA as LDL-C/HDL-C.     

Prolonged stimulation of the adrenals by corticotropin suppresses hepatic low-density lipoprotein and high-density lipoprotein receptors and increases plasma cholesterol

Pituitary ACTH has been shown to strongly stimulate adrenal receptors for low-density lipoprotein (LDL) and high-density lipoprotein (HDL) scavenger receptor class B type 1(SR-BI) to provide precursor cholesterol for glucocorticoid synthesis. The present study aimed to determine the effects of ACTH on hepatic cholesterol metabolism and plasma lipoproteins. Treatment of Sprague Dawley rats or normal C57BL/6J mice with ACTH for 3.5 d reduced hepatic SR-BI and LDL receptors. Simultaneously, cholesterol in plasma LDL and HDL was increased. None of these effects could be reproduced using glucocorticoids instead of ACTH, and they were abolished in adrenalectomized rats, indicating an obligate role of the adrenals for the effects of ACTH observed in the liver. When ACTH was given to LDL receptor-deficient mice, plasma LDL did not increase and the increase in HDL cholesterol remained, as did the suppression of hepatic SR-BI. Our data show that prolonged ACTH treatment suppresses hepatic SR-BI and LDL receptors in vivo in rodents, resulting in elevated plasma HDL and LDL. The adrenals are obligate for these effects, suggesting that ACTH releases some factor(s) that suppresses hepatic LDL and SR-BI receptors. Hypothetically, this novel mechanism would further promote channeling of cholesterol to the adrenals in situations of prolonged stress.     

Plasma fasting and nonfasting triglycerides and high-density lipoprotein cholesterol in atherosclerotic stroke: Different profiles according to low-density lipoprotein cholesterol

Although low-density lipoprotein cholesterol (LDL-C) is the main lipid target for cardiovascular risk reduction, recent studies suggest that other lipid indicies are also associated with vascular events. We hypothesized that the association of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) with atherosclerotic stroke (AS) differs depending on LDL-C levels. Data prospectively collected on subjects admitted with acute ischemic stroke to a university medical center were analyzed. We divided the patients into AS and non-atherosclerotic stroke (NAS) groups and independent association of lipid parameters and genetic influences of apolipoprotein A5 (ApoA5) polymorphisms with AS were evaluated. Of 268 patients, 160 (59.7%) were classified with AS and 108 (40.3%) were classified with NAS. Vascular risk factors were more prevalent in AS patients than in those with NAS; additionally, AS patients' anthropometric indexes and laboratory findings showed that they were prone to atherosclerosis. AS was independently associated with fasting TG (OR per 10 mg/dL increase, 1.38; 95% CI, 1.16–1.64; OR for highest vs. lowest tertile, 12.85; 95% CI, 3.31–49.85), HDL-C (OR per 10 mg/dL increase, 0.61; 95% CI, 0.42–0.88; OR for lowest vs. highest tertile, 4.28; 95% CI, 1.16–15.86), and nonfasting TG (OR per 10 10 mg/dL increase, 1.25; 95% CI, 1.11–1.42; OR for highest vs. lowest tertile, 8.20; 95% CI, 1.98–33.88) only among patients with LDL <100 mg/dL. No interaction was observed between fasting and nonfasting TG and ApoA5 polymorphisms. In conclusion, fasting and nonfasting TG and HDL-C were associated with AS only when patients had low levels of LDL-C. Non-LDL-C may have an additional role in addition to the LDL-C levels in AS development.     

Mechanisms of high-density lipoprotein cholesterol effects on the endothelial function in hyperlipemia

High-density lipoprotein-cholesterol (HDL-c) has a favorable influence on the endothelial function, but the mechanisms of this protective action are not fully understood. We studied lipid parameters, soluble adhesion molecules (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule [ICAM-1], E-selectin) oxidized low-density lipoproteins (LDL), and brachial-artery flow-mediated vasodilation (FMV) in 184 hyperlipemic patients (90 men, age 54 +/- 10 years, waist/hip circumference ratio 0.89 +/- 0.07, LDL-cholesterol [LDL-c] 4.9 +/- 1.3 mmol/L, triglycerides 1.8 +/- 0.9 mmol/L, HDL-c 1.3 +/- 0.5 mmol/L) after excluding those with current smoking, diabetes, hypertension, and vascular diseases. Patients were divided into 2 groups on the basis of HDL-c levels: < 1.03 mmol/L (n = 53) v >or= 1.03 mmol/L (n = 131). Patients with low HDL-c showed significantly lower LDL-c (P <.05), higher triglycerides (P <.001), higher body mass index (P <.02), lower FMV (3.7% +/- 2.0% v 4.9% +/- 3.4%, P <.002), higher VCAM-1 (1,195 +/- 395 ng/mL v 984 +/- 303 ng/mL, P <.01), and higher ICAM-1 (406 +/- 78 ng/mL v 364 +/- 68 ng/mL, P <.01). E-selectin and oxidized LDL showed no significant differences. In a multivariate age, oxidized LDL and brachial artery diameter predicted a lower FMV, while HDL-c was an independent predictor of a greater FMV (P =.003). Increasing levels of VCAM-1 and ICAM-1 were predicted by lower HDL-c, while higher oxidized LDL predicted higher VCAM-1 (P <.05). Our data suggest that in hyperlipemic subjects free of cardiovascular disease low HDL-c negatively modulates endothelial function through a lack of oxidation inhibition and a concomitant overexpression of adhesion molecules.     

Effect of dietary cholesterol and indomethacin on cholelithiasis and gallbladder motility in guinea pig

This study examines the effects of dietary cholesterol and subcutaneous indomethacin on gallstone formation, gallbladder motility, and bile composition in guinea pigs. Guinea pigs on cholesterol diets developed gallstones which were not primarily composed of cholesterol and were not prevented by indomethacin. Animals receiving cholesterol diets showed significant gallbladder enlargement which was inhibited by indomethacin. Cholesterol did not alter gallbladder pressure-volume relationships or the response to CCK, while indomethacin diminished gallbladder tone. Although cholesterol feeding did not appear to alter smooth muscle contractility in the guinea pig gallbladder, it caused significant gallbladder enlargement by a mechanism which may be dependent on prostaglandins.This study was supported by National Institutes of Health grant AM 15304.     

Association between the severity of obstructive sleep apnea and the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol

The positive association between the ratio of serum low-density lipoprotein cholesterol (LDL-C) to serum high-density lipoprotein cholesterol (HDL-C) and cardiovascular events has recently been receiving much attention. However, the association between the severity of obstructive sleep apnea (OSA) and this ratio has not yet been investigated. Accordingly, we sought to clarify this association and the effect of continuous positive airway pressure (CPAP) therapy on the ratio. We performed polysomnography and LDL-C/HDL-C measurements in 215 patients who were suspected of having OSA. Furthermore, LDL-C/HDL-C was again evaluated 6 months after polysomnography in 30 OSA patients for whom CPAP therapy was initiated and continued, and in 11 age- and sex-matched OSA patients for whom the therapy could not be initiated. The LDL-C/HDL-C correlated positively with apnea-hypopnea index (ρ = 0.28, P < .001) and negatively with the lowest arterial oxyhemoglobin saturation (ρ = -0.30, P < .001). Multivariate regression analysis revealed that ln apnea-hypopnea index (or ln lowest arterial oxyhemoglobin saturation) was independently associated with LDL-C/HDL-C. The LDL-C/HDL-C decreased after 6 months in the CPAP group (2.29 ± 0.67 to 2.11 ± 0.74, P = .02), whereas it did not change in the non-CPAP group (2.65 ± 0.82 to 2.62 ± 0.66, P = .81). The severity of OSA was independently associated with LDL-C/HDL-C, and LDL-C/HDL-C was significantly reduced at 6 months after CPAP therapy. These findings suggest that LDL-C/HDL-C increases in proportion to the severity of OSA, which may contribute partly to an increased risk for cardiovascular events in OSA patients.     

Effect of low-density lipoprotein apheresis on inflammatory and noninflammatory high-density lipoprotein cholesterol

Low-density lipoprotein (LDL) apheresis, a treatment for familial hypercholesterolemia, significantly decreases LDL cholesterol and inflammatory markers such as C-reactive protein, CD40 ligand, and tissue factor. LDL apheresis also decreases high-density lipoprotein (HDL) cholesterol, which might be considered therapeutically counterproductive because HDL is known to be anti-inflammatory. However, recent studies have shown that HDL also possesses proinflammatory properties, as seen in its ability to alter LDL-induced monocyte chemotactic activity. We examined the acute effects of LDL apheresis on inflammatory HDL activity in 13 patients with familial hypercholesterolemia and cardiovascular disease who had been receiving bi-weekly LDL apheresis treatments. Immediately before and immediately after treatment, each patient's plasma was collected for analysis of inflammatory HDL and full lipid profile. LDL apheresis reduced LDL by 52% (from 208 +/- 89 to 99 +/- 48 mg/dl, p <0.002), and HDL decreased by 16% (49 +/- 15 to 41 +/- 13 mg/dl, p <0.003). At the same time, inflammatory HDL activity (in migrated monocytes per high-power field) decreased from 22 +/- 4 to 14 +/- 2, a 37% acute reduction (p <0.003). Moreover, inflammatory HDL before HDL apheresis was highly correlated with its acute reduction (r(s) = 0.85, p <0.001). In conclusion, our findings indicate that, in addition to decreasing LDL, LDL apheresis also decreases inflammatory HDL. The clinical significance of reducing inflammatory HDL is currently unknown, and further research is needed to examine its potential benefit for cardiovascular disease.     

Influence of cholesterol/fat feeding on cholesterol esterification and morphological structures in intestinal mucosa from guinea pigs

Guinea pigs were fed a semisynthetic diet containing 10% (by weight) cottonseed oil and 1% cholesterol. In response to cholesterol/fat feeding there was an increase in both the unesterified cholesterol (UC) and cholesteryl ester (CE) of the intestinal mucosal cell. Along with the increased cholesterol levels there was a 4-fold increase in the microsomal acylCoA:cholesterol acyltransferase (ACAT) activity after only two days of cholesterol/fat feeding. After 6 days on the experimental diet the ACAT activity was up to 8-fold the activity of the control, and then remained at this level for up to 20 days. The increased ACAT activity was probably not due to increased substrate concentration alone, since the fractional esterification of cholesterol also increased when the cholesterol/fat containing diet was given. There was also an increase in the triglyceride content of the intestinal mucosal cells from guinea pigs on the experimental diet. The mucosal cells of the cholesterol/fat fed animals accumulated varying amounts of lipid droplets, which were without an enveloping membrane, suggesting that the uptake of lipids from the intestinal lumen was higher than the capacity to synthesize and/or secrete lipoproteins. Simultaneously the size and amount of secondary lysosomes increased. A considerable increase in lipid droplets, lipolysosomes, and residual bodies was observed in the lamina propria macrophages while no crystalline clefts were seen.     

Epistatic effect of cholesteryl ester transfer protein and hepatic lipase on serum high-density lipoprotein cholesterol levels

OBJECTIVES: Polymorphisms in the hepatic lipase (LIPC -514C > T) and cholesteryl ester transfer protein (CETP I405V) genes affect high-density lipoprotein cholesterol (HDL-c) levels, but their relationship with cardiovascular disease and their combined effect is unclear. The objectives of the current study were to characterize the effect of the hepatic lipase variant, and its interaction with the CETP variant, in terms of cholesterol levels, atherosclerosis, and risk of myocardial infarction (MI). DESIGN: The study was conducted in the Rotterdam Study, a large single-center prospective cohort study in people aged 55 yr and older. Lipid levels were analyzed using linear regression models, and risk of MI was assessed with Cox proportional hazards models. RESULTS: The hepatic lipase variant was associated with an increase in serum HDL-c levels of 0.11 mmol/liter in both genders, whereas an increased risk of MI was observed only in men [hazard ratio, 1.32 (95% confidence interval, 1.05-1.66) for CT vs. CC and 1.75 (95% confidence interval, 1.39-2.20) for TT vs. CC]. This effect was independent of serum HDL-c. LIPC -514C > T interacted with CETP I405V with respect to serum HDL-c concentrations. Those homozygous for both mutations saw a marked elevation in HDL-c levels (0.29 mmol/liter, P(interaction) = 0.05). These increased HDL-c levels, however, were not inversely associated with atherosclerosis or MI risk. CONCLUSIONS: LIPC genotype affects HDL-c levels and risk of MI in males. The interaction of this variant with CETP on HDL-c levels helps elucidate the underlying mechanisms and suggests that the beneficial effects of CETP inhibition may vary in particular subgroups.     

Characterization of cholesterol ester hydrolase activities in rabbit and guinea pig aortas.

Cholesterol ester hydrolase activity was determined in preparations of rabbit and guinea pig aorta utilizing micellar and glycerol-dispersed cholesterol oleate substrates. Both substrate preparations demonstrated an acid pH optimum of 4--5 for the soluble and particulate rabbit media cholesterol ester hydrolase, suggesting a lysosomal origin for this activity. Approximately one-fifth of the total recovered activity was particulate. Particulate media preparations from guinea pig aorta also demonstrated cholesterol ester hydrolase activity at acid pH values with a definite optimum at pH 5 for the glycerol-dispersed substrate. However, in contrast to the rabbit media enzyme, activity was also observed at neutral pH with another optimum at pH 7. The supernatant enzyme from guinea pig media exhibited only a single pH optimum of 7. Cholesterol ester hydrolase activity from either rabbit or guinea pig media was not influenced by preincubation with cyclic AMP, ATP and protein kinase. The addition of chloroquine resulted in the inhibition of both the rabbit and guinea pig enzyme. Cholesterol ester hydrolase activity from rabbit and guinea pig media was also inhibited by phenyl methane sulfonyl fluoride; activity measured at pH 7 (guinea pig) was more sensitive to inhibition than activity measured at pH 5 (guinea pig and rabbit).     

The effects of polyoxyethylated cholesterol feeding on hepatic cholesterol synthesis and intestinal cholesterol absorption in rats

Adduction of ethylene glycol moieties to the 3-hydroxy position of cholesterol produces polyoxyethylated cholesterol (POEC), a water-soluble compound that suppresses cholesterol synthesis and esterification in cultured human fibroblasts. Feeding Sprague-Dawley rats a diet containing 2% (wt/wt) POEC with 10 ethoxy groups resulted in a 3-fold increase in hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity compared to activity in rats pair-fed a diet of standard rat chow. POEC with an average of 20 ethoxy groups (POEC-20) caused comparable changes in hepatic [2-14C]acetate incorporation into non-saponifiable lipids under ad libitum feeding conditions, significantly reduced cholesterol absorption (18% vs 57%), and increased fecal excretion of neutral steroids (5.1 vs 2.0 mg/g food intake). POEC-20 also reduced cholesterol absorption in rats fed a diet enriched with 2% cholesterol (11% vs 31%). Histologic studies of intestinal mucosa and hepatic tissues from rats fed POEC showed no pathologic changes. These experiments indicate that POEC reduces cholesterol absorption and causes compensatory increases in hepatic cholesterol synthesis.     

Effect of enhancement of cholesterol degradation during neonatal life of guinea pig on its subsequent response to dietary cholesterol.

The effect of feeding cholestyramine to neonatal guinea pigs on their subsequent plasma cholesterol levels and response to dietary cholesterol were studied. Male neonatal guinea pigs were suckled for 6 days. One group was maintained on a 1.1% cholestyramine diet for 6 weeks and the control group weaned normally. Both groups of guinea pigs were then fed a standard diet of Guinea Pig Chow for 6 weeks. During the standard diet period bile acid and neutral sterol excretion rates were significantly higher in the group previously treated with cholestyramine than the control group despite the similarity in plasma cholesterol levels. When both groups of guinea pigs were subjected to a 0.5% cholesterol diet for 4 weeks, plasma cholesterol levels were significantly lower in the group previously treated with cholestyramine than the control group. The plasma cholesterol levels continued to be significantly lower in the group previously treated with cholestyramine after an additional four weeks on standard diet. These results suggest that stimulation of cholesterol catabolism in the neonatal period can influence the subsequent response to dietary cholesterol.     

单核细胞/高密度脂蛋白胆固醇比值与冠心病关系的探讨

目的：探讨单核细胞与高密度脂蛋白胆固醇比值（monocyte to high-density lipoprotein cholesterol ratio,MHR）和冠状动脉狭窄程度的关系,并探讨MHR对冠心病的预测价值。方法：回顾性分析我院2013年3月至2018年6月行冠状动脉造影的患者1867例,其中非冠心病组385例、冠心病组1482例,比较两组患者MHR的差异;根据Gensini评分或SYNTAX评分进一步将冠心病组患者分为三个亚组（轻度病变组、中度病变组、重度病变组）,比较三组间MHR的差异;使用Spearman相关对MHR与冠状动脉狭窄程度进行相关性分析,多因素Logistic回归分析冠心病的独立危险因素,同时使用ROC曲线计算MHR对冠心病的预测价值。 结果：冠心病组MHR水平明显高于非冠心病组（0.53±0.30 vs 0.40±0.20,P<0.001）;冠心病三个亚组间比较显示冠状动脉病变程度越重,MHR水平越高,差异具有统计学意义（Gensini评分：0.48±0.24 vs 0.52±0.33 vs 0.59±0.31,P<0.001;SYNTAX评分：0.50±0.26 vs 0.52±0.21 vs 0.56±0.30,P<0.01）。Spearman相关分析显示,MHR水平与冠状动脉狭窄程度（Gensini评分：r=0.258,P<0.001;SYNTAX评分：r=0.216,P<0.001）呈正相关。多因素Logistic回归分析结果显示,年龄、吸烟、糖尿病、高血压、超敏C反应蛋白和MHR均可作为冠心病的独立危险因素。ROC曲线显示,当MHR诊断临界值取0.34时,其诊断冠心病的效能最高,灵敏度为77.1%,特异度为46.4%。结论 MHR与冠心病的严重程度显著相关,MHR值越大,冠状动脉狭窄程度越重;MHR临界值取0.34时,其诊断冠心病的效能最高,可作为冠心病诊断和治疗评估的检测指标。     

Nonpharmacologic and pharmacologic alteration of high-density lipoprotein cholesterol: therapeutic approaches to prevention of atherosclerosis

High-density lipoprotein (HDL) cholesterol, an independent coronary heart disease (CHD) risk factor, is inversely associated with CHD. Whether interventions to increase concentrations of HDL--particularly the HDL2, HDL3, and apolipoprotein A1 subfractions--will reduce the incidence of CHD in high-risk patients is thus an area of intense speculation. Both nonpharmacologic and pharmacologic regimens will raise HDL concentrations. Nonpharmacologic approaches include habitual high-level aerobic exercise and weight loss--both of these somewhat more effective in men than in women--cessation of cigarette smoking, and changing of dietary habits. A number of drugs have been found to elevate HDL cholesterol. These include the bile acid-binding resin cholestyramine, nicotinic acid, gemfibrozil, phenytoin, exogenous estrogens, and alcohol. Terbutaline has also been reported to raise HDL cholesterol. It is not yet known whether, and to what degree, pharmacologic and nonpharmacologic elevation of HDL cholesterol will retard or reverse the progression of atherosclerosis. Conversely, HDL cholesterol is lowered by a broad variety of drugs, including anabolic--androgenic steroids, exogenous progestins, and probucol, which are used therapeutically to reduce low-density lipoprotein (LDL) cholesterol. Some agents used to treat hypertension also reduce HDL cholesterol, especially thiazide diuretics and the beta blockers, with the possible exception of pindolol. In the antiadrenergic class of antihypertensive agents, reserpine and methyldopa lower HDL cholesterol, but the alpha blocker prazosin does not appear to affect HDL cholesterol. The alpha agonist guanabenz has no effect on HDL cholesterol, and the vasodilator carprazidil has been reported to raise HDL cholesterol. In light of these facts, investigations should be undertaken to determine whether the metabolic effects of antihypertensive agents blunt their beneficial effects on CHD.(ABSTRACT TRUNCATED AT 250 WORDS)