Changes In Lipoprotein Metabolism Research Articles

Management of dyslipidemia in the elderly population

The elderly population is increasing worldwide. Despite a major decrease in deaths from coronary heart disease (CHD), this malady remains the major cause of death in elderly men and women. In this paper, we review the role of dyslipidemia as a major known risk factor in the pathogenesis of CHD, age-related changes in lipoprotein metabolism, and differences in changes in lipids that occur in men and women during aging. Next we provide an overview of the available studies and recommendations from ATP III. Finally, we comment on the screening and management, cost and side effects of therapy as it applies to an aging population.

Influence of apolipoprotein E plasma levels and tobacco smoking on the induction of neutralising antibodies to interferon-beta

Interferon-beta (IFN-beta) therapy for multiple sclerosis (MS) is associated with a potential for induction of neutralizing antibodies (NAbs). Because immune reactivity depends on changes in lipoprotein metabolism, we investigated whether plasma lipoprotein profiles could be associated with the development of NAbs. Thirty-one female MS patients treated with subcutaneously administered IFN-beta were included. Demographic and clinical characteristics were compared between NAbs response groups using t tests for continuous and logistic regression analysis and Fisher's exact tests for categorical data, respectively. Multivariate logistic regression was used to evaluate the effect of potential confounders. Patients who developed NAbs had lower apoE levels before treatment, 67 (47-74) mg/L median (interquartile range), and at the moment of NAb analysis, 53 (50-84) mg/L, in comparison to those who remained NAb-negative, 83 (68-107) mg/L, P = 0.03, and 76 (66-87) mg/L, P = 0.04, respectively. When adjusting for age and smoking for a one-standard deviation decrease in apoE levels, a 5.6-fold increase in the odds of becoming NAb-positive was detected: odds ratios (OR) 0.18 (95% CI 0.04-0.77), P = 0.04. When adjusting for apoE, smoking habit became associated with NAb induction: OR 5.6 (95% CI 1.3-87), P = 0.03. These results suggest that apoE-containing lipoprotein metabolism and, possibly, tobacco smoking may be associated with risk of NAb production in female MS patients treated with IFN-beta.

Senescence-Related Truncation and Multimerization of Apolipoprotein A-I in High-Density Lipoprotein With an Elevated Level of Advanced Glycated End Products and Cholesteryl Ester Transfer Activity

To compare the change in lipoprotein metabolism with aging, we analyzed the lipid and protein compositions of individual lipoprotein fractions. Healthy and nonobese elderly participants (elderly group, n = 26) had a serum lipid profile within the normal range, although slightly higher than in young participants (control group, n = 18). However, the elderly group had a twofold higher serum uric acid level and triglyceride (TG):high-density lipoprotein cholesterol ratio. The elderly group had less antioxidant ability and elevated TG content in high-density lipoprotein (HDL) with enhanced cholesteryl ester transfer activity. An elevated level of advanced glycated end products in lipoproteins and fragmentation of apoA-I were present in the elderly group, with detected lower apoA-I level and more multimerized apoA-I in HDL. The protein levels of apoA-I, apoC-III, and serum amyloid A in lipoprotein-deficient serum were increased in the elderly group.

Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size

Increased plasma cholesterol is a known risk factor for cardiovascular disease. Lipoprotein particles transport both cholesterol and triglycerides through the blood. It is thought that the size distribution of these particles codetermines cardiovascular disease risk. New types of measurements can determine the concentration of many lipoprotein size-classes but exactly how each small class relates to disease risk is difficult to clear up. Because relating physiological process status to disease risk seems promising, we propose investigating how lipoprotein production, lipolysis, and uptake processes depend on particle size. To do this, we introduced a novel model framework (Particle Profiler) and evaluated its feasibility. The framework was tested using existing stable isotope flux data. The model framework implementation we present here reproduced the flux data and derived lipoprotein size pattern changes that corresponded to measured changes. It also sensitively indicated changes in lipoprotein metabolism between patient groups that are biologically plausible. Finally, the model was able to reproduce the cholesterol and triglyceride phenotype of known genetic diseases like familial hypercholesterolemia and familial hyperchylomicronemia. In the future, Particle Profiler can be applied for analyzing detailed lipoprotein size profile data and deriving rates of various lipolysis and uptake processes if an independent production estimate is given.

Effects of high doses of oestrogens and androgens on lipoproteins: observations in the treatment of excessive growth with sexual hormones.

In a prospective study we investigated the changes of lipoprotein metabolism under therapy with high doses of oestrogens or androgens, applied to stop the excessive growth of very tall girls or boys. Therapy with 2 mg ethinyl oestradiol sulfonate per week for one year in 11 girls resulted in an increase in serum triglycerides, which was reversible after cessation, and a minimal rise of total cholesterol and HDL-cholesterol in the phase of adaptation to this treatment. Therapy with 1000 mg testosterone oenanthate per month for one year lead to a fall of triglycerides and HDL-cholesterol. These changes are considered as a regulative phenomenon, without consequences for the application of the high dosage therapy with these steroid hormones in the treatment of excessive growth.

Plasma phospholipid transfer activity is essential for increased atherogenesis in PLTP transgenic mice: a mutation-inactivation study

Plasma phospholipid transfer protein (PLTP) interacts with HDL particles and facilitates the transfer of phospholipids from triglyceride (TG)-rich lipoproteins to HDL. Overexpressing human PLTP in mice increases the susceptibility to atherosclerosis. In human plasma, high-active and low-active forms of PLTP exist. To elucidate the contribution of phospholipid transfer activity to changes in lipoprotein metabolism and atherogenesis, we developed mice expressing mutant PLTP, still able to associate with HDL but lacking phospholipid transfer activity. In mice heterozygous for the LDL receptor, effects of the mutant and normal human PLTP transgene (mutPLTP tg and PLTP tg, respectively) were compared. In PLTP tg mice, plasma PLTP activity was increased 2.9-fold, resulting in markedly reduced HDL lipid levels. In contrast, in mutPLTP tg mice, lipid levels were not different from controls. Furthermore, hepatic VLDL-TG secretion was stimulated in PLTP tg mice, but not in mutPLTP tg mice. When mice were fed a cholesterol-enriched diet, atherosclerotic lesion size in PLTP tg mice was increased more than 2-fold compared with control mice, whereas in mutPLTP tg mice, there was no change. Our findings demonstrate that PLTP transfer activity is essential for the development of atherosclerosis in PLTP transgenic mice, identifying PLTP activity as a possible target to prevent atherogenesis, independent of plasma PLTP concentration.

Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on VLDL apolipoprotein E metabolism

Cholesteryl ester transfer protein (CETP) inhibition leads to changes in lipoprotein metabolism. We studied the effect of the CETP inhibitor torcetrapib on VLDL apolipoprotein E (apoE) metabolism. Subjects, pretreated with atorvastatin (n = 9) or untreated (n = 10), received placebo followed by torcetrapib (4 weeks each). After each treatment, subjects underwent a primed-constant infusion of D(3)-leucine to determine the VLDL apoE production rate (PR) and fractional catabolic rate (FCR). Torcetrapib alone reduced the VLDL apoE pool size (PS) (-28%) by increasing the VLDL apoE FCR (77%) and leaving the VLDL apoE PR unchanged. In subjects pretreated with atorvastatin, torcetrapib increased the VLDL apoE FCR (25%) and PR (21%). This left the VLDL apoE PS unchanged but increased the VLDL apoE content, likely enhancing VLDL clearance and reducing LDL production in this group. Used alone, torcetrapib reduces the VLDL apoE PS by increasing the apoE FCR while leaving the VLDL apoE content unchanged. In contrast, torcetrapib added to atorvastatin treatment increases both the VLDL apoE FCR and PR, leaving the VLDL apoE PS unchanged. Adding torcetrapib to atorvastatin treatment increases the VLDL apoE content, likely leading to decreased conversion of VLDL to LDL, reduced LDL production, and lower levels of circulating VLDL and LDL.

Metabolic Modulation of Inflammation-Induced Activation of Coagulation

The bidirectional interaction between coagulation and inflammation, which is relevant in various disease states that are dominated by systemic inflammatory responses, such as severe infection or chronic vascular disease, is modulated by metabolic factors. Changes in lipoprotein metabolism affect the inflammation-induced activation of coagulation, which may have impact on downstream effects, including organ dysfunction and survival. Likewise, glucose and insulin seem to influence inflammation-induced effects on coagulation and fibrinolysis. Hyperglycemia affects inflammation-induced and tissue factor-driven activation of coagulation, whereas hyperinsulinemia modulates the fibrinolytic response. There are indications that this modulatory role of metabolic factors in inflammation and coagulation may also have an impact on clinical outcome in various disease states.

Depletion of High‐density Lipoprotein and Appearance of Triglyceride‐rich Low‐density Lipoprotein in a Japanese Patient With FIC1 Deficiency Manifesting Benign Recurrent Intrahepatic Cholestasis

Lipoprotein metabolism in FIC1 deficiency due to ATP8B1 mutations has never been studied sufficiently. This study was performed to investigate the detailed lipoprotein metabolism in benign recurrent intrahepatic cholestasis (BRIC) caused by FIC1 deficiency. Lipoprotein profile and major lipoprotein regulators such as lecithin:cholesterol acyltransferase (LCAT), hepatic triglyceride lipase (HTGL), lipoprotein lipase, and cholesteryl ester transfer protein in a Japanese patient with BRIC were serially examined during a bout of cholestasis. Liver expression of farnesoid X receptor (FXR), which suppresses high-density lipoprotein (HDL) generation, was also examined. Hypercholesterolemia and lipoprotein X accumulation were never observed throughout this study. When the cholestasis was severe, triglyceride-rich low-density lipoprotein (LDL) accounted for most of the plasma lipoproteins whereas HDL was hardly detectable. Concurrently, activities of all regulators were decreased, together with decreases of the serum parameter for liver protein synthesis. In particular, suppressions of LCAT and HTGL activities were severe and greatly contributed to the appearance of triglyceride-rich LDL. As the cholestasis improved, this LDL gradually transformed into normal LDL with the recoveries of LCAT and HTGL activities. The activities of all regulators for the last 1 to 2 months were normal but HDL remained depleted. His liver showed low FXR expression compared with control livers. The present study showed an appearance of triglyceride-rich LDL due to suppressions of LCAT and HTGL activities and a depletion of HDL that is not able to be explained by lipoprotein regulators or FXR in our patient.

Metabolic Syndrome Phenotype in Very Obese Women

Severe obesity is increasingly common in the United States. Very obese persons are at increased risk for the metabolic consequences of obesity. A common multidimensional risk condition associated with obesity is the metabolic syndrome. It is accompanied by increased risk for cardiovascular disease and type 2 diabetes. Clinical manifestations of the metabolic syndrome can vary among obese individuals depending on ethnicity and gender. This study was carried out to determine the pattern of metabolic risk factors in very obese women who were considered candidates for bariatric surgery. Twenty-eight women of this type were compared to 28 nonobese women. Among the former, 11 had categorical hyperglycemia (type 2 diabetes), and 26 had metabolic syndrome by current criteria. Both those with and without diabetes had higher triglycerides and lower high-density lipoprotein (HDL) cholesterol levels than nonobese, but their levels were not categorically abnormal. These changes may have been related to observed lower postheparin lipoprotein lipase activities and higher hepatic lipase activities. In spite of lipid changes, apolipoprotein B levels were only marginally higher in very obese women. In contrast to small changes in lipoprotein metabolism, the obese women were severely insulin resistant, as indicated by hyperglycemia and elevated insulin levels. In addition, they had very high C-reactive protein levels. Thus, the metabolic syndrome, which appears to be typical of very obese women, is characterized by insulin resistance, glucose intolerance and a proinflammatory state. Atherogenic dyslipidemia as a metabolic risk factor in contrast is relatively mild. This pattern is more likely to lead to type 2 diabetes prior to development of clinically evident cardiovascular disease.

Magnesium and the inflammatory response: Potential physiopathological implications

The purpose of this review is to summarize experimental findings showing that magnesium modulates cellular events involved in inflammation. Experimental magnesium deficiency in the rat induces after a few days a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines and acute phase proteins, excessive production of free radicals. Increase in extracellular magnesium concentration, decreases inflammatory response while reduction in the extracellular magnesium results in cell activation. Because magnesium acts as a natural calcium antagonist, the molecular basis for inflammatory response is probably the result of modulation of intracellular calcium concentration. The priming of phagocytic cells, the opening calcium channel and activation of N-methyl- d-aspartate (NMDA) receptors, the activation of nuclear factor-kappa B (NFκB) have been considered as potential mechanisms. Moreover, magnesium deficiency induces a systemic stress response by activation of neuro endocrinological pathways. As nervous and immune systems interact bidirectionally, the roles of neuromediators have also been considered. Magnesium deficiency contributes to an exaggerated response to immune stress and oxidative stress is the consequence of the inflammatory response. Inflammation contributes to the pro-atherogenic changes in lipoprotein metabolism, endothelial dysfunction, thrombosis, hypertension and explains the aggravating effect of magnesium deficiency on the development of metabolic syndrome. Further studies are still needed to assess more accurately the role of magnesium in immune response in humans, but these experimental findings in animal models suggest that inflammation is the missing link to explain the role of magnesium in many pathological conditions.

Mode of action of fibrates in the regulation of triglyceride and HDL-cholesterol metabolism

Epidemiological studies have shown that hypertriglyceridemia and low HDL-cholesterol were both associated with an increased risk of coronary heart disease. Furthermore, hypertriglyceridemia is now recognized as an independent risk factor for coronary artery disease. Secondary prevention trials (e.g., LOCAT, BECAIT, BIP and DAIS) in coronary artery disease with drugs acting primarily on triglycerides (e.g., the PPAR-alpha activators bezafibrate, fenofibrate and gemfibrozil) have shown that reducing triglycerides and increasing HDL-cholesterol, without significantly affecting LDL-cholesterol, slows down coronary artery luminal narrowing. Furthermore, the VA-HIT study recently showed that gemfibrozil decreased coronary artery disease mortality in secondary prevention trials, partly by increasing HDL-cholesterol. The peroxisome proliferator-activated receptors (PPARs) (i.e., PPAR-alpha, -beta(delta) and -gamma) form a subfamily of the nuclear receptor gene family. Whereas all PPARs are, albeit to differing extents, activated by fatty acids and derivatives, PPAR-alpha binds the hypolipidemic fibrates. PPAR-alpha activation mediates changes in lipoprotein metabolism. Moreover, PPAR-alpha activators increase hepatic uptake and esterification of free fatty acids, in addition to increasing mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation. The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha-dependent stimulation of lipoprotein lipase and of apolipoprotein (apo)A-V and to an inhibition of apoC-III expression, whereas the increase in plasma HDL-cholesterol depends partly on an overexpression of apoA-I and apoA-II. PPARs are also expressed in atherosclerotic lesions.

Metabolic and clinical effects of progestogens

Synthetic progestogens differ not only in their hormonal potency, but also in their spectrum of hormonal activities. Beside their progestogenic and anti-oestrogenic effects, they may exert oestrogenic, androgenic, antiandrogenic, glucocorticoid and/or anti-mineralocorticoid activities. Consequently, progestogens may influence various metabolic parameters and modulate oestrogen-induced alterations in lipid metabolism, haemostasis, and various other factors. Progestogens with androgenic properties may counteract ethinyloestradiol (EE)-induced changes in lipoprotein metabolism, but do not cause atherosclerosis in the presence of EE. Oral contraceptives (OCs) containing androgenic progestogens which attenuate the EE-dependent changes in haemostasis, may be associated with a lower risk of venous thromboembolic disease than OCs whose progestogens have a less androgenic profile. Progestogens with androgenic activity may also antagonize oestrogen-induced alterations in various other hepatic proteins and modulate the effect of EE on growth factors. Progestogens with antiandrogenic activity may enhance the beneficial effect of EE in women with hyperandrogenic manifestations. Progestogens with glucocorticoid effects may increase procoagulatory activity in the vessel wall, while progestogens with anti-mineralocorticoid activity may reduce the aldosterone-induced water-retention in some women. For most women the differences in the hormonal pattern of progestogens used in OCs are without clinical relevance, but may be useful for women predisposed for the development of certain disorders.

Thyroid Substitution Therapy Induces High-Density Lipoprotein–Associated Platelet-Activating Factor–Acetylhydrolase in Patients with Subclinical Hypothyroidism: A Potential Antiatherogenic Effect

Subclinical hypothyroidism (SH) has been associated with an increased risk of ischemic heart disease, which has been partly attributed to lipid abnormalities. Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme associated with lipoproteins (both low-density lipoproteins [LDL], and high-density lipoproteins [HDL]). Plasma paraoxonase 1 (PON1) is an esterase exclusively associated with HDL. To evaluate qualitative changes in lipoprotein metabolism with respect to PAF-AH and PON1 activities in patients with SH before and after the restoration of euthyroidism. We determined the PAF-AH activity in plasma and on HDL and PON1 activities as well as the lipid profile patients with SH at baseline and after 6 months of levothyroxine substitution therapy. Thirty normolipidemic healthy individuals comprised the control group. Compared to controls, patients with SH showed higher levels of total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B. Triglycerides were significantly reduced after levothyroxine treatment. Patients with SH exhibited higher plasma baseline PAF-AH activity (63.0 +/- 16.5 versus 44.3 +/- 9.5 nmol/mL per minute p < 0.0001) and lower baseline HDL associated PAF-AH (2.9 +/- 1.1 versus 3.6 +/- 0.9 nmol/mL per minute p = 0.02) compared to the control group. PON1 activities were similar in both groups. Levothyroxine treatment had no effect on plasma PAF-AH activity or PON1 activities but resulted in a significant elevation of HDL-associated PAF-AH activity (from 2.9 +/- 1.1 to 3.5 +/- 1.0 nmol/mL per minute, p = 0.003). Patients with SH exhibit increased plasma PAF-AH activity and low HDL-associated PAF-AH activity. Levothyroxine induces a significant increase in HDL-PAF-AH activity. This action may represent a potential antiatherogenic effect of thyroid replacement therapy.

Lipoprotein metabolism in patients with anorexia nervosa: a case-control study investigating the mechanisms leading to hypercholesterolaemia.

Hypercholesterolaemia is a common finding in patients with anorexia nervosa (AN). To investigate the type, frequency and pathophysiological mechanisms of changes in lipoprotein metabolism in AN we performed a cross-sectional study in fifty-eight female patients (mean age 24.2 years, BMI 15.3 (sd 1.5) kg/m(2)) and fifty-eight healthy age-matched controls (CO; BMI 22.2 (sd 1.7) kg/m(2)). Total cholesterol and LDL-cholesterol were higher in AN (5.5 (sd 1.3) v. 5.0 (sd 0.8) mmol/l, P=0.023; 3.6 (sd 1.1) v. 3.2 (sd 0.7) mmol/l, P=0.025 respectively). LDL particles were significantly more enriched in cholesterol and triacylglycerol in AN. In multiple regression analysis with LDL-cholesterol as the dependent and BMI, total body fat ( %), lathosterol:cholesterol ratio (endogenous cholesterol synthesis), 7alpha-hydroxy-4-cholesten-3-one (bile acid synthesis), non-esterified glycerol, free triiodothyronine and free thyroxine as independent variables, BMI was the only significant predictor in CO (R(2) 0.36, overall P=0.001). In AN the variability of LDL-cholesterol was significantly predicted by total body fat, free thyroxine, BMI, free triiodothyronine and non-esterified glycerol (R(2) 0.55, overall P<0.001). Subgroup analysis between restricting (AN-R) and binge-eating-purging patients (AN-B) indicated that in AN-R changes in lipoproteins, BMI and total body fat were more pronounced. AN-R patients had lower bile acid synthesis than AN-B (P=0.02). We conclude that elevated cholesterol concentrations in AN are generally due to an increase in LDL-cholesterol, which is mostly determined by the severe loss of body fat and the resulting changes in thyroid hormones, increased lipolysis and decreased endogenous cholesterol synthesis with resulting decrease in LDL removal. The clinical subtype of AN plays a major role in the mechanisms leading to hypercholesterolaemia.

Double-blind, randomized study comparing the effects of two monophasic oral contraceptives containing ethinylestradiol (20 μg or 30 μg) and levonorgestrel (100 μg or 150 μg) on lipoprotein metabolism

The effects of two monophasic oral contraceptives containing ethinylestradiol 20 μg in combination with levonorgestrel 100 μg (EE20/LNG100) or 30 μg and 150 μg (EE30/LNG150), respectively, on lipoprotein metabolism was investigated in a double-blind, randomized study of 12 treatment cycles in healthy female volunteers. Total triglycerides (+32% to +46%, p < 0.05 in comparison to baseline) increased significantly. Triglycerides were highest after six cycles of treatment, decreasing thereafter. Total cholesterol (+1% to +7%), apolipoprotein (apo) B (+21% to +29%) and low-density lipoprotein (LDL) cholesterol (+7% to +17%) increased slightly. High-density lipoprotein (HDL) cholesterol decreased slightly (−11% and −5%), HDL triglycerides increased (+16% and +26%). Apo AI did not change during the study, suggesting that the molar concentration of HDL particles did not change. Apo E (−23% to −14%) decreased, and there was a transitory decrease of lipoprotein (a). Essentially, there was no difference regarding the changes in lipoprotein metabolism between the two treatment groups. The effects of the two combinations of ethinylestradiol and levonorgestrel on triglyceride-rich lipoproteins appear less pronounced than those produced by preparations containing third-generation progestins. It is not likely that the changes in lipoprotein metabolism brought about by the two preparations will alter the risk of future cardiovascular disease in a clinically relevant fashion.

Study of Diet-Induced Changes in Lipoprotein Metabolism in Two Strains of Golden-Syrian Hamsters

The objective of this study was to characterize two strains of Golden-Syrian hamsters for use in the study of diet-induced changes in lipoprotein metabolism. In Experiment 1, the time course and response to dietary saturated fat was investigated for serum lipoprotein profiles and aortic lesion formation in Golden-Syrian hamsters from Charles River Laboratories, Wilmington, MA (CR) and Bio Breeders, Watertown, MA (F(1)B). Hamsters were fed a nonpurified diet containing 10 g/100 g saturated fat and 0.1 g/100 g dietary cholesterol. After 12 wk, CR hamsters had significantly lower serum total and non-HDL cholesterol (TC and nHDL-C) levels, but higher aortic cholesteryl ester (CE) than the F(1)B hamsters (P < 0.05). In Experiment 2, CR hamsters were fed a nonpurified diet containing 10 g/100 g saturated fat and 0.1, 0.5 or 1 g/100 g dietary cholesterol. After 10 wk of dietary intervention, TC and nHDL-C levels were significantly higher in the 0.5 and 1.0 g/100 g cholesterol groups than in the 0.1 g/100 g cholesterol group. These levels declined after 20 wk of dietary intervention in all groups, potentially reflecting the toxic effect of high cholesterol intakes. CR hamsters fed a 10 g/100 g saturated fat containing 0.1 g/100 g dietary cholesterol for 10 wk appear to be a good model for investigating diet-induced change in plasma lipids.

Lipoprotein risk factors for cardiovascular disease in patients with type 2 diabetes mellitus treated with oral antihyperglycaemic agents.

To compare lipoprotein risk factors for cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (DM) treated with a sulphonylurea (SU) compound only, metformin (MET) only, or combined SU + MET. The study population consisted of 62 patients with type 2 DM, whose antihyperglycaemic treatment program had been stable for at least 3 months, divided into three groups: 26 patients in the SU group, 17 patients in the MET group and 19 patients in the SU + MET group. None of the patients were taking lipid-lowering drugs. Fasting venous blood samples were taken to measure concentrations of glucose, total cholesterol, triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and remnant lipoprotein-cholesterol (RLP-C) as well as for determination of LDL particle diameter. The three groups were similar in terms of age, gender, body mass index and fasting plasma glucose concentrations. Total cholesterol concentrations were significantly lower (p < 0.05 for trend) in those treated with SU + MET as compared with the other two groups. However, there were no significant differences between the three groups in their plasma concentrations of TG, LDL-C, HDL-C or RLP-C; furthermore, the proportion of individuals within each treatment group with small LDL particle diameter was also not different. The lipoprotein profile of patients with type 2 DM, matched for level of fasting hyperglycaemia, was similar irrespective of treatment with SU alone, MET alone or SU + MET. Thus, we could not identify any changes in lipoprotein metabolism that could account for differences in risk of CVD as a function of treatment.

Regulation of biliary cholesterol secretion is associated with abcg5 and abcg8 expressions in the rats: effects of diosgenin and ethinyl estradiol

In this study, we evaluate the effect of diosgenin, ethinyl estradiol and these co-administration on changes of lipoprotein metabolism and expression of hepatic genes those are important for cholesterol metabolism including the recently identified abcg5 and abcg8 in male Wistar rats. Rats were subjected to four experimental groups: (1) control group, (2) diosgenin group, which was fed the diet containing 1% diosgenin for 7 days, (3) ethinyl estradiol group, which received ethinyl estradiol in a dose of 5 mg/kg daily for 5 days, (4) diosgenin–ethinyl estradiol group, which received ethinyl estradiol treatment and was fed the diet containing 1% diosgenin. Diosgenin-feeding induced the hepatic abcg5/ abcg8 expressions and biliary cholesterol secretion. Ethinyl estradiol administration reduced hepatic abcg5/ abcg8 expressions and biliary cholesterol secretion. There was a positive correlation between hepatic expressions of abcg5/abcg8 and biliary cholesterol secretion. These findings strongly suggest that abcg5 and abcg8 are key proteins for biliary cholesterol excretion. Diosgenin-feeding did not affect the hepatic abcg5/ abcg8 expressions and biliary cholesterol excretion in ethinyl estradiol-treated rat. Serum bile acid and bilirubin were higher and biliary bile acid and bilirubin secretions were lower in diosgenin–ethinyl estradiol group than those in ethinyl estradiol group. This finding suggests that diosgenin enhances the cholestatic effect of ethinyl estradiol in the rat. In conclusion, alteration of biliary cholesterol secretion is related to the expressions of hepatic abcg5 and abcg8 in diosgenin- or ethinyl estradiol-treated rat.

Experimental model of postprandial hypertriglyceridemia in sucrose-fed rats and the effectiveness of atorvastatin in the model

Although postprandial hypertriglyceridemia has drawn attention as an independent risk factor of cardiovascular disease, there is no established animal model that shows a physiological transitory change in lipoprotein metabolism after ingestion of a fatty meal. We developed an animal model of postprandial hypertriglyceridemia using sucrose-fed rats, and used this model to evaluate the effect of atorvastatin on this condition. Compared with normal rats, sucrose-fed rats orally loaded with olive oil showed a high and prolonged increase in plasma triglyceride (TG) concentration accompanied by both an increase in TG secretion and decrease in TG clearance. Atorvastatin (30 mg/kg orally) for 2 weeks reduced not only fasting plasma TG concentration, but also the postprandial TG concentration. Atorvastatin also suppressed rates of TG secretion in both chylomicron (CM)-rich (d < 0.96 g/mL) and very-low-density lipoprotein (VLDL) (d = 0.96 to 1.006 g/mL) fractions after oral fat loading. Further, atorvastatin improved the elimination time of exogenous TG emulsion only in the nonfasted, namely, high plasma TG condition. These results indicate that this animal model satisfactorily replicates the postprandial hypertriglyceridemia observed in humans and may therefore be useful in evaluation of lipid-lowering agents. Furthermore, atorvastatin not only improves fasting but also postprandial lipoprotein metabolism, presumably by reducing TG secretion from the liver or intestine or both, and by secondarily increasing TG-rich lipoprotein clearance by eliminating saturation. © 2003 Elsevier Inc. All rights reserved.