Lipids in Health and Disease - Latest Articles

Decreased NPC1L1 expression in the liver from Chinese female gallstone patients

Wei Cui — 2010-02-08T00:00:00Z

Background: Cholesterol gallstone disease is a very common disease in both industrialized and developing countries. Many studies have found that cholesterol gallstones are more common in women than men. The molecular mechanisms underlying the relationship between female gallstone disease and hepatic sterol transporters are still undergoing definition and have not been evaluated in humans. Aims: The aim of this study is to probe for underlying hepatic molecular defects associated with development of gallstones in female. Methods/Results: Fifty-seven nonobese, normolipidemic Chinese female gallstone patients (GS) were investigated with 12 age- and body mass index-matched female gallstone-free controls (GSF). The bile from the female GS had higher cholesterol saturation than that from the female GSF. The hepatic NPC1L1 mRNA levels were lower in female GS, correlated with SREBP2 mRNA. NPC1L1 downregulation was confirmed at protein levels. Consistently, immunohistochemistry showed decreased NPC1L1 expression in female GS. Conclusions: The decreased hepatic NPC1L1 levels in female GS might indicate a downregulated reabsorption of biliary cholesterol in the liver, which, in turn, leads to the cholesterol supersaturation of bile. Our data are consistent with the possibility that hepatic NPC1L1 may be mediated by SREBP2.

Regulations of the key mediators in inflammation and atherosclerosis by Aspirin in human macrophages

Li Lu — 2010-02-06T00:00:00Z

Although its role to prevent secondary cardiovascular complications has been well established, how acetyl salicylic acid (ASA, aspirin) regulates certain key molecules in the atherogenesis is still not known. Considering the role of matrix metalloproteinase-9 (MMP-9) to destabilize the atherosclerotic plaques, the roles of the scavenger receptor class BI (SR-BI) and ATP-binding cassette transporter A1 (ABCA1) to promote cholesterol efflux in the foam cells at the plaques, and the role of NF-kappaB in the overall inflammation related to the atherosclerosis, we addressed whether these molecules are all related to a common mechanism that may be regulated by acetyl salicylic acid. We investigated the effect of ASA to regulate the expressions and activities of these molecules in THP-1 macrophages. Our results showed that ASA inhibited MMP-9 mRNA expression, and caused the decrease in the MMP-9 activities from the cell culture supernatants. In addition, it inhibited the nuclear translocation of NF-kappaB p65 subunit, thus the activity of this inflammatory molecule. On the contrary, acetyl salicylic acid induced the expressions of ABCA1 and SR-BI, two molecules known to reduce the progression of atherosclerosis, at both mRNA and protein levels. It also stimulated the cholesterol efflux out of macrophages. These data suggest that acetyl salicylic acid may alleviate symptoms of atherosclerosis by two potential mechanisms: maintaining the plaque stability via inhibiting activities of inflammatory molecules MMP-9 and NF-kappaB, and increasing the cholesterol efflux through inducing expressions of ABCA1 and SR-BI.

Ceramide and ceramide 1-phosphate in health and disease

Lide Arana — 2010-02-05T00:00:00Z

Sphingolipids are essential components of cell membranes, and many of them regulate vital cell functions. In particular, ceramide plays crucial roles in cell signaling processes. Two major actions of ceramides are the promotion of cell cycle arrest and the induction of apoptosis. Phosphorylation of ceramide produces ceramide 1-phosphate (C1P), which has opposite effects to ceramide. C1P is mitogenic and has prosurvival properties. In addition, C1P is an important mediator of inflammatory responses, an action that takes place through stimulation of cytosolic phospholipase A2, and the subsequent release of arachidonic acid and prostaglandin formation. All of the former actions are thought to be mediated by intracellularly generated C1P. However, the recent observation that C1P stimulates macrophage chemotaxis implicates specific plasma membrane receptors that are coupled to Gi proteins. Hence, it can be concluded that C1P has dual actions in cells, as it can act as an intracellular second messenger to promote cell survival, or as an extracellular receptor agonist to stimulate cell migration.

Safety and efficacy trial of adipose-tissue derived oral preparation V-6 Immunitor (V-6): results of open-label, two-month, follow-up study

Aldar Bourinbaiar — 2010-02-02T00:00:00Z

Background: Chronic inflammations, atherosclerosis and obesity, are major risk factors for cardiovascular diseases. Immune modulation of the inflammatory response has shown promise in animal models of atherogenesis and metabolic disease. Tableted dietary supplement, V-6, containing pooled antigens derived from pig adipose tissue has been administered daily to 12 volunteers for 2 months. Results: No significant changes were observed in liver ALT and AST enzymes, i.e., 28 vs 23.8 IU and 22.6 vs 24.8 IU, with p=0.07 and p=0.49, respectively. Creatinine decreased; 0.88 vs 0.84 mg/dL (p=0.05) while BUN moved upward; 14.5 vs 17.5 mg/dL (p=0.01), but both values remained within normal range. Blood glucose remained within normal range; 96.1 vs 101.1 mg/dL (p=0.04). Complete blood cell analysis has not revealed any change except slight increase in hemoglobin; 13.13 to 13.96 g/dL (p=0.0002); hematocrit and red blood cells count 40.3 to 42.3% (p=0.02) and 5.15 to 5.35 x 106 cells/mm3 (p=0.03) respectively. Blood pressure systolic and diastolic values were not affected, i.e., 116.1 vs 116.3 (p=0.12) and 76.8 vs 76.6 (p=0.99). Body weight and body mass index (BMI) remained same; 66.4 vs 66.3 kg (p=0.47) and 25.7 vs 25.6 kg/m2 (p=0.2). Body fat deposit indices, such as abdomen; mid-arm; and thigh circumferences declined by 3.5 cm (p=0.008); 1.2 cm (p=0.004); and 3.0 cm (p=0.0007) respectively. The total cholesterol and LDL levels did not change; 195.5 vs 195.1 (-0.2%; p=0.8) and 113.4 vs 120.3 (6.1%; p=0.08) respectively. Triglycerides have been reduced but not statistically significant; 168.1 vs 118 mg/dL (-29.8%; p=0.2). In contrast, HDL content had risen by 29.7% from 39.4 to 51.1 mg/dL in all 12 patients (p=0.000003). TG/HDL ratio - a marker of insulin resistance - was reduced from 4.78 to 2.56 (-46.5%; p=0.04). Conclusions: These results demonstrate that V-6 is safe and has a potential as an anti-atherogenic and overweight/obesity immune intervention.

Rapid bioassay-guided screening of toxic substances in vegetable oils that shorten the life of SHRSP rats

Sunil Ratnayake — 2010-02-02T00:00:00Z

It has been consistently reported that vegetable oils including canola oil have a life shortening effect in Stroke-Prone Spontaneously Hypertensive Rats (SHRSP) and this toxic effect is not due to the fatty acid composition of the oil. Although it is possible that the phytosterol content or type of phytosterol present in vegetable oils may play some role in the life shortening effect observed in SHRSP rats this is still not completely resolved. Furthermore supercritical CO2 fractionation of canola oil with subsequent testing in SHRSP rats identified safe and toxic fractions however, the compounds responsible for life shortening effect were not characterised. The conventional approach to screen toxic substances in oils using rats takes more than six months and involves large number of animals. In this article we describe how rapid bioassay-guided screening could be used to identify toxic substances derived from vegetable oils and/or processed foods fortified with vegetable oils. The technique incorporates sequential fractionation of oils/processed foods and subsequent treatment of human cell lines that can be used in place of animal studies to determine cytotoxicity of the fractions with structural elucidation of compounds of interest determined via HPLC-MS and GC-MS. The rapid bioassay-guided screening proposed would require two weeks to test multiple fractions from oils, compared with six months if animal experiments were used to screen toxic effects. Fractionation of oil before bio-assay enhances the effectiveness of the detection of active compounds as fractionation increases the relative concentration of minor components.

Docosahexaenoic acid prevents dendritic cell maturation and in vitro and in vivo expression of the IL-12 cytokine family

Weimin Kong — 2010-02-01T00:00:00Z

Background: Acute and chronic inflammation play essential roles in inflammatory/autoimmune conditions. Protective anti-inflammatory effects of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were reported in animal models of colitis, sepsis, and stroke. Since dendritic cells (DC) represent the essential cellular link between innate and adaptive immunity and have a prominent role in tolerance for self-antigens, we sought to investigate the impact of DHA on DC maturation and proinflammatory cytokine production. Methods: Murine bone marrow-derived DC were treated with DHA and stimulated with various toll-like receptor (TLR) ligands. Flow cytometry was used to determine the levels of surface maturation markers and endocytic activity. Cytokine expression and secretion were measured by real-time RT-PCR and ELISA assays. PPARgamma and NFkB activity in nuclear extracts were determined by binding to specific oligonucleotide sequences using ELISA-based assays. In vivo effects of DHA were assessed in splenic DC from LPS-inoculated mice maintained on a DHA-enriched diet. Results: DHA maintained the immature phenotype in bone marrow-derived DC by preventing the upregulation of MHCII and costimulatory molecules (CD40, CD80 and CD86) and maintaining high levels of endocytic activity. DHA inhibited the production of pro-inflammatory cytokines, including the IL-12 cytokine family (IL-12p70, IL-23, and IL-27), from DC stimulated with TLR2, 3, 4, and 9 ligands. DHA inhibition of IL-12 expression was mediated through activation of PPARgamma and inhibition of NFkBp65 nuclear translocation. DHA exerted a similar inhibitory effect on IL-12 and IL-23 expression in vivo in LPS-inoculated mice maintained on a DHA-enriched diet. Conclusions: Exposure of bone marrow-derived DC to DHA resulted in the maintenance of an immature phenotype and drastic reduction in proinflammatory cytokine release. DHA inhibited the expression and secretion of the IL-12 cytokine family members (IL-12p70, IL-23 and IL-27), which play essential roles in the differentiation of the proinflammatory Th1/Th17 effector cells. The effect of DHA on IL-12 expression was mediated through activation of PPARgamma and inhibition of NFkB. Inhibition of IL-12 and IL-23 expression was also evident in splenic DC from mice fed a DHA-enriched diet, suggesting that dietary DHA acts as an anti-inflammatory agent in vivo.

The association between serum levels of oxLDL-lgG and oxLDL-lgM autoantibody with adult acute myeloblastic leukaemia

Hao Li — 2010-01-31T00:00:00Z

Aim: To evaluate the relationship between serum antibodies against ox-LDL levels and adult acute myeloblastic leukemia (AML). Methods: Forty three patients with AML and 52 normal controls were enrolled in this study in the Department of Hematology, Tumor Center of Qilu Hospital of Shandong University from Feb. 2008 to Mar.2009. Serum lgG and lgM antibodies versus the oxLDL levels were evaluated by ELISA method. Data was analyzed by covariance and binary Logistic regression. Results: Serum mean levels of oxLDL-lgG in patients (38.92+/-21.1259ug/ml) were significantly lower than in control subjects (78.88+/-9.3705ug/ml); Meanwhile, Serum mean levels of oxLDL-lgM in patients (20.53+/-10.2990IU/L) were significantly higher than in control subjects (10.29+/-10.5771IU/L). Binary logistic regression showed the odds ratios of association of oxLDL-lgG and oxLDL-lgM with adult AML were 0.72(95%CI: 0.55-0.94) and 1.11(95%CI: 1.01-1.21) respectively after adjusted for potential confounders. Conclusion: In the preliminary investigation we found a descensive oxLDL- lgG and an elevated oxLDL-lgM serum levels for the adult AML. Future studies need to confirm the hypothesis whether they related to the development and progression of adult AML.

Acute effects of vinegar intake on some biochemical risk factors of atherosclerosis in hypercholesterolemic rabbits

Mahbubeh Setorki — 2010-01-28T00:00:00Z

Background: Exaggerated postprandial spikes in blood glucose and lipids induce proportional increases in oxidative stress, which acutely trigger impairment endothelial, inflammation and increased risk of future cardiovascular events.In this research, we have investigated acute effects of vinegar intake on some of the biochemical atherosclerosis risk factors in high cholesterol fed rabbits to see if we can find a probable protective value for it. Methods: The rabbits were randomly divided into four groups: normal diet, high cholesterol diet (%1cholesterol), %1 cholesterol with 5ml vinegar (low dose), %1 cholesterol with 10ml vinegar (high dose). After fasting for 12-15 hours, blood samples were taken to determine baseline values. Three hours after feeding, blood samples were collected again to investigate acute effects of vinegar intake on the measured factors. Results: Using high-dose vinegar with cholesterolemic diet caused significant reduce in LDL-cholesterol (LDL-C), oxidized-LDL (ox-LDL), malondialdehyde (MDA), total cholesterol (TC) and apolipoprotein B (ApoB) in comparison with hypercholesterolemic diet. Consumption low-dose vinegar with cholesterolemic diet induced a significant decrease in fibrinogen and glucose compared to hypercholesterolemic diet. Level of serum nitrite, nitrate, triacylglycerol (TAG), HDL-cholesterol (HDL-C), apolipoprotein A (ApoA), serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetate transaminase (SGOT) and C-reactive protein (CRP) were not significantly difference in low and high doses vinegar with cholesterolemic diet compared to hypercholesterolemic diet. A significant difference was observed for LDL-C, ApoB100 and TC between low and high doses vinegar. Conclusion: This study suggest that vinegar, might have some acute effects on biochemical risk factors of atherosclerosis and a probable protective value can be considered for its postprandial use.

Polysaccharide from Fuzi (FPS) prevents hypercholesterolemia in rats

Xiongqing Huang — 2010-01-28T00:00:00Z

Background and aim: Polysaccharide from fuzi (FPS), a Chinese herbal medicine extract, has been demonstrated to exert lipid lowering affects. In this study we examined potential mechanisms underlying this affect, specifically alterations in expression of the LDL-receptor (LDL-R), 3-hydroxy-3-methyl glutaryl (HMG)-CoA reductase and cytochrome P450 7alpha-1 (CYP7alpha-1), using a rat model of hypercholesterolemia.Methods and results: Male rats were fed either a normal or high cholesterol (HC) diet for two-weeks. Half of the rats on the HC diet were orally gavaged with FPS (224 mg/kg, 448 mg/kg or 896 mg/kg diet) daily. Serum lipid levels were quantified at end of the study period as were liver levels of LDL-R protein and mRNA expression of CYP7alpha-1 and HMG-CoA. Serum cholesterol and LDL-C concentrations were significantly elevated from control in HC rats, but not in those treated with FPS (P<0.05). LDL-R expression was significantly decreased in the HC group compared to control (P<0.05), but significantly increased in the FPS group (P<0.05). HMG-CoA mRNA levels were significantly increased in the HC group compared both other groups (P<0.05), while CYP7alpha-1 expression was significantly higher in the FPS group compared to both other groups (P<0.05). Conclusion: These findings suggest that the cholesterol lowering effect of FPS in hypercholesteremic rats is caused at least in part by increased hepatic LDL-R and CYP7alpha-1 expression and decreased HMG-CoA expression. Further study is needed to determine precisely where and how FPS exerts these effects. FPS offers potential as a therapeutic agent for the treatment of hypercholesterolemia.

Effect of Apolipoprotein E genotype on Hepatitis C, HIV and Herpes Simplex disease risk: a literature review

Inga Kuhlmann — 2010-01-28T00:00:00Z

Apolipoprotein E is a polymorphic and multifunctional protein with numerous roles in lipoprotein metabolism. The three common isoforms apoE2, apoE3 and apoE4 show isoform-specific functional properties including different susceptibilities to diseases. ApoE4 is an accepted risk factor for Alzheimer's disease and cardiovascular disorders. Recently, associations between apoE4 and infectious diseases have been demonstrated. This review summarises how apoE4 may be involved in the infection incidence and associated pathologies of specific infectious diseases, namely hepatitis C, human immunodeficiency virus disease and herpes simplex.ApoE4 seems to be protective against chronic hepatitis C virus infection and retards fibrosis progression. In contrast apoE4 enhances the fusion rate of human immunodeficiency virus with target cell membranes, resulting in accelerated cell entry and faster disease progression. Its association with human immunodeficiency virus-associated dementia remains controversial. Regarding herpes simplex virus infection, apoE4 intensifies virus latency and is associated with increased oxidative damage of the central nervous system, and there is some evidence that herpes simplex virus infection in combination with the apoE4 genotype may be associated with an increased risk of Alzheimer's disease. In addition to reviewing available data from human trials, evidence derived from a variety of cell culture and animal models are considered in this review in order to provide mechanistic insights into observed association between apoE4 genotype and viral disease infection and pathology.