Lipoprotein(a) (Lp(a)) is a unique lipoprotein, elevated serum levels of which are independently associated with an increased risk of coronary heart disease (CHD). Primary biliary cirrhosis (PBC) is often associated with high serum cholesterol, itself a risk factor for CHD. Despite this, patients with PBC are thought to have a lower than expected incidence of CHD. We hypothesised that this may be related to low serum levels of Lp(a) in PBC patients. This was investigated by collecting fasting blood samples from 42 patients with PBC, 39 age- and sex-matched subjects with non-PBC liver disease and 432 community control subjects. Serum was analysed for total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol and apolipoproteins A1 and B (apo A1 and apo B). Lp(a) was measured by an enzyme-linked immunosorbent assay (ELISA) technique. There was a significant reduction of Lp(a) concentrations in the PBC group compared with the healthy controls (median value 28.5 mg/l vs. 75.0 mg/l, P < 0.005) and between the non-PBC liver disease group (median value 52.0 mg/l) and control group (P = 0.001). Within both the liver disease and PBC patient groups there were significant negative correlations between Lp(a) levels and bilirubin (R = -0.564, P < 0.001 and R = -0.395, P = 0.010 respectively). This preliminary study has demonstrated reduced Lp(a) levels in PBC patients which may be a contributory factor to explain a possible cardioprotective effect in such patients, despite elevated LDL cholesterol levels.

OBJECTIVE

Liver biopsy is the gold standard for detecting fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Due to limitations of biopsy, various combinations of serum markers have been studied to predict liver fibrosis; many of these are patented and expensive, thereby restricting their evaluation. We prospectively evaluated the correlation of commonly used serum markers with fibrosis in Indian patients with NAFLD.

METHODS

Fifty-one patients (age 50.4 [SD 11.5] years) with biopsy-proven NAFLD underwent estimation of platelet count, total bilirubin, AST, ALT, serum albumin, γ-glutamyl transpeptidase (GGT), prothrombin time, serum cholesterol, triglycerides, α2-macroglobulin (A2M), apolipoprotein A1 (Apo A1), and haptoglobin. FIB-4, AST/platelet ratio index (APRI), and AST/ALT ratio were calculated and correlated with fibrosis (NAS-II score) on liver biopsy.

RESULTS

Thirty-eight (74.5 %) patients had inflammation and 48 (94.1 %) had ballooning degeneration on histology; 29 had fibrosis, of whom 11 had ≥F2 fibrosis. High GGT (odds ratio [OR] 8.4 [1.85-38.10]; p = 0.007, area under the curve [AUROC] 0.65), low platelet count (OR 7.57 [1.83-31.45]; p = 0.001, AUROC 0.833), and low Apo A1 (OR 12.04 [2.98-47.3]; p = 0.0002, AUROC 0.76) were associated with advanced fibrosis on multiple logistic regression; a novel score formulated by assigning 1 point for an abnormal value for each of these parameters correlated with absence of fibrosis (p = 0.0001; OR 0.102 [95 % confidence interval (CI) CI 0.025-0.418]), with negative predictive value of 94.29 % [95 % CI 80.81 to 99.13].

CONCLUSIONS

A score using simple markers including GGT, Apo A1, and platelet count correlated with absence of liver fibrosis in patients with NAFLD.

Nine cynomolgus monkeys were rotated randomly through four dietary treatments with each treatment lasting 6 weeks. A wash-out period of 4 weeks was maintained between each dietary rotation. The animals were fed diets containing 32% energy fat derived from palm olein (POL), lauric-myristic-rich oil blend (LM), American Heart Association (AHA) rich oil blend and hydrogenated soybean oil blend (trans). Diets were fed with (phase 1) or without (phase 2) the addition of dietary cholesterol (0.1%). In phase 1, when animals were fed without dietary cholesterol, plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) was significantly raised and high-density lipoprotein cholesterol (HDL-C) was significantly depressed by the trans diets relative to all other dietary treatments. The resulting LDL-C/HDL-C ratio was also significantly increased. The LM diet increased TC significantly relative to the AHA diet while LDL-C was significantly increased compared to both POL and AHA. Apolipoprotein (apo) B was not affected significantly by these dietary treatments. Apo A1 was significantly increased by POL relative to all other dietary treatments. The trans diet reduced apo A1 and the resulting apo B/A1 ratio was increased significantly by trans relative to all other dietary treatments. Addition of 0.1% dietary cholesterol to these diets almost doubled the plasma TC and LDL-C in all dietary treatments. However, HDL-C was only marginally higher with the addition of dietary cholesterol. The LM + C (cholesterol added) diet resulted in the highest TC and LDL-C that was significant compared to all other dietary treatments. Trans + C increased TC compared to POL + C and AHA + C diets while increases in the LDL-C did not attain significance. The addition of dietary cholesterol did not affect HDL-C between treatments whereas plasma triglycerides were significantly increased by the trans + C diet relative to all other treatments. Both the trans + C and LM + C diets increased apo B and decreased apo A1 relative to the POL + C and AHA + C diets. The resulting apo B/A1 ratio was similarly altered. These results affirm that the lauric + myristic acid combination, along with trans fatty acids, increased lipoprotein-associated coronary heart disease risk factors compared to either POL or AHA.

Severe alcoholic hepatitis (SAH) has high mortality. Dysregulated lipid transport and metabolism in liver/macrophages contributes to disease pathophysiology. Paraoxonase/arylesterase 1 (PON1), a liver-specific enzyme, inhibits oxidation of phospholipids and prevents lipid-mediated oxidative damage. However, its functional contribution in macrophage-mediated hepatic injury warrants elucidation. Plasma proteome of patients with SAH (n = 20), alcoholic cirrhosis (n = 20), and healthy controls was analyzed. Dysregulated pathways were identified, validated, and correlated with severity and outcomes in 200 patients with SAH. Tohoku-Hospital-Pediatrics-1 (THP1)-derived macrophages were treated with plasma from study groups in the presence/absence of recombinant PON1 and the phenotype; intracellular lipid bodies and linked functions were evaluated. In patients with SAH, 208 proteins were >1.5 fold differentially regulated (32 up-regulated and 176 down-regulated; P < 0.01).Validation studies confirmed lower levels of lipid transporter proteins (Pon1, apolipoprotein [Apo]B, ApoA1, ApoA2, and ApoC3; P < 0.01). Low PON1 levels inversely correlated with severity and mortality (r² > 0.3; hazard ratio, 0.91; P < 0.01) and predicted nonsurvivors (area under the receiver operating characteristic curve, 0.86; cut-off, <18 μg/mL; log rank, <0.01). Low PON1 levels corroborated with increased oxidized low-density lipoprotein levels, intracellular lipid bodies, lipid uptake, lipid metabolism, biosynthesis, and alternative macrophage activation genes in nonsurvivors (P < 0.01). Importantly, in vitro recombinant PON1 treatment on THP1 macrophages reversed these changes (P < 0.01), specifically by alteration in expression of clusters of differentiation 36 (CD36) and adenosine triphosphate-binding cassette subfamily A1 (ABCA1) receptor on macrophages. Conclusion: Lipid transport proteins contribute to the pathogenesis of SAH, and low PON1 levels inversely correlate with the severity of alcoholic hepatitis and 28-day mortality. Restitution of circulating PON1 may be beneficial and needs therapeutic evaluation in patients with SAH.

The relationship between levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular (CV) risk is well recognized; however, in recent years, large-scale phase III studies with HDL-C-raising or -mimicking agents have failed to demonstrate a clinical benefit on CV outcomes associated with raising HDL-C, casting doubt on the "HDL hypothesis." This article reviews potential reasons for the observed negative findings with these pharmaceutical compounds, focusing on the paucity of translational models and relevant biomarkers related to HDL metabolism that may have confounded understanding of in vivo mechanisms. A unique function of HDL is its ability to interact with the ATP-binding cassette transporter (ABC) A1 via apolipoprotein (Apo) A1. Only recently, studies have shown that this process may be involved in the intestinal uptake of dietary sterols and antioxidants (vitamin E, lutein and zeaxanthin) at the basolateral surface of enterocytes. This parameter should be assessed for HDL-raising drugs in addition to the more documented reverse cholesterol transport (RCT) from peripheral tissues to the liver. Indeed, a single mechanism involving the same interaction between ApoA1 and ABCA1 may encompass two HDL functions previously considered as separate: antioxidant through the intestinal uptake of antioxidants and RCT through cholesterol efflux from loaded cells such as macrophages.

BACKGROUND

The idea that statin therapy decreases asymmetric dimethylarginine through lowering low-density lipoprotein cholesterol levels seems logic. However, controversy exists in the literature concerning this issue. This study compares the effect of moderate (40 mg) to high (80 mg) simvastatin doses on asymmetric dimethylarginine levels in patients with newly detected severe hypercholesterolemia (after targeted LDL levels of < or = 2.6 mmol/L are reached).

METHODS

The study included 120 adult patients with newly detected severe hypercholesterolemia (total cholesterol>> or = 7.5 mmol/L and low-density lipoprotein cholesterol>> or = 4.9 mmol/L). Asymmetric dimethylarginine levels were determined by enzyme-linked immunosorbent assay, total homocystein by the high performance liquid chromatography method.

RESULTS

A statistically significant decrease exists in total cholesterol, triglycerides, low-density lipoprotein cholesterol and apolipoprotein-B levels as well as apolipoprotein-B/apolipoprotein-A1 index following one month of 40 mg simvastatin therapy (P < 0.001). Asymmetric dimethylarginine and total homocystein levels were also decreased but the difference was not significant (p = 0.571; p = 0.569). A dose-dependent effect was established comparing the influence of moderate (40 mg) to high (80 mg) simvastatin doses on the tested atherogenic biomarkers (lipid profile, apolipoprotein-A1, apolipoprotein-B). Asymmetric dimethylarginine and total homocystein levels showed a statistically significant decrease with 80 mg simvastatin (p < 0.001; p = 0.038). In the group of 40 patients, who had reached LDL-cholesterol target levels on 80 mg simvastatin, a reduction in ADMA levels demonstrated a statistically significant correlation with the reduction of LDL-cholesterol (r(xy) = 0.355; p < 0.01) and of Apo-B (r(xy) = 0.508; p < 0.001). The backward selection process selected percent ApoB-change as the most important statistically significant factor related to percent ADMA-change (F = 21.127; p = 0.001; R2 = 0.265).

CONCLUSIONS

Optimizing the target values of low-density lipoprotein cholesterol to the moderate dose (40 mg) of simvastatin has no effect on asymmetric dimethylarginine and total homocysteine in contrast to high dose (80 mg) after targeted LDL of < or = 2.6 mmol/L levels are reached in patients with newly detected severe hypercholesterolemia.

The effect of apo very low density lipoprotein (apo VLDL) and apoprotein C-II on the phospholipase A1 activity associated with lipoprotein lipase (E.C.3.1.1.3) was studied using purified bovine milk lipoprotein lipase. The enzyme degraded 14C phosphatidylcholine (PC) to 14C 2-acyl lysophosphatidylcholine at a rate of 0.28 +/- 0.01 nmol/min/ml and triolein at a rate of 20.3 +/- 0.4 nmol/min/ml in mixed emulsions of PC and triolein. The phospholipase activity and triacylglycerol lipase activity were both increased by the addition of apo VLDL and apoprotein C-II. After maximal activation, the rate of PC degradation was 1.19 +/- 0.02 nmol/min/ml and triolein degradation 64.4 +/- 0.4 nmol/min/ml. Activation of phospholipase A1 activity and triacylglycerol lipase activity occurred in parallel.

OBJECTIVE

Changes in some rhythmometric parameters have been reported in the elderly as a consequence of both structural and neurochemical changes occurring in the central nervous system. Since alterations of lipid and lipoprotein metabolism are directly involved in several age-related disorders, the aim of this study was to investigate the circadian temporal organization of some important lipidic fractions (total cholesterol, triacylglycerol, apolipoprotein A1 and B) in physiological aging.

METHODS

Thirty old hospitalized subjects were synchronized for daily activities, sleeping/waking habits, and time/quality of meals. Twenty-four healthy young individuals served as controls. After an overnight fast, samples were taken beginning at 08:00 every 4 hours until 20:00, and every 2 hours from 20:00 to 04:00. Rhythmometric data were analyzed by single and population mean Cosinor analysis, and by ANOVA; the comparison of the rhythm's parameters between elderly and young subjects was carried out by the Mesor test and the amplitude-acrophase using Hotelling's test.

RESULTS

Elderly subjects exhibited statistically significant circadian rhythms for total cholesterol (p<0.00002), triacylglycerol (p<0.000001), apo A-1 (p<0.0013), and apo B (p<O.0104). Young subjects also exhibited statistically significant daily fluctuations for total cholesterol (p<0. 0003), triacylglycerol (p<0. 03), apo A-1 (p<0.002) and apo B (p<0.003). The mean level of apo B rhythm was higher in old subjects than in controls.

CONCLUSIONS

These data suggest that the circadian temporal organization of lipidic fractions is maintained in physiological aging and underline the importance of the feeding schedule as a powerful synchronizer of the daily lipidic profile.

The effect of nutritional factors on apolipoprotein gene expression by rat liver were studied. Dietary carbohydrates or fatty acids regulate the expression of apo E gene, by altering either gene transcription or mRNA stability. Conversely, apo A1 regulation occurs at a post transcriptional level. In vivo and in vitro experiments gave contradictory results concerning apo B gene expression. The more dramatic changes in plasma lipids and apolipoproteins are obtained under dietary fish oil. Hepatocytes from fish oil-fed rats retain for several days modification in fatty acid metabolism, i.e. a shift in oleic acid channeling towards oxidation at the expense of esterification and a reduced ability to synthesize and secrete triacylglycerol. These modifications are paralleled with a decrease in the synthesis and in the secretion of apo Bs. Hepatocytes from fish oil fed rats secrete degradative forms of apo B which might result from either a sluggish VLDL synthesis and secretion or a more specific effect of n-3 long chain polyunsaturated fatty acid peroxidative products. Hepatocytes from fish oil fed rats exhibit a reduced ability to synthesize cholesterol, associated with a decrease in apo A1 synthesis and secretion without any modification in apo A1 mRNA. In contrast, the hepatocytes exhibit a concomitent decrease in apo E synthesis and secretion and in cellular apo E mRNA levels.

Plasma lipids, lipoproteins and apolipoproteins A1 and B were determined in a reference population and in 273 patients who underwent coronary arteriography for evaluation of chest pain. The patients were divided into 3 groups according to arteriographic findings. The 102 patients in group A had normal coronary arteries; the 30 patients in group B had small vascular abnormalities but no significant narrowing; the 141 patients in group C had significant vascular lesions with greater than or equal to 50% narrowing. Total cholesterol and triglycerides were quantified using enzymatic methods. HDL cholesterol and phospholipids were enzymatically analyzed after phosphotungstate precipitation. Plasma lipoproteins were evaluated by quantitative electrophoresis based on densitometric scanning of the lipoprotein bands after separation and visualization by polyanion precipitation. Apoproteins A1 and B were measured by electroimmuno-diffusion assay using ready-for-use plates. Statistical evaluation of the data showed that group C patients had higher betalipoprotein and apo B levels and lower alphalipoprotein and apo A1 levels than subjects with normal coronary arteries. The predictive value of these results was established in relation to clinical findings. Plasma lipid measurements proved inadequate to separate the 3 groups. In contrast, the betalipoprotein/alphalipoprotein ratio and, still better, the apo A1/apo B ratio provided good discrimination. The results suggest that measurement of plasma apo A1 and apo B levels is the best means of assessing the risk of coronary artery disease.

OBJECTIVE

It is not clear whether changes in waist circumference (WC), sums of skinfold thickness (SSF), or levels of physical activity (PA) during adolescence are associated with cardiovascular risk factors, or if associations are independent or interactive.

RESULTS

In a US cohort of adolescent girls (n = 617-904) girls, examined at ages 12 and 14, WC, SSF, PA, systolic and diastolic blood pressure (SBP & DBP) were assessed. Fasting blood samples were used to determine concentrations of triglycerides (TG), cholesterol (TC), high and low density lipoproteins (HDL-C and LDL-C), and apolipoprotein A1 and B (Apo-A1 and Apo-B). After adjustment for change in SSF and PA, increases in WC were associated with change in TG (z = 1.73, 95% CI = 0.77, 2.69), TC (z = 0.45, 95% CI = 0.01, 0.90), HDL-C (z = -0.18, 95% CI = -0.37, -0.01), LDL-C (z = 0.41, 95% CI = 0.03, 0.80), Apo-A1 (z = -0.52, 95% CI = -1.02, -0.02), Apo-B (z = 0.60, 95% CI = 0.24, 0.97) and SBP levels (z = 0.31, 95% CI = 0.15, 0.47). Associations between changes in SSF and PA with cardiovascular risk were eliminated after adjustment for WC, and all interactions between WC, SSF and PA were non-significant at conventional levels.

CONCLUSIONS

Changes in WC were independently associated with the development of cardiovascular risk factors, whereas changes in SSF and PA were not. Clinicians should consider the routine screening of WC to monitor cardiovascular health in adolescent girls.

One hundred and three patients, 76 with diabetes mellitus alone (48- Non-Insulin dependent diabetes and 28 Insulin dependent diabetes) and 27 diabetics having coronary heart disease (CHD) and 27 normal control subjects were included in this study. All the 27 diabetics with CHD were Non-Insulin dependent. The patients and the controls were investigated for serum Lp (a), triglycerides, cholesterol, VLDL-C, LDL-C, HDL-C, apo A1 and apo B. The objective was to assess and compare the level of lipoproteins, especially the lipoprotein (a), in diabetic and non-diabetic subjects and to compare the level of the aforementioned parameters in diabetics with and without CHD. The Lp (a) and other lipid parameters were significantly raised (P < 0.001) except HDL-C and apo A1 that were significantly decreased (P < 0.001) both in diabetic patients with and without CHD, as compared to the control group. The diabetics with CHD showed significantly elevated (P < 0.001) Lp (a) and lipid profile, and significantly low (P < 0.001) HDL-C and apo A1 levels as compared to the patients having diabetes alone. No significant difference was observed in the levels of the above parameters when NIDDM patients were compared with IDDM group. In both NIDDM and IDDM patients significantly low (P < 0.001) HDL-C level and significantly high (P < 0.001) Lp (a) level along with the aforementioned lipid parameters was observed as compared to control group. Elevated levels of Lp (a) and lipid profile in diabetic subjects suggest their involvement in atherogenesis and subsequent development of CHD.

Serum lipids were measured in 30 Finnish and Japanese postmenopausal women. Total cholesterol, HDL cholesterol, LDL cholesterol, apo B and the HDL cholesterol/apo A1 ratio were higher in Finnish than in Japanese women. The LDL cholesterol/apo B and apo A1/apo B ratios were lower in Finns than in Japanese. In serum phospholipids the percentage of arachidonic acid was higher and the percentage of the n - 3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, and the eicosapentaenoic acid/arachidonic acid ratio were lower in Finnish than in Japanese women. No significant correlations were found between serum oestrone levels and lipid parameters.

Objectives: The aim of this study was to investigate the uncertain effects of high saturated fatty acids (SFAs) or fructose intake on cholesterol and lipoproteins with an insight of proprotein convertase subtilisin/kexin type 9 (PCSK9)- and cluster of differentiation 36 (CD36)-induced mechanisms.

Methods: Forty male C57 BL/6 mice (8 wks of age) were divided into four groups and fed ad libitum with standard chow or three isocaloric diets containing high SFAs (SFA group), monounsaturated fatty acids (MUFA group, vehicle), or fructose for 15 wks. Subsequently, mice were sacrificed and blood, liver, and heart were collected for further analysis.

Results: Consequently, fructose or SFA intake resulted in higher plasma and liver total cholesterol (TC) levels, plasma low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo)-B levels, TC/HDL-C, and LDL-C/HDL-C ratios, and lower plasma levels of HDL-C and Apo-A1 (P < 0.05). Levels of 3-hydroxy-3-methylglutaryl-CoA reductase and acetyl-CoA acetyltransferase 1 enzymes in liver and CD36 levels in plasma were elevated by high SFAs and fructose intake (P < 0.05), whereas plasma PCSK9 levels were not significantly changed. Fructose and SFA intake increased PCSK9 and CD36 levels in the heart, along with increased CD36 levels in the liver (P < 0.05). Furthermore, plasma LDL-C was found to be positively correlated with liver PCSK9 (r = 0.85, P = 0.02), and CD36 (r = 0.70, P = 0.02) in the SFA and fructose groups.

Conclusion: High intakes of dietary SFAs and fructose might induce dysregulations in the cholesterol synthesis and blood lipoprotein levels via proposed nutrient-sensitive biomarkers PCSK9 and CD36 in liver and extrahepatic tissues involved in cholesterol homeostasis.

Keywords: CD36; Cholesterol metabolism; Fructose; PCSK9; Saturated fatty acids.

Depleted uranium (DU) is uranium with a lower content of the fissile isotope U-235 than natural uranium. It is a radioelement and a waste product from the enrichment process of natural uranium. Because of its very high density, it is used in the civil industry and for military purposes. DU exposure can affect many vital systems in the human body, because in addition to being weakly radioactive, uranium is a toxic metal. It should be emphasized that, to be exposed to radiation from DU, you have to eat, drink, or breathe it, or get it on your skin. This particular study is focusing on the health effects of DU for the cholesterol metabolism. Previous studies on the same issue have shown that the cholesterol metabolism was modulated at molecular level in the liver of laboratory rodents contaminated for nine months with DU. However, this modulation was not correlated with some effects at organs or body levels. It was therefore decided to use a "pathological model" such as hypercholesterolemic apolipoprotein E-deficient laboratory mice in order to try to clarify the situation. The purpose of the present study is to assess the effects of a chronic ingestion (during 3 months) of a low level DU-supplemented water (20 mg L(-1)) on the above mentioned mice in order to determine a possible contamination effect. Afterwards the cholesterol metabolism was studied in the liver especially focused on the gene expressions of cholesterol-catabolising enzymes (CYP7A1, CYP27A1 and CYP7B1), as well as those of associated nuclear receptors (LXRα, FXR, PPARα, and SREBP 2). In addition, mRNA levels of other enzymes of interest were measured (ACAT 2, as well as HMGCoA Reductase and HMGCoA Synthase). The gene expression study was completed with SRB1 and LDLr, apolipoproteins A1 and B and membrane transporters ABC A1, ABC G5. The major effect induced by a low level of DU contamination in apo-E deficient mice was a decrease in hepatic gene expression of the enzyme CYP7B1 (-23%) and nuclear receptors LXRα (-24%), RXR (-32%), HNF4α (-21%) when compared to unexposed ones. These modifications on cholesterol metabolism did not lead to increased disturbances that are specific for apolipoprotein E-deficient mice, suggesting that chronic DU exposure did not worsen the pathology in this experimental model. In conclusion, the results of this study indicate that even for a sensitive pathologic model the exposure to a low dose of DU has no relevant impact. The results confirm the results of our first study carried out on healthy laboratory rodents where a sub-chronic contamination with low dose DU did not affect in vivo the metabolism of cholesterol.

Cadmium (Cd²⁺) in the environment is a significant health hazard. Chronic low Cd²⁺ exposure mainly results from food and tobacco smoking and causes kidney damage, predominantly in the proximal tubule. Blood Cd²⁺ binds to thiol-containing high (e.g., albumin, transferrin) and low molecular weight proteins (e.g., the high-affinity metal-binding protein metallothionein, β2-microglobulin, α1-microglobulin and lipocalin-2). These plasma proteins reach the glomerular filtrate and are endocytosed at the proximal tubule via the multiligand receptor complex megalin:cubilin. The current dogma of chronic Cd²⁺ nephrotoxicity claims that Cd²⁺-metallothionein endocytosed via megalin:cubilin causes renal damage. However, a thorough study of the literature strongly argues for revision of this model for various reasons, mainly: (i) It relied on studies with unusually high Cd²⁺-metallothionein concentrations; (ii) the K_D of megalin for metallothionein is ~10⁵-times higher than (Cd²⁺)-metallothionein plasma concentrations. Here we investigated the uptake and toxicity of ultrafiltrated Cd²⁺-binding protein ligands that are endocytosed via megalin:cubilin in the proximal tubule. Metallothionein, β2-microglobulin, α1-microglobulin, lipocalin-2, albumin and transferrin were investigated, both as apo- and Cd²⁺-protein complexes, in a rat proximal tubule cell line (WKPT-0293 Cl.2) expressing megalin:cubilin at low passage, but is lost at high passage. Uptake was determined by fluorescence microscopy and toxicity by MTT cell viability assay. Apo-proteins in low and high passage cells as well as Cd²⁺-protein complexes in megalin:cubilin deficient high passage cells did not affect cell viability. The data prove Cd²⁺-metallothionein is not toxic, even at >100-fold physiological metallothionein concentrations in the primary filtrate. Rather, Cd²⁺-β2-microglobulin, Cd²⁺-albumin and Cd²⁺-lipocalin-2 at concentrations present in the primary filtrate are taken up by low passage proximal tubule cells and cause toxicity. They are therefore likely candidates of Cd²⁺-protein complexes damaging the proximal tubule via megalin:cubilin at concentrations found in the ultrafiltrate.

The objective of this study was to explore the molecular mechanisms of acute noise-induced hearing loss and recovery of steady-state noise-induced hearing loss using miniature pigs. We used miniature pigs exposed to white noise at 120 dB (A) as a model. Auditory brainstem response (ABR) measurements were made before noise exposure, 1 day and 7 days after noise exposure. Proteomic Isobaric Tags for Relative and Absolute Quantification (iTRAQ) was used to observe changes in proteins of the miniature pig inner ear following noise exposure. Western blot and immunofluorescence were performed for further quantitative and qualitative analysis of proteomic changes. The average ABR-click threshold of miniature pigs before noise exposure, 1 day and 7 days after noise exposure, were 39.4 dB SPL, 67.1 dB SPL, and 50.8 dB SPL, respectively. In total, 2,158 proteins were identified using iTRAQ. Both gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) database analyses showed that immune and metabolic pathways were prominently involved during the impairment stage of acute hearing loss. During the recovery stage of acute hearing loss, most differentially expressed proteins were related to cholesterol metabolism. Western blot and immunofluorescence showed accumulation of reactive oxygen species and nuclear translocation of NF-κB (p65) in the hair cells of miniature pig inner ears during the acute hearing loss stage after noise exposure. Nuclear translocation of NF-κB (p65) may be associated with overexpression of downstream inflammatory factors. Apolipoprotein (Apo) A1 and Apo E were significantly upregulated during the recovery stage of hearing loss and may be related to activation of cholesterol metabolic pathways. This is the first study to use proteomics analysis to analyze the molecular mechanisms of acute noise-induced hearing loss and its recovery in a large animal model (miniature pigs). Our results showed that activation of metabolic, inflammatory, and innate immunity pathways may be involved in acute noise-induced hearing loss, while cholesterol metabolic pathways may play an important role in recovery of hearing ability following noise-induced hearing loss.

<p><div><b>Background</b></div>Paraoxonase 1 (PON1) is a calcium-dependent multifunctional enzyme that binds to high-density lipoproteins. The physiological function of PON1 is related to its lactonase activity. However, this activity has not been analyzed in women with gestational diabetes mellitus (GDM). The present study investigated the lactonase activities and status of PON1 and their association with <i>PON1</i> genetic variants and oxidative stress indices in Chinese women with GDM.</p><p><div><b>Methods</b></div>This is a case-control study of 347 women with GDM and 288 women with uncomplicated pregnancies. PON1 levels and lactonase activities were analyzed using 7-O-diethylphosphoryl-3-cyano-4-methyl-7-hydroxycoumarin (DEPCyMC) and 5-thiobutyl butyrolactone (TBBL), respectively. A normalized lactonase activity (NLA) was estimated based on the ratio of TBBLase to DEPCyMCase activity. Serum malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC) levels, and <i>PON1</i> genetic variants and oxidative stress indices in Chinese women with GDM.</p><p><div><b>Results</b></div>PON1 lactonase activity and levels of TOS, TAC, and MDA were higher in the GDM women compared with the control women. The <i>PON1 -108C→T</i> genetic variation decreased the levels and lactonase activities of PON1 in a genotype-dependent manner in the patient and control groups. GDM patients with the <i>PON1 -108TT</i> genotype displayed lower NLA than those with the <i>-108CC</i> or <i>-108CT</i> genotype. GDM patients with the <i>RR</i> genotype of <i>PON1 192Q/R</i> polymorphism had significantly lower PON1 lactonase activities and NLA and tended to have decreased PON1 levels compared with those with the <i>QQ</i> or <i>QR</i> genotype. Multivariable regression analysis revealed that the <i>PON1 -108C/T</i> or <i>192Q/R</i> variations, <em>apo</em>lipoprotein (<em>apo</em>) <em>A1</em>, <em>apo</em>B, TAC, MDA, or age was significant predictors of the levels, lactonase activities, or NLA of PON1.</p><p><div><b>Conclusions</b></div>The lactonase activities of PON1 are increased in women with GDM. <i>PON1</i> genetic variants, increased oxidative stress, and abnormalities in lipoproteins may be associated with these changes.<i>PON1</i> genetic variants and oxidative stress indices in Chinese women with GDM.</p>

Purpose of the review: Apolipoprotein (APO) A1, the main apolipoprotein of plasma high-density lipoproteins (HDLs), has several well documented cardioprotective functions. A number of additional potentially beneficial functions of APOA1 have recently been identified. This review is concerned with the therapeutic potential of all of these functions in multiple disease states.

Recent findings: Knowledge of the beneficial functions of APOA1 in atherosclerosis, thrombosis, diabetes, cancer, and neurological disorders is increasing exponentially. These insights have led to the development of clinically relevant peptides and APOA1-containing, synthetic reconstituted HDL (rHDL) preparations that mimic the functions of full-length APOA1. APOA1 is a multifunctional apolipoprotein that has therapeutic potential in several diseases. Translation of this knowledge into the clinic is likely to be dependent on the efficacy and bioavailability of small peptides and synthetic rHDL preparations that are currently under investigation, or in development.

Keywords: APOA1; Atherosclerosis; Cancer; Diabetes; Neurological disorders; Thrombosis.

BACKGROUND

[corrected] Abnormal lipid profile is an important risk factor in the development of macrovascular atherosclerotic complications in patients with type 2 diabetes mellitus (T2D). Factors that contribute to endothelial cell dysfunction associated with the initiation of atherosclerosis include oxidative stress. The aim of this study was to investigate the relationship between lipid profile and oxidative stress in type 2 diabetics with and without ischemic heart disease (IHD).

METHODS

We studied 80 patients with T2D, 40 with IHD (group A1) and 40 without IHD (group A2). We also studied 51 non-diabetics, 31 with IHD (group B1), and 20 without IHD (group B2 control group). Lipid profile was estimated by the total cholesterol, HDL cholesterol, LDL cholesterol, the level of triglyceride (Tg), lipoproteina a (Lp a), Apo A I, A II, B 100 and E. To evaluate the oxidative status we measured circulating oxidized LDL (ox LDL), erythrocyte antioxidative enzyme activity: superoxide dismutase (E-SOD), glutathione peroxidase (E-GPX), as well as the total antioxidative serum activity (TAS). Inflammatory reaction was estimated by C-reactive protein (CRP) and fibrinogen.

RESULTS

No significant difference was found in the lipid profile in groups A1, A2 and B1, but the group B2 had the lowest one. Lp a level was significantly higher in group B1 comparing to other groups (p < 0.05). There was no significant difference in the level of ox LDL between the groups. In diabetics, ox LDL positively correlated with the total cholesterol, LDL cholesterol, non HDL cholesterol, Apo B 100 and the relations between LDL/HDL and Tg/HDL (p < 0.001), as well as with Tg and fibrinogen (p < 0.05). In group B1, ox LDL positively correlated with total cholesterol, Tg (p < 0.01), LDL, and non HDL cholesterol (p < 0.05) and significantly with Apo B 100 (p < 0.001). There was no significant difference in the antioxidant enzyme activities between the groups of diabetics (A1 and A2), but fibrinogen was higher in the group with IHD (group A1, p < 0.05). Group B1 had lower E-SOD activity than the groups A1 and A2 (p < 0.05), but CRP was higher (p < 0.05). There were no significant correlations between oxLDL and CRP in groups A1 and A2, but it was statistically significant in the group B1 (p < 0.05).

CONCLUSIONS

In this study we demonstrated the increased oxidative stress in diabetics compared to non-diabetics regardless of the presence of IHD. Fibrinogen, but not CRP, was higher in diabetics with IHD, compared to diabetics without IHD. The increased oxidative stress, the reduced antioxidative activity E-SOD, and the higher level of CRP were found in non-diabetics with IHD compared to non-diabetics without IHD.

BACKGROUND

Dyslipoproteinaemia is an important risk factor for cardiovascular disease in uraemic patients on continuous ambulatory peritoneal dialysis (CAPD). Lovastatin is an HMG Coenzyme A reductase inhibitor which is useful in treating non-uraemic patients with hypercholesterolaemia.

OBJECTIVE

We conducted a single blind cross-over study versus placebo in 10 CAPD patients to examine the effect of lovastatin (20-40 mg) on the serum lipid profile and its safety in uraemic patients.

METHODS

Treatment phases were of eight weeks' duration. Each four weeks' measurements were made of serum total cholesterol (TC), triglyceride (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), VLDL-cholesterol (VLDL-C), Apolipoprotein A1 & B (Apo A1 & Apo B) and Lipoprotein (a). After eight weeks, lovastatin significantly reduced TC by 29% from 6.7 +/- 0.3 (mean +/- S.E.M.) to 4.8 +/- 0.1 mmol/L, LDL-C by 41% from 4.6 +/- 0.3 to 2.7 +/- 0.1 mmol/L and Apo B by 32% from 116 +/- 7 to 78 +/- 3 mg/dl (p < 0.01). HDL-C increased by 8% from 1.2 +/- 0.1 to 1.3 +/- 0.2 mmol/L after eight weeks' therapy (p < 0.05). TG decreased by 18% from 1.9 +/- 0.4 to 1.6 +/- 0.3 mmol/L (p < 0.05). There was no significant difference in changes of other lipid profiles between placebo and drug. No adverse effects of the drug were noted during treatment and the liver function and muscle enzymes were not significantly altered by either drug therapy or placebo.

RESULTS

Lovastatin appears to be a safe and useful drug in effectively treating dyslipoproteinaemia in CAPD patients.

A clinical trial, to evaluate the effects of Baoshen Pill (Rheum palmatum extract, RPE) on hemodialytic patients was conducted. 42 cases with terminal stage of renal failure (Scr < 10 ml/min) on HD were divided at random into RPE treated group and control group. The results showed there were no statistically significant differences between two groups for Scr or BUN. Serum levels of TC, LDL-c, apo B and apo B/apo A1 dropped down and HDL-c, apo A1, albumin, pro-albumin and fibrinectin increased during the follow-up period (P < 0.05) in the treated patients. It is considered that the mechanisms of RPE in preventing chronic renal failure were not the action of whole body. Improving serum levels of albumin, lipoprotein, apolipoproteins might play important role in treatment.

OBJECTIVE

To examine the relationship between lipid values and BMI (body mass index) on hospitalizations in hemodialysis (HD) patients.

METHODS

Retrospective (2-year) study.

METHODS

Outpatient dialysis center in a large metropolitan city.

METHODS

This study used 158 HD patients stratified on the basis of ethnicity (non-Black and Black) and diabetic status (nondiabetic and diabetic).

METHODS

Subjects were observed for 2 years. Body weight, BMI, lipid parameters, and hospitalization duration were determined 8 times (3-month intervals).

METHODS

Body weight, BMI, lipid parameters (serum triglyceride concentration, serum total cholesterol, high-density lipoprotein [HDL]-, low-density lipoprotein [LDL]-, very low-density lipoprotein [VLDL]- cholesterol concentrations, serum Apo-protein A1 [Apo-A1] concentration, and serum Apo-protein B [Apo-B] concentration), and morbidity data were recorded.

RESULTS

Hemodialysis subjects were hospitalized 2.3 +/- 1.6 times over the 2-year experimental period. Length of hospital stay averaged 6.6 +/- 0.5 days/hospitalization. Length of hospital stay was inversely related to HDL concentration (r = -0.21, P <.05, n = 89), but not significantly related to BMI in HD subjects. BMI was positively associated with LDL concentration (r = +0.28, P <.01, n = 97). Cholesterol concentration was directly associated with LDL concentration (r = +0.52, P <.01, n = 138), VLDL concentration (r = +0.47, P <.01, n = 139), and triglyceride concentration (r = +0.54, P <.01, n = 155). Mean concentration of HDL-cholesterol was inversely related serum triglyceride concentration (r = -0.43, P <.01, n = 140). Although Apo-A1 concentration was directly associated with HDL level (r = +0.39, P <.01, n = 139), Apo-B was inversely related to HDL level (r = -0.37, P <.01, n = 138) and directly related to cholesterol concentration (r = +0.71, P <.01, n = 138), VLDL concentration (r = +0.87, P <.01, n = 138), and triglyceride concentration (r = +0.81, P <.01, n = 138).

CONCLUSIONS

Cardiac disease remains the primary cause of morbidity and mortality in HD patients, and results of the present study suggest that dyslipidemias present in the HD population negatively impact cardiovascular profiles which, in turn, influence the frequency/duration of hospitalizations. Among all lipid parameters analyzed in the present study, increased LDL and decreased HDL concentrations were more strongly related to length of hospital stay than was BMI.

The anorexia of chronic renal failure (CRF) is frequently managed with enteral feeds using combinations of commercial preparations, glucose polymers and fat emulsions. Such feeds might predispose to atherogenic blood lipid profiles. Our aim, therefore, was to compare the blood lipid profiles of enterally fed and non-enterally fed children. Plasma lipid subfractions were measured in 37 children with CRF managed conservatively and 10 managed with peritoneal dialysis (PD); 10 of the children were tube fed, 5 of whom were on PD. Results were compared between these groups. Overall, triglycerides (TGs, mean +/- SD) were high (2.3 +/- 1.4 mmol/l) and total cholesterol (TC) was at the upper limit of normal (5.2 +/- 1.5 mmol/l). Low-density lipoprotein (LDL), high-density lipoprotein (HDL), apoprotein A1 (apo A1), A2 (apo A2) and B (apo B), and lipoprotein (a) [Lp(a)] were within the normal range. There was an inverse correlation between TGs and glomerular filtration rate (P = 0.0001). There were no differences in the levels of TC, TG, LDL, HDL, apo A1, apo A2 or Lp(a) between tube-fed and non-tube-fed children. We conclude that enteral feeding does not enhance hyperlipidaemia.