Chylomicron remnants stimulate release of interleukin-1beta by THP-1 cells

Recent findings suggest that the oxidative modification of low-density lipoproteins (LDL) and an increase in triglyceride-rich lipoprotein particles including chylomicron remnants contribute to the progression of atherosclerosis, as does the inflammatory response. We therefore examined whether and how these lipoproteins affected interleukin (IL)-1beta release and mRNA expression for IL-1beta and IL-18 in THP-1 cells, a human monocyte cell line. Chylomicron remnants increased IL-1beta release into the conditioned medium by THP-1 in a dose- and time-dependent manner. At concentrations up to 1 microg/ml, chylomicron remnants increased IL-1beta release by 4-fold compared with the control. Neither native LDL nor oxidized LDL (OxLDL) significantly increased IL-1beta release. Chylomicron remnants increased IL-1beta mRNA expression by 3 times. Native LDL or OxLDL did not increase IL-1beta mRNA, while neither these lipoproteins nor chylomicron remnants increased IL-18 mRNA. Chylomicron remnants also increased the activities of caspase-1 and nuclear factor (NF)-kappaB significantly, while native LDL or OxLDL did not. In conclusion, chylomicron remnants stimulated IL-1beta mRNA expression and IL-1beta protein production probably via caspase-1 and NF-kappaB activation in THP-1 cells.     

Interrelationship of triglycerides with lipoproteins and high-density lipoproteins

Triglycerides are transported by the largest and most lipid-rich of the lipoprotein particles, namely, chylomicrons and very low density lipoproteins (VLDL). These particles are buoyant because of the high triglyceride content, which makes up approximately 90% by weight of the chylomicron and 70% by weight of the VLDL. The chylomicron transports exogenous or dietary fat and cholesterol, whereas VLDL transports endogenous triglyceride and cholesterol in lipoproteins synthesized and secreted by the liver. Both chylomicrons and VLDL are hydrolyzed at the capillary surface by the enzyme lipoprotein lipase. Lipoprotein lipase catalyzes the hydrolysis of triglyceride in the lipid core of these particles, producing smaller particles known as remnants. We currently believe the remnants are atherogenic and that this is one reason why hypertriglyceridemia may predispose to coronary artery disease. Chylomicron remnants are recognized and removed by hepatic receptors that contain apolipoprotein (apo) E. The rate of clearance of remnant particles depends on which subfraction of apo E is present. Particles containing apo EII are removed more slowly than those with apo EIII and EIV. The dietary cholesterol from the chylomicron remnant particles is thought to down-regulate the hepatic low-density lipoprotein (LDL) receptors. VLDL remnants, also called intermediate-density lipoprotein (IDL), contain apo E and may be removed by the liver through the LDL or B/E receptor. The decrease in activity of these receptors results in apparent oversynthesis of LDL, the end-product of VLDL and IDL metabolism. LDL is the major cholesterol carrier, followed by high-density lipoprotein (HDL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatic lipase: Friend or foe and under what circumstances?

Hepatic lipase (HL) plays a role in the metabolism of chylomicron and very low-density lipoprotein remnants, low-density lipoproteins (LDL), and high-density lipoproteins (HDL), which are all implicated in atherosclerosis. Considering the effects of HL on these lipoproteins, it appears that HL has pro- as well as antiatherogenic potential. In line with clinical observations, most effects of HL on lipoprotein metabolism during hypertriglyceridemia may be interpreted as promoting atherosclerosis (formation of small, dense LDL, lowering of HDL levels), whereas most effects during hypercholesterolemia seem to be potentially antiatherogenic (stimulation of reverse cholesterol transport, clearing of intermediate-density lipoprotein). The potential modulation of pro- or antiatherogenics effect of HL by other factors, such as LDL receptor, cholesterol ester transfer protein, lipoprotein lipase, and ATP-binding cassette A-1 activity, is discussed.     

Atherosclerosis and systemic lupus erythematosus: the role of altered lipids and of autoantibodies

The accelerated atherosclerosis that occurs in some patients with systemic lupus erythematosus (SLE) has a complex pathogenesis, including alterations in lipids, inflammation and the immune system. In this article, we review the evidence that peroxidase-related alteration of normal, protective high-density lipoprotein (HDL) converts them to pro-inflammatory HDL (piHDL), characterized by lower content of the cholesterol transport lipoprotein ApoA1 and impaired function of the antioxidant enzyme paroxonase, which prevents oxidation of low-density lipoprotein (LDL). Forty-five per cent of women with SLE have piHDL compared with 20% of patients with rheumatoid arthritis and 4% of healthy controls. The presence of piHDL increases risk for coronary artery events and carotid artery plaque. Another result of lipid oxidation in patients with SLE is generation of highly oxidized LDL and phospholipids (PL), probably stimulating antibodies to OxPL phospholipids. These antibodies along with promoting thrombosis also interfere with deposits of Annexin V onto endothelial cells, which probably promote increased instability of atherosclerotic plaque. Thus, piHDL and anti-OxPL promote plaque formation, plaque instability and thrombosis, accounting for some of the large increase in atherosclerosis and coronary artery events in SLE.     

Paraoxonase activity in high-density lipoproteins: a comparison between healthy and obese females

Paraoxonase, an enzyme associated with high-density lipoprotein (HDL-PON), exerts a protective effect against oxidative damage of circulating cells and lipoproteins, modulates the susceptibility of HDL to atherogenic modifications such as glycation and homocysteinylation, and even exerts an antiinflammatory role. The aim of the present study was to investigate the relationship between lipoprotein oxidative stress and the activity of HDL-PON in healthy and obese subjects. Therefore, the activity of HDL-PON and the levels of lipid hydroperoxides in HDL and low-density lipoprotein (LDL) isolated from plasma of obese females (n = 12) and age-sex-matched controls (n = 31) were compared. Our results demonstrated for the first time that the activity of HDL-PON in obese subjects was significantly lower compared with that in controls (P < 0.001). Moreover, our results showed a significant increase in the levels of lipid hydroperoxides in HDL and LDL isolated from obese subjects (P < 0.001). The negative correlations established between HDL-PON activity and the levels of lipid hydroperoxides associated with HDL and LDL confirm the relationship between paraoxonase activity and lipid peroxidation of lipoproteins. Plasma levels of leptin correlated negatively with HDL-PON activity and positively with levels of lipid hydroperoxides in HDL and LDL of obese subjects, suggesting a relationship between leptin and oxidative damage of lipoproteins. In conclusion, our study demonstrated that the increase in oxidative stress in LDL and HDL of obese subjects is associated with a decrease in HDL-PON activity. The lower paraoxonase activity and the compositional changes in HDL and LDL could contribute to the greater risk of cardiovascular disease associated with obesity.     

Management of type IIb dyslipidemia

Although the Japan Atherosclerosis Society guideline for the diagnosis and prevention of atherosclerosis cardiovascular diseases for the Japanese population provides targets for low-density lipoprotein (LDL) cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol to prevent cardiovascular disease in patients with dyslipidemia, there is no guideline specifically targeting the treatment of type IIb dyslipidemia, which is one of the most common types of dyslipidemia, along with type IIa and type IV dyslipidemia. Type IIb dyslipidemia is important because it sometimes accompanies atherogenic lipid profiles, such as small, dense LDL, remnants, low HDL cholesterolemia. It is also associated with type 2 diabetes mellitus, metabolic syndrome, and chronic kidney disease (CKD), and most patients with familial combined hyperlipidemia (FCHL) show this phenotype; therefore, it is assumed that patients with type IIb dyslipidemia have a high risk for cardiovascular disease. Thus, the management of type IIb dyslipidemia is very important for the prevention of cardiovascular disease, so we have attempted to provide a guideline for the management of type IIb dyslipidemia.     

Effects of Dialysis Purity on Uremic Dyslipidemia

Dyslipidemia, a prominent feature of end-stage renal disease, is considered a risk factor for premature atherosclerosis in hemodialysis (HD) patients. Dyslipidemia is related to loss of kidney function as well as use of low-flux cellulosic dialyzer membranes, but the effects of dialysate purity are unknown. Forty-eight incident HD patients started high-flux polysulfone maintenance HD, either with conventional (potentially contaminated) or with on-line produced ultrapure dialysate. The quality of the dialysis fluid (CFU/mL, endotoxin concentration), markers of inflammation (C-reactive protein, Il-6), and parameters of the lipid profile and oxidative stress (oxidized low-density lipoprotein) were measured before initiation of HD, and after 6, 12 and 24 months on HD. Compared to baseline, treatment with conventional (mildly contaminated) dialysate significantly increased the uremic low-grade systemic inflammatory response syndrome (SIRS), augmented uremic dyslipidemia (triglycerides by +21%, and high-density lipoprotein (HDL) cholesterol by −10%) and enhanced oxidative stress. In contrast, the use of ultrapure dialysate significantly decreased uremia-associated SIRS, dyslipidemia (triglycerides −7% and HDL cholesterol +11%) and oxidative stress. Ultrapure dialysis fluid improves potential parameters of cardiovascular risk by decreasing inflammatory reactions, improving uremic dyslipidemia and lowering oxidative stress.     

LDL-cholesterol,HDL-cholesterol or triglycerides--which is the culprit?

Dyslipidaemia in patients with type 2 diabetes commonly consists of elevated triglyceride levels; normal or slightly elevated low-density lipoprotein (LDL)-cholesterol levels with a preponderance of small, dense LDL particles; and low high-density lipoprotein (HDL)-cholesterol levels with a preponderance of small, dense HDL. These abnormalities are closely connected, with prolonged residence of high levels of triglyceride-rich particles in the circulation favoring abnormalities in LDL and HDL. Each of these factors has been associated with endothelial dysfunction; each contributes directly or indirectly to atheroma formation, with small, dense LDL and triglyceride-rich remnants increasing deposition of cholesteryl ester in vessel walls. This process is facilitated by reduced reverse cholesterol transport in association with low levels of HDL-cholesterol and abnormal HDL. Lipid-lowering therapy focused on LDL-cholesterol reduction is highly successful in preventing coronary disease in diabetic patients. Additional strategies for treating the cluster of risk factors in dyslipidaemia are necessary to further reduce atherosclerotic disease in this population.     

Uremia-specific alterations in lipid metabolism

Uremic patients suffer from a secondary form of complex dyslipidemia consisting of quantitative and qualitative abnormalities in serum lipoproteins resulting in altered lipoprotein composition and metabolism. The most prominent are an increase in serum triglyceride levels (due to elevated very-low-density lipoprotein remnants and intermediate-density lipoprotein) and low high-density lipoprotein (HDL) cholesterol. Low-density lipoprotein (LDL) cholesterol is often normal, but the cholesterol may originate from the atherogenic small and dense LDL subclass. The apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide modification of the enzymatic and advanced glycation end-product, oxidation or glycosylation). Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote prolonged circulation. HDL particles are structurally altered during states of inflammation. The contribution of this complex and atherogenic form of dyslipidemia to cardiovascular disease in patients with renal disease is at present unclear. Most studies are negative in demonstrating the predictive power of serum lipids for the development of cardiovascular disease. This is most likely due to interference with deteriorating aspects of the activated acute-phase response. Since it is also still unclear whether we have therapeutics available with a sufficient impact on LDL size, remnant lipoprotein lowering and restoration of HDL function, we urgently need specific intervention trials.     

Comparison of atorvastatin versus fenofibrate in reaching lipid targets and influencing biomarkers of endothelial damage in patients with familial combined hyperlipidemia

Statins and fibrates have different effects on lipid abnormalities of familial combined hyperlipidemia (FCHL); thus, the selection of the first-line drug is troublesome. We evaluated to what extent monotherapy with a potent statin is more effective than fibrate in reaching the recommended lipid targets in FCHL. Fifty-six patients were randomized to receive optimal dosage of atorvastatin (n = 27) or 200 mg/d micronized fenofibrate (n = 29) for 24 weeks. To reach the optimal dosage, atorvastatin was up-titrated at each follow-up visit if low-density lipoprotein (LDL) cholesterol >130 mg/dL (>100 mg/dL in patients with coronary or cerebrovascular disease). The effects of fenofibrate and atorvastatin on lipoprotein fractions as well as on plasma levels of endothelin-1 (ET-1) and adrenomedullin (AM) were also evaluated. At end of trial, a greater proportion of patients on atorvastatin (average dosage, 20.8 mg/d) reached lipid targets in comparison with those on fenofibrate (64% vs 32.1%, P = .02). Atorvastatin was significantly more effective in reducing total cholesterol, LDL cholesterol, apolipoprotein B, and non-high-density lipoprotein (HDL) cholesterol. Conversely, triglycerides decreased and HDL increased more during fenofibrate. Nevertheless, atorvastatin produced a marked reduction in very low-density lipoprotein and very low-density lipoprotein remnants. Atorvastatin lowered all LDL subtypes, although fenofibrate appeared to be more effective on denser LDL. Compared with 43 normolipemic controls, FCHL patients presented increased baseline plasma levels of ET-1 (P = .007) but not of AM. Fenofibrate, but not atorvastatin, significantly lowered ET-1 levels by 16.7% (P < .05). Neither drug significantly affected plasma concentrations of AM. In summary, although fenofibrate showed superiority in raising HDL and reducing ET-1, atorvastatin was more effective in reaching lipid targets in FCHL so that it can be proposed as the first-line option in the management of this atherogenic hyperlipidemia.     

Endothelial Dysfunction,Oxidation of Low-Density Lipoprotein,and Cardiovascular Disease

Abstract: The oxidative modification of low-density lipoprotein (LDL) may be dependent or independent of lipid peroxidation. This peroxidation may be initiated by metal ions, possibly in association with phospholipase activity or catalyzed by myeloperoxidase independent of metal ions. It results in the generation of aldehydes, which substitute lysine residues in the apolipoprotein B-100 moiety and thus in the generation of oxidized LDL. Endothelial injury, associated with increased production of free radicals during oxidative stress, is associated with increased prostaglandin synthesis and platelet adhesion/activation. These processes are associated with the release of aldehydes, which induce the oxidative modification of LDL in the absence of lipid peroxidation and thus in the generation of malondialdehyde (MDA)-modified LDL. We have demonstrated an association between coronary artery disease (CAD) and increased plasma levels of oxidized LDL. The increase of circulating oxidized LDL is most probably independent of plaque instability. Indeed, plasma levels of oxidized LDL were very similar for patients with stable CAD and for patients with acute coronary syndromes. Acute coronary syndromes, however, were associated with increased release of MDA-modified LDL that was independent of the necrosis of myocardial cells. These data suggest that oxidized LDL is a marker of coronary atherosclerosis whereas MDA-modified LDL is a marker of plaque instability. Recently, a prospective study in cardiac transplant patients suggested an active role of oxidized LDL in the development of CAD. Oxidized LDL may contribute to the progression of atherosclerosis by enhancing endothelial injury by inducing foam cell generation and smooth muscle proliferation.     

Improved identification of patients with coronary artery disease by the use of new lipid and lipoprotein biomarkers

Increasing attention is being directed toward new lipid and lipoprotein biomarkers as risk factors for coronary artery disease, although limited information is available on the diagnostic accuracy of these new biomarkers for the identification of patients with coronary artery disease. In the present study, levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, lipoprotein-associated phospholipase A2 (Lp-PLA2), and oxidized LDL/HDL cholesterol were determined in 431 apparently healthy men and women without clinical evidence of coronary artery disease who were matched for age and gender with 490 men and women with coronary artery disease who participated in the Second Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC-II) trial. Diagnostic accuracy was determined by receiver-operating characteristic curve analysis by measuring the area under the curve. The diagnostic accuracies of each lipid or lipoprotein biomarker (in descending order of area under the curve) were 0.867 for oxidized LDL/HDL cholesterol (95% confidence interval [CI] 0.844 to 0.890), 0.826 for oxidized LDL (95% CI 0.800 to 0.852), 0.775 for 1/HDL cholesterol (95% CI 0.745 to 0.805), 0.764 for total/HDL cholesterol (95% CI 0.733 to 0.795), 0.631 for triglycerides (95% CI 0.594 to 0.667), 0.597 for Lp-PLA2 (95% CI 0.558 to 0.615), 0.577 for LDL cholesterol (95% CI 0.539 to 0.615), and 0.520 for total cholesterol (95% CI 0.482 to 0.537). In conclusion, these findings indicate that the ratio of oxidized LDL to HDL cholesterol was a more potent biomarker for discriminating between subjects with and without coronary artery disease than traditionally measured lipids and lipoproteins and Lp-PLA2.     

LDL concentration is correlated with the removal from the plasma of a chylomicron-like emulsion in subjects with coronary artery disease

In animal model studies, the uptake of chylomicron remnants after entering in the space of Disse occurs mainly by low-density lipoprotein (LDL) receptor and LDL receptor-related protein (LRP). In subjects, the relative importance of each one of these receptors for the clearance of chylomicron remnants is not fully understood. In our study, LDL cholesterol and apolipoprotein (apo) B were correlated to the plasma kinetics of a chylomicron-like emulsion in 77 subjects (11 women, mean age 58 +/- 12 years) with coronary artery disease (CAD). Their total cholesterol was 227 +/- 25 mg/dl, triglyceride 159 +/- 25 mg/dl, LDL cholesterol 148 +/- 27 mg/dl, HDL cholesterol 40 +/- 9 mg/dl, apo A1 1.80 +/- 0.53 g/l and apo B 1.65 +/- 0.48 g/l. The emulsion was double-labeled with 3H-triolein and 14C-cholesteryl oleate and injected intravenously after 12-h fasting. The decay curves of the radioisotopes were determined from blood samples collected at predetermined intervals during 60 min. A negative correlation between FCR of the emulsion cholesterol esters and LDL cholesterol and apo B plasma concentrations was found (r=-0.4, P=0.005 and r=-0.3, P=0.01, respectively) whereas FCR of the emulsion triglycerides did not correlate with any of the plasma lipids or apolipoprotein parameters. Concluding, in patients with CAD, LDL catabolic pathway significantly influences the removal from plasma of chylomicron remnants.     

The effects of lipid-lowering therapy on paraoxonase activities and their relationships with the oxidant-antioxidant system in patients with dyslipidemia

BACKGROUND: Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is used for lipid-lowering therapy, is an effective statin modulating process involved in atherosclerosis. Paraoxonase (PON) associated with high-density lipoprotein (HDL) has been postulated to have a role in protecting low-density lipoprotein (LDL) against oxidative modification. Oxidation of serum LDL is an important early step in the development of atherosclerosis and auto-antibodies against oxidized LDL (AuAb-oxLDL) reflect in-vivo LDL oxidation. DESIGN AND METHODS: To examine the effect of atorvastatin (10 mg/day) therapy on PON activity in serum and HDL, the study group included 40 patients with dyslipidemia (19 women and 21 men), 25 of whom had hypercholesterolemia and of 15 of whom had mixed-type hyperlipidemia. By taking blood samples from the patients, levels of serum lipids, lipid peroxidation product as malondialdehyde (MDA), total antioxidant status (TAS) and AuAb-oxLDL and the activities of PON in serum and isolated HDL were determined. RESULTS: The mean levels of total cholesterol, triglyceride, LDL-cholesterol, MDA and AuAb-oxLDL were decreased while HDL-cholesterol and TAS were increased significantly after lipid-lowering therapy in patients with dyslipidemia. On the other hand, PON activities in serum and HDL were increased significantly. The percentage increase in serum PON activity was associated significantly with the percentage decrease in serum AuAb-oxLDL (r=-0.32, P=0.047) and that of HDL PON activity was associated with the percentage increase in HDL-cholesterol level after atorvastatin therapy (r=0.52, P=0.001). The therapy was more effective in increasing PON activity in patients with HDL levels above 35 mg/dl. CONCLUSION: It was concluded that atorvastatin therapy in dyslipidemic patients decreases the level of oxidative stress and increases PON activity, especially in patients with HDL levels above 35mg/dl.     

LOX-1, Oxidative Stress and Inflammation: A Novel Mechanism for Diabetic Cardiovascular Complications

Diabetes mellitus is a common metabolic disease characterized by a state of oxidative stress, inflammation and endothelial dysfunction. This malady can lead to a number of complications such as ischemic heart disease, nephropathy, neuropathy, retinopathy and impaired wound healing. The etiology of diabetic complications is multifactorial, and is closely associated with oxidative stress and inflammation. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a receptor for oxidized low density lipoprotein (ox-LDL), plays critical roles in multiple signal transduction pathways and is involved in the process of oxidative stress and inflammation. Recent studies provide important insights into the roles of LOX-1 in the development and progression of diabetic vasculopathy which is the underlying mechanism of diabetic complications. In this review, we summarize mechanistic studies, mainly related to LOX-1, on the development and progression of diabetes mellitus and its cardiovascular complications.     

Comparison effect of atorvastatin (10 versus 80 mg) on biomarkers of inflammation and oxidative stress in subjects with metabolic syndrome

Metabolic syndrome (MS), characterized by low-grade inflammation, confers an increased risk for cardiovascular disease. Statins, in addition to having lipid-lowering effects, have pleiotropic effects and decrease biomarkers of inflammation and oxidative stress. The Treating to New Target Study showed a greater decrease in low-density lipoprotein (LDL) cholesterol and cardiovascular events with atorvastatin 80 mg versus 10 mg in patients with MS with coronary heart disease. However, part of this benefit could be caused by the greater pleiotropic effects of the higher dose of atorvastatin. The dose-response effect of atorvastatin on biomarkers of inflammation and oxidative stress has not been investigated in subjects with MS. Thus, the dose-response effect of atorvastatin on biomarkers of inflammation (high-sensitivity C-reactive protein [hs-CRP], matrix metalloproteinase-9, and nuclear factor-kappaB [NF-kB] activity) and oxidative stress (oxidized LDL, urinary nitrotyrosine, F2-isoprostanes, and monocyte superoxide release) was tested in a randomized double-blind clinical trial in subjects with MS. Seventy subjects were randomly assigned to receive placebo or atorvastatin 10 or 80 mg/day for 12 weeks. A strong dose-response (atorvastatin 10 compared with 80 mg, p <0.05) was observed for changes in total, LDL (32% and 44% reduction), non-high-density lipoprotein (28% and 40% reduction), and oxidized LDL cholesterol (24% and 39% reduction) at atorvastatin 10 and 80 mg, respectively. Hs-CRP, matrix metalloproteinase-9, and NF-kB significantly decreased in the 80-mg atorvastatin group compared with baseline. In conclusion, this randomized trial of subjects with MS showed the superiority of atorvastatin 80 mg compared with its 10-mg dose in decreasing oxidized LDL, hs-CRP, matrix metalloproteinase-9, and NF-kB activity.     

Re-emergence of fibrates in the management of dyslipidemia and cardiovascular risk

It is now widely accepted that low-density lipoprotein (LDL) is not the only atherogenic component of the lipid profile and that abnormalities in the metabolism and plasma levels of triglycerides and high-density lipoprotein (HDL) may lead to accelerated growth of atherosclerotic lesions. Fibrates are the drugs of first choice in the management of hypertriglyceridemia, and are also able to substantially raise HDL. The recently published Veterans Administration-High-density Lipoprotein Intervention Trial (VA-HIT) trial showed that fibrate treatment in patients with coronary heart disease (CHD), low HDL, modestly elevated triglycerides, and normal LDL reduces the risk of a recurrent coronary event by 25%. A reasonable approach to the dyslipidemic patient with high CHD risk is to tailor the intervention to the specific lipoprotein abnormality. Under these assumptions fibrate therapy should become widespread, considering that the most common lipid alteration in CHD and patients with diabetes is low HDL and high triglycerides.     

Regulation of lipoprotein receptors on a rat hepatoma cell line

The rat H-35 cultured hepatoma cell line expresses receptors for homologous lipoproteins. In previously reported experiments distinct receptors were identified for chylomicron remnants, HDL and LDL, by direct binding studies that yielded distinctive binding constants, cross competition assays, and by differential inhibitory effects of EDTA and suramin. In the present experiments, the regulation of expression of these receptors was assessed by growing cells either in the presence or absence of lipoproteins in the media and by growing cells to different densities (50-800 micrograms cell protein/dish). LDL binding to cells was increased by lipoprotein deprivation at all cell densities. LDL binding was inversely related to cell density when cells were grown in lipoprotein deficient serum (LPDS) but cell density did not affect LDL binding by cells grown in newborn calf serum (NBCS). By contrast HDL binding was not appreciably different whether cells were grown in NBCS or in LPDS. However, HDL binding was inversely related to cell density by cells grown either in LPDS or in NBCS. Binding of chylomicron remnants was increased by growth in LPDS at all densities, but altering growth density in either culture medium had little effect on the cellular binding of chylomicron remnants. The distinctive effects of these experimental perturbations on the binding of the 3 lipoprotein classes tend to confirm the presence of 3 separate receptor activities. The experiments also demonstrate that the responses at least of some of the receptors of the hepatoma cells in culture resemble those of hepatocytes in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)     

Induction of atherosclerosis by human chylomicron remnants: a hypothesis

Epidemiologic studies have provided support for the association between delayed remnant removal and premature atherosclerosis. Triglyceride-rich particles such as chylomicrons and chylomicron remnants that carry dietary derived fats, may play a role in the early stages of developing arteriosclerosis. Currently research focuses on these lipoprotein classes seeking distinguishing factors that causes some lipoproteins to be atherogenic while others are not. Such lipoproteins could be involved in atherogenesis directly or indirectly. Direct involvement occurs by interaction of triglyceride-rich particles with the arterial wall, possibly affecting the artery wall by oxidative stress, direct endothelial toxicity by constituents such as lysophosphatidylcholine or oxysterols, induction of prothrombotic changes, stimulation of endothelial expression of cell adhesion molecules and direct interaction with circulating blood cells. Indirect involvement refers to the influence of triglyceride-rich lipoproteins on other lipoproteins on the composition of low density lipoprotein (LDL) and high density lipoprotein (HDL) particles. We propose that in individuals with delayed removal of chylomicron remnants, the prolonged exposure of areas of endothelium that have been partially activated by turbulent flow, to specific components of the remnants, results in the endothelial cells becoming further activated and able to bind monocytes. During or shortly after the transcytosis to the intima and transformation of monocytes to macrophages, the macrophages become engorged with remnant derived lipids and form the nidus of a fatty streak.     

Pathophysiology of the atherogenic process

Atherosclerosis is conceptually defined as the result of a multiplicity of interactive cascades among injurious stimuli and the healing responses of the arterial wall, occurring concurrently within a hyperlipidemic environment. In this discussion, the inflammatory nature of the disease is emphasized. Four aspects of the pathophysiology of atherogenesis are addressed: (1) The role(s) of fluid mechanical or hemodynamic stresses in the focal initiation and/or augmentation of lesions is discussed in terms of the influence of shear stress on endothelial cellular geometry, compliance, membrane anisotropy (r), low-density lipoprotein (LDL)-receptor expression, intracellular potential and replication; (2) mechanisms of blood monocyte recruitment to the arterial intima, including the roles of chemoattractants such as smooth muscle cell-derived chemotactic factor and oxidized LDL; (3) the alternate or "scavenger" receptor pathway of the macrophage and its pivotal roles in foam cell formation and plaque pathogenesis; and (4) the emerging significance of various lipoprotein modifications, and in particular, the oxidative modification of LDL, which facilitates the uptake of the cytotoxic oxidized LDL via the scavenger receptor, thus providing a non-down-regulating mechanism for foam cell formation and plaque development. Evidence indicates that the antioxidant drug probucol prevents the oxidative modification of LDL, thereby retarding atherogenesis independently of cholesterol reduction.