Lipids in Health and Disease Latest Content

Increased plasma apoM levels in the patients suffered from hepatocellular carcinoma and other chronic liver diseases

2008-07-24

[Abstract] Objective To determine plasma apolipoprotein M (apoM) levels and other lipid profiles in hepatocellular carcinoma (HCC) patients compared to other chronic liver diseases and normal subjects. Materials and methods 36 HCC, 68 chronic hepatitis, 29 liver cirrhosis patients and 64 normal controls were subjected in the present study. Serum lipids, lipoproteins, apolipoprotein AI (apoAI) and apoB were determined by the conventional methods. Plasma apoM levels were semi-quantitatively determined by both dot-blotting and western blotting analysis. Results Serum levels of triglycerides (TG), HDL-cholesterol, apoAI and lipoprotein (a) (Lp(a)) were significantly lower in the HCC patients than in the normal subjects, whereas there were no obvious differences on serum total cholesterol, LDL-cholesterol and apoB between HCC patients and normal subjects. However, plasma apoM levels in HCC patients were significantly increased than those in the normal subjects, but lower than those in the chronic hepatitis and cirrhosis patients. Conclusions It is concluded that serum TG, apoAI, HDL-C and Lp(a) were significantly decreased in HCC patients than in controls, whereas plasma apoM levels were significantly increased in the HCC patients. Decreased serum TG, apoAI, HDL-C and Lp(a) may reflect the liver damage in HCC patients, whereas the clinical significance of increased plasma apoM levels in relation to HCC is not clear.

The omega-3 fatty acid, eicosapentaenoic acid (EPA), prevents the damaging effects of Tumour Necrosis Factor (TNF)-alpha during murine skeletal muscle cell differentiation

Peter Magee, Stephen Pearson and Jeremy Allen — 2008-07-18

Background: Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid with anti-inflammatory and anti-cachetic properties that may have potential benefits with regards to skeletal muscle atrophy conditions where inflammation is present. It is also reported that pathologic levels of the pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha are associated with muscle wasting, exerted through inhibition of myogenic differentiation and enhanced apoptosis. These findings led us to hypothesize that EPA may have a protective effect against skeletal muscle damage induced by the actions of TNF-alpha. Results: The deleterious effects of TNF-alpha on C2C12 myogenesis were completely inhibited by co-treatment with EPA. Thus, EPA prevented the TNF-mediated loss of MyHC expression and restored myogenic fusion and myotube diameter indices back to control levels. EPA protective activity was associated with blocking cell death pathways as EPA completely attenuated TNF-mediated increases in caspase-8 activity and cellular necrosis back to their respective control levels. EPA alone significantly reduced spontaneous apoptosis and necrosis of differentiating myotubes (p<0.001 and p<0.05, respectively). A 2 hour pre-treatment with EPA, prior to treatment with TNF alone, gave similar results. Conclusion: In conclusion, EPA has a protective action against the damaging effects of TNF-alpha on C2C12 myogenesis. These findings support further investigations of EPA as a potential therapeutic agent during skeletal muscle regeneration following injury.

Lipoprotein binding preference of CD36 is altered by filipin treatment

Jianshe Zhang, Wuying Chu and Ian Crandall — 2008-06-26

The class B scavenger receptor CD36 binds multiple ligands, including oxidized and native lipoprotein species. CD36 and the related receptor SR-B1 have been localized to caveolae, domains that participate in cell signaling, transcytosis, and regulation of cellular cholesterol homeostasis. Previous work has indicated that the ligand preference of CD36 may depend on the cell type in which it is expressed. To determine if the presence or absence of caveolae is the determining factor for lipoprotein preference, we treated CHO-CD36 and C32 cells with filipin. Filipin treatment rapidly increased the binding capacity of CD36 for the native lipoproteins HDL and LDL, but did not affect the binding capacity of CD36 for oxidized LDL. Filipin treatment affected the distribution of caveolin and CD36 suggesting that the presence caveolae may modulate the ligand preference of CD36. However, its molecular mechanism how CD36 and caveolin interaction in regulating lipoprotein transport remains to be further studied.

Plasma PCSK9 levels are significantly modified by statins and fibrates in humans

2008-06-11

Background: Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men. Results: Herein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6× vs 1.5×, respectively at 10 μM), while fenofibrate did not induce changes in either. Conclusion: These results suggest that in vivo (1) statins directly increase PCSK9 expression while (2) fibrates affect PCSK9 expression indirectly through its modulation of cholesterol levels and (3) that these therapies could be improved by combination with a PCSK9 inhibitor, constituting a novel hypercholesterolemic therapy, since PCSK9 was significantly upregulated by both treatments.

Effect of dietary fat on hepatic liver X receptor expression in P-glycoprotein deficient mice: implications for cholesterol metabolism

Sheila J Thornton, Evelyn Wong, Stephen D Lee and Kishor M Wasan — 2008-06-11

Pgp (P-glycoprotein, MDR1, ABCB1) is an energy-dependent drug efflux pump that is a member of the ATP-binding cassette (ABC) family of proteins. Preliminary studies have reported that nonspecific inhibitors of Pgp affect synthesis and esterification of cholesterol, putatively by blocking trafficking of cholesterol from the plasma membrane to the endoplasmic reticulum, and that relative increases in Pgp within a given cell type are associated with increased accumulation of cholesterol. Several key efflux proteins involved in the cholesterol metabolic pathway are transcriptionally regulated by the nuclear hormone liver X receptor (LXR). Therefore, to examine the interplay between P-glycoprotein and the cholesterol metabolic pathway, we utilized a high fat, normal cholesterol diet to upregulate LXRα without affecting dietary cholesterol. Our research has demonstrated that mice lacking in P-glycoprotein do not exhibit alterations in hepatic total cholesterol storage, circulating plasma total cholesterol levels, or total cholesterol concentration in the bile when compared to control animals on either a normal (25% calories from dietary fat) or high fat (45% calories from dietary fat) diet. However, p-glycoprotein deficient mice (Mdr1a-/-/1b-/-) exhibit increased hepatic LXRα protein expression and an elevation in fecal cholesterol concentration when compared to controls.

The effects of beta2 adrenergic receptor gene polymorphism in lipid profiles

Wei-Tsung Kao, Yung-Chieh Yen and For-Wey Lung — 2008-05-21

Background: Explore the interaction between apolipoprotein E (Apo E), phospholipase A2 (PLA2) and β2 adrenergic receptor (β2-AR) gene polymorphisms and lipid profiles in an elderly Chinese population. Methods: Five hundred subjects aged 65 to 74 years were randomly selected from a community in southern Taiwan to assess the relationship between Apo E, PLA2 and β2-AR gene polymorphisms and lipid profiles. Two hundred sixty-seven participants agreed to have venous blood drawn for DNA studies. Results: Two statistically significant differences were noted in TC and LDL-C in the Gln27Glu of the β2-AR gene polymorphism (P = 0.007, P = 0.022). The low-income group had a higher HDL-C level (p = 0.076). The Gln27Glu polymorphism Glu/Glu or Gln/Glu subjects had lower TC levels compared to the Gln27Glu polymorphism Gln/Gln subjects (p = 0.092). Lower TC levels (p = 0.082) and lower LDL-C levels (p = 0.045) in subjects with the Cys19Arg16Glu27 haplotype. Lower TC levels (p = 0.06) were also noted in subjects with the Cys19Gly 16Glu27 haplotype. On the other hand, higher VLDL-C levels (p = 0.185) and higher triglyceride (TG) levels (p = 0.190) were noted in subjects with the Cys19Gly 16Gln27 haplotype. The ε2 allele combined with low income had a positive effect on HDL-C (p = 0.0011), after adding the income factor in this study. Conclusion: When the effects of Apo E and PLA2 on lipid profiles were included in this study, β2-AR gene polymorphisms reduced significant effect on lipid profiles. Similarly, low income increased effect on HDL-C. This study appeared that the results of gene-gene and gene-environment interaction, it should be considered in further studies for lipid profiles.

Can endogenous lipid molecules serve as predictors and prognostic markers of coronary heart disease?

Undurti N Das — 2008-05-20

Dyslipidemia, and inflammatory markers: high-sensitivity C-reactive protein (hs-CRP), myeloperoxidase (MPO), lipoprotein associated phospholipase A2(Lp-PLA2), and lipid peroxides (LP) are insufficient to predict the onset, extent, and prognosis of CHD. Lipoxins (LXs), resolvins, and protectins are derived from ω-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and ω-6 arachidonic acid in the presence of aspirin; whereas nitrolipids are formed due to the interaction between polyunsaturated fatty acids and nitric oxide (NO). LXs, resolvins, protectins, and nitrolipids are endogenous anti-inflammatory lipid molecules that inhibit production of interleukin-6 (IL-6) and tumor necrosis factor- α (TNF-α), suppress free radical generation, enhance NO generation; and accelerate tissue repair. Thus, beneficial actions of EPA/DHA and aspirin in CHD could be attributed to the formation of LXs, resolvins, protectins, and nitrolipids and suggest that their plasma levels aid in the prediction and prognosis of CHD.

Characteristic comparison of triglyceride-rich remnant lipoprotein measurement between a new homogenous assay (RemL-C) and a conventional immunoseparation method (RLP-C)

2008-05-17

Background: Increased serum remnant lipoproteins are supposed to predict cardiovascular disease in addition to increased LDL. A new homogenous assay for remnant lipoprotein-cholesterol (RemL-C) has been developed as an alternative to remnant-like particle-cholesterol (RLP-C), an immunoseparation assay, widely used for the measurement of remnant lipoprotein cholesterol. Methods: We evaluated the correlations and data validation between the 2 assays in 83 subjects (49 men and 34 women) without diabetes, hypertension and medications for hyperlipidemia, diabetes, and hypertension, and investigated the characteristics of remnant lipoproteins obtained by the two methods (RLP-C and RemL-C) and their relationships with IDL-cholesterol determined by our developed HPLC method. Results: A positive correlation was significantly found between the two methods (r = 0.853, 95%CI 0.781–0.903, p < 0.0001). Bland & Altman analysis revealed that RemL-C values were likely to be significantly higher than RLP-C values, particularly in samples with high levels of remnant lipoproteins. Several data dissociations between the RemL-C and RLP-C were also observed. The HPLC chromatograms show high concentrations of chylomicron cholesterol in serum samples with RemL-C level < RLP-C level, but high concentrations of IDL-cholesterol in samples with RemL-C level > RLP-C level. RemL-C (r = 0.339, 95%CI 0.152–0.903; p = 0.0005) significantly correlated with IDL-cholesterol, but not RLP-C (r = 0.17, 95%CI -0.047–0.372; p = 0.1237) in all the samples (n = 83). Conclusion: These results suggest that there is generally a significant correlation between RemL-C and RLP-C. However, RemL-C assay is likely to reflect IDL more closely than RLP-C.

Changes in cholesterol kinetics following sugar cane policosanol supplementation: a randomized control trial

Amira N Kassis and Peter JH Jones — 2008-04-30

Background: Sugar cane policosanols (SCP) have been shown to exert cholesterol-modulating properties in various studies conducted in Cuba by substantially reducing cholesterol synthesis. Independent research examining changes in cholesterol kinetics in response to SCP is limited to few studies, none of which was able to replicate findings of the original research. Moreover, no data are available on the effect of SCP on cholesterol absorption to date. The present study was undertaken to determine effects on cholesterol kinetics, namely synthesis and absorption, within hypercholesterolemic individuals consuming a SCP treatment. Twenty-one otherwise healthy hypercholesterolemic subjects participated in a randomized double-blind crossover study where they received 10 mg/day of policosanols or a placebo incorporated in margarine as an evening snack for a period of 28 days. The last week of the study phase, subjects were given 13C labelled cholesterol and deuterated water for the measurement of cholesterol absorption and synthesis respectively. Blood was collected on the first two and last five days of the trial. Cholesterol absorption and synthesis were determined by measuring red cell cholesterol 13C and deuterium enrichment, respectively. Results: There was no significant change in LDL cholesterol levels as compared to control. In addition, the area under the curve for red cell cholesterol 13C enrichment across 96 hours was not significantly different in the SCP group as compared to control. Similarly, no difference was observed in the fractional rate of cholesterol synthesis over the period of 24 hours between the two treatment groups. Conclusion: The findings of the present study fail to support previous research concerning efficacy and mechanism of action for policosanols.

Effects of a high fat diet on bone of growing rats. Correlations between visceral fat, adiponectin and bone mass density

Gerard Lac, Helian Cavalie, Edmond Ebal and Odile Michaux — 2008-04-28

In this study, we investigated some bone parameters (bone mineral content, bone mineral density, skeleton area) in growing rats fed with a high fat diet. Correlations between bone and body composition parameters are reported. Two groups of Wistar male rats (35 days old, body mass 80 ± 6 g) were used. Water and food were given "ad libitum" during 10 weeks. Sixteen rats (L) were given a lipid enriched diet and were compared to 16 rats (S) fed with a standard diet. Body composition and bone parameters were assessed using DXA. Results indicated that L rats had lower body mass, lean body mass; fat mass was not different between the two groups. Bone mineral content, bone mineral density, skeleton area of L rats were lower compared with S rats. Significant correlations were noted between body composition, adiponectin and bone parameters. High fat diet intake during the growing period has deleterious effects on bone parameters in rats. This study confirms in growing rats that a high fat diet is pathogenic, including bone metabolism.