Low-density Apolipoprotein Research Articles

Quantitative lipidomics reveals the changes of lipids and antioxidant capacity in egg yolk from laying hens with fatty liver hemorrhagic syndrome

In laying hens, fatty liver hemorrhagic syndrome (FLHS) is a common metabolic disorder, which can affect egg production and nutritional value. However, the impact of FLHS on the lipid content in egg yolks was not clear. In this study, FLHS model was induced by using high-energy low-protein diet, and the egg quality was evaluated. Egg yolk lipids were quantitatively analyzed by using ultra-performance liquid chromatography-mass spectrometry combined with multivariate statistical analysis. Gene expressions of the lipoprotein were determined by qRT-PCR and antioxidant capacity of the egg yolk were determined by kits. The elevated blood lipids and extensive lipid droplets observed indicated successful establishment of the FLHS model in laying hens. Measurements of egg quality showed that egg yolk weight was increased in the FLHS group. Lipidomics revealed that 1,401 lipids, comprising 27 lipid subclasses in the egg yolk. According to score plots of principal component analysis and orthogonal partial least squares discriminant analysis, different lipid profile was observed between the control and FLHS groups. A total of 97 different lipid species were screen out. Sphingolipid and glycerophospholipid metabolism were identified as key pathways. Free polyunsaturated fatty acids (PUFA) exhibited an increase in the FLHS group (P < 0.05). Notably, the form of PUFAs was changed that the FLHS group showed an increase in triacylglycerol-docosahexenoic acid and triacylglycerol-arachidonic acid in the egg yolk, while triacylglycerol-α-linolenic acid was decreased (P < 0.05). Total superoxide dismutase was decreased in the egg yolks affected by FLHS. Gene expressions of vitellogenin 2 (VTG2), VTG3, very low-density apolipoprotein II and apolipoprotein B were increased in the liver of laying hens with FLHS (P < 0.05). In conclusion, FLHS promoted the lipid transport from the liver to the yolk by upregulating lipoprotein expression, which altered lipid profile, and reduced antioxidant capacity in the yolk. This study provided a foundation for understanding the changes in lipids, lipid transport and lipid antioxidation capacity in egg yolk from laying hens with FLHS.

Recent developments in the regulation of cholesterol transport by natural molecules

The dysregulation of cholesterol metabolism is a high-risk factor for non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and atherosclerosis (AS). Cholesterol transport maintains whole-body cholesterol homeostasis. Low-density apolipoprotein receptor (LDLR) mediates cholesterol uptake in cells and plays an important role in the primary route of circulatory cholesterol clearance in liver cells. Caveolins 1 is an integral membrane protein and shuttle between the cytoplasm and cell membrane. Caveolins 1 not only plays a role in promoting cholesterol absorption in cells but also in the transport of cellular cholesterol efflux by interacting with the ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI). These proteins, which are associated with reverse cholesterol transport (RCT), are potential therapeutic targets for NAFLD and AS. Many studies have indicated that natural products have lipid-lowering effects. Moreover, natural molecules, derived from natural products, have the potential to be developed into novel drugs. However, the mechanisms underlying the regulation of cholesterol transport by natural molecules have not yet been adequately investigated. In this review, we briefly describe the process of cholesterol transport and summarize the mechanisms by which molecules regulate cholesterol transport. This article provides an overview of recent studies and focuses on the potential therapeutic effects of natural molecules; however, further high-quality studies are needed to firmly establish the clinical efficacies of natural molecules.

ДИНАМИКА ПОКАЗАТЕЛЕЙ ЛИПИДНОГО ОБМЕНА У ИСПЫТУЕМЫХ В ЭКСПЕРИМЕНТЕ С 5-СУТОЧНОЙ «СУХОЙ» ИММЕРСИЕЙ

Blood samples from six 25–40 y.o. male subjects in a 5-d dry immersion (DI) experiment were analyzed for cholesterol, cholesterol of high- (HDLP), low- (LDLP) and very low density lipoproteins, triglycerides, apolipoproteins А1 (аpoА1) and apolipoproteins В (аpоВ), non-esterified (free) fatty acids (NEFA), β-hydroxibutyrate and phospholipids. Atherogenic indices were calculated, as well as the ratios of cholesterol, аpоВ/аpоА1 and cholesterol/phospholipids. No significant changes in cholesterol or lipoprotein fractions were determined. Increases in the triglyceride level and apoB/apoA1 ratio as harbingers of incipient atherogenesis showed up on the final day in DI and disappeared two days later. The process of readaptation to normal conditions is accompanied by the development of a stress reaction characterized by increased use of lipid substrates (phospholipids, β-hydroxybutyrate, NEFA) for energy synthesis.

Articles of Significant Interest in This Issue

This article refers to:Human Insulin Growth Factor 2 mRNA Binding Protein 2 Increases MicroRNA 33a/b Inhibition of Liver ABCA1 Expression and Alters Low-Density Apolipoprotein Levels in MiceImmunoglobulin Class Switch Recombination Is Initiated by Rare Cytosine Deamination Events at Switch Regions

Human Insulin Growth Factor 2 mRNA Binding Protein 2 Increases MicroRNA 33a/b Inhibition of Liver ABCA1 Expression and Alters Low-Density Apolipoprotein Levels in Mice.

Genome-wide association studies (GWAS) have linked IGF2BP2 single-nucleotide polymorphisms (SNPs) with type 2 diabetes (T2D). Mice overexpressing mIGF2BP2 have elevated cholesterol levels when fed a diet that induces hepatic steatosis. These and other studies suggest an important role for insulin growth factor 2 mRNA binding protein 2 (IGF2BP2) in the initiation and progression of several metabolic disorders. The ATPase binding cassette protein ABCA1 initiates nascent high-density apolipoprotein (HDL) biogenesis by transferring phospholipid and cholesterol to delipidated apolipoprotein AI (ApoAI). Individuals with mutational ablation of ABCA1 have Tangier disease, which is characterized by a complete loss of HDL. MicroRNA 33a and 33b (miR-33a/b) bind to the 3' untranslated region (UTR) of ABCA1 and repress its posttranscriptional gene expression. Here, we show that IGF2BP2 works together with miR-33a/b in repressing ABCA1 expression. Our data suggest that IGF2BP2 is an accessory protein of the argonaute (AGO2)-miR-33a/b-RISC complex, as it directly binds to miR-33a/b, AGO2, and the 3' UTR of ABCA1 Finally, we show that mice overexpressing human IGF2BP2 have decreased ABCA1 expression, increased low-density lipoprotein-cholesterol (LDL-C) and cholesterol blood levels, and elevated SREBP-dependent signaling. Our data support the hypothesis that IGF2BP2 has an important role in maintaining lipid homeostasis through its modulation of ABCA1 expression, as its overexpression or loss leads to dyslipidemia.

Mesial Temporal Lobe Epilepsy: Role of Reelin Signalling Pathway

Abstract INTRODUCTION Granule cell dispersion (GCD) is pathognomonic of hippocampal sclerosis seen in mesial temporal lobe epilepsy (MTLE). Current animal studies associate GCD to deficiency of Reelin, an extracellular matrix protein. The present study evaluated complete Reelin signalling pathway in MTLE in human tissue hippocampus and anterior temporal lobe (ATL). ATL was included, as ATL resection along with amygdalo-hippocampectomy results in better disease control. METHODS Hematoxylin and Eosin (H&amp;E) staining was done to identify the MTLE. Gene expression profiles of Reelin and its receptors (very low density lipoprotein-VLDLR and Apolipoprotein E 2-ApoER2), its downstream molecule Disabled 1 (Dab1) and its upstream inhibitor tissue inhibitor of metalloproteinases-1 (TIMP-1) were compared in normal and epileptic human tissue. Quantitative real-time PCR was done to determine the gene expression in the hippocampus and ATL. Western blotting was done to quantify the protein expression. Ethical clearance was taken from the Institute Ethical committee. RESULTS Typical features of MTLE were seen histologically. Width of granule cell layer was found to be broadened than normal controls. The expression of Reelin was found to be in same order to that of control. But its expression has been reduced as compared to the other genes. Reactive increase in the expression of both receptors was found. In hippocampus increase was more for ApoER2 while in ATL VLDLR showed increased expression. Similarly increased expression of Dab1 was seen, more in the hippocampus. Significantly increased expression was found in TIMP-1. CONCLUSION Data suggests a causative role of Reelin deficiency in MTLE. The increase in TIMP-1 would inhibit the Reelin cleavage, leading to deficiency of active Reelin. Downstream components of the Reelin show reactive increase. Reelin deficiency in ATL validates the surgical significance of ATL resection. Establishing a causative role of Reelin in MTLE in human tissue might have significant therapeutic potential.

Combined effect of shortened photoperiod and low crude protein diet on liver triglyceride accumulation and lipid-related gene expression in quail

A short photoperiod is reported to promote body weight gain in quail, and might therefore influence lipid metabolism and induce liver steatosis. Protein deficiency or malnutrition can also cause hepatic steatosis in mammals, but the effect in birds has not previously been investigated. In order to determine the influence of a shortened photoperiod and low crude protein diet on avian hepatic lipid metabolism, 10-day-old male Japanese quail (Coturnix coturnix japonica) were assigned to a 2 × 2 factorial arrangement of treatments in four groups, each of eight birds, and fed for three days, after which liver triglyceride (TG) accumulation and lipid-related gene expression were measured. Experimental factors included two dietary protein levels of 24% or 10% crude protein (CP), and two photoperiod conditions of a 12:12 h light/dark cycle (12L:12D) or a 1:23 h light/dark cycle (1L:23D). The liver TG level in quail fed the 10% CP diet under 1L:23D was higher than in birds maintained on either the 10% CP diet under 12L:12D (15.86 vs. 10.56 mg/g liver, P < 0.01) or 24% CP diet under 1L:23D (7.95 mg/g liver, P < 0.01). The sterol regulatory element-binding protein 1 mRNA, which is involved in TG synthesis, was more highly expressed in quail on the 10% CP diet under 1L:23D than in those maintained on the 24% CP diet under 12L:12D (2.2 vs. 7.9, P < 0.01), whereas the mRNA level of very low-density apolipoprotein II (apoVLDLII), which encodes a VLDL structural protein, was lower (157.3 vs. 12.5, P < 0.01). To our knowledge, this is the first report of a selective protein restriction and shorter photoperiod, alone and in combination, inducing a fatty liver state in an avian species. Our study provides insight into factors that govern lipid metabolism in birds, and the efficiency of domestic fowl production.

Differential Effects of Estrogen and Progestin on Apolipoprotein B100 and B48 Kinetics in Postmenopausal Women.

The distinct effects of the estrogen and progestin components of hormonal therapy on the metabolism of apolipoprotein (apo) B-containing lipoproteins have not been studied. We enrolled eight healthy postmenopausal women in a placebo-controlled, randomized, double-blind crossover study. Each subject received placebo, conjugated equine estrogen (CEE, 0.625 mg/day) and CEE plus medroxyprogesterone acetate (MPA, 2.5 mg/day) for 8 weeks in a randomized order, with a 4-week washout between phases. Main outcomes were the fractional catabolic rate (FCR) and production rate (PR) of apo B100 in triglyceride-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low -density lipoprotein (LDL) and of apo B48 in TRL. Compared to placebo, CEE increased TRL apo B100 PR (p = 0.04). CEE also increased LDL apo B100 FCR (p = 0.02), but this effect was offset by a significant increase in LDL apo B100 PR (p = 0.04). Adding MPA to CEE negated the CEE effects resulting in no significant changes in TRL apo B100 PR and LDL apo B100 FCR and PR relative to placebo. Relative to placebo, during CEE there was a trend toward a reduction in plasma apo B48 concentrations and PR (p = 0.07 and p = 0.12, respectively). Compared with CEE, CEE + MPA significantly increased TRL apo B48 FCR (p = 0.02) as well as apo B48 PR (p = 0.01), resulting in no significant changes in apo B48 concentration. Estrogen and progestin have independent and opposing effects on the metabolism of the atherogenic apo B100- and apo B48-containing lipoproteins.

RETRACTED ARTICLE: Increased Aβ42-α7-like nicotinic acetylcholine receptor complex level in lymphocytes is associated with apolipoprotein E4-driven Alzheimer’s disease pathogenesis

BackgroundThe apolipoprotein E ε4 (APOE4) genotype is a prominent late-onset Alzheimer’s disease (AD) risk factor. ApoE4 disrupts memory function in rodents and may contribute to both plaque and tangle formation.MethodsCoimmunoprecipitation and Western blot detection were used to determine: 1) the effects of select fragments from the apoE low-density lipoprotein (LDL) binding domain and recombinant apoE subtypes on amyloid beta (Aβ)42-α7 nicotinic acetylcholine receptor (α7nAChR) interaction and tau phosphorylation in rodent brain synaptosomes; and 2) the level of Aβ42-α7nAChR complexes in matched controls and patients with mild cognitive impairment (MCI) and dementia due to AD with known APOE genotypes.ResultsIn an ex vivo study using rodent synaptosomes, apoE141–148 of the apoE promotes Aβ42-α7nAChR association and Aβ42-induced α7nAChR-dependent tau phosphorylation. In a single-blind study, we examined lymphocytes isolated from control subjects, patients with MCI and dementia due to AD with known APOE genotypes, sampled at two time points (1 year apart). APOE ε4 genotype was closely correlated with heightened Aβ42-α7nAChR complex levels and with blunted exogenous Aβ42 effects in lymphocytes derived from AD and MCI due to AD cases. Similarly, plasma from APOE ε4 carriers enhanced the Aβ42-induced Aβ42-α7nAChR association in rat cortical synaptosomes. The progression of cognitive decline in APOE ε4 carriers correlated with higher levels of Aβ42-α7nAChR complexes in lymphocytes and greater enhancement by their plasma of Aβ42-induced Aβ42-α7nAChR association in rat cortical synaptosomes.ConclusionsOur data suggest that increased lymphocyte Aβ42-α7nAChR-like complexes may indicate the presence of AD pathology especially in APOE ε4 carriers. We show that apoE, especially apoE4, promotes Aβ42-α7nAChR interaction and Aβ42-induced α7nAChR-dependent tau phosphorylation via its apoE141–148 domain. These apoE-mediated effects may contribute to the APOE ε4-driven neurodysfunction and AD pathologies.

Multifunctional LUV liposomes decorated for BBB and amyloid targeting - B. In vivo brain targeting potential in wild-type and APP/PS1 mice

Multifunctional liposomes (mf-LIPs) having a curcumin-lipid ligand (to target amyloids) together with two ligands to target the transferrin, and the low-density apolipoprotein receptor of the blood-brain-barrier (BBB) on their surface, were previously studied (in vitro) as potential theranostic systems for Alzheimer's disease (AD) (Papadia et al., 2017, Eur. J. Pharm. Sciences; 101:140–148). Herein, the targeting potential of mf-LIPs was compared to that of BBB-LIPs (liposomes having only the two BBB-specific ligands) in FVB mice (normal), as well as in double transgenic mice (APP/PS1) and their corresponding littermates (WT), by live-animal (in vivo) and explanted organ (ex vivo) imaging. In FVB mice, the head-signals of mf-LIPs and BBB-LIPs are either similar, or signals from mf-LIP are higher, suggesting that the co-presence of the curcumin derivative on the liposome surface does not disturb the functionality of the BBB-specific ligands. Higher brain/liver+spleen ratios (ex vivo) were calculated post-injection of mf-LIP, compared to those found after BBB-LIP injection, due to the reduced distribution of mf-LIPs in the liver and spleen; showing that the curcumin ligand increases the stealth properties of liposomes by reducing their uptake by liver and spleen. The later effect is more pronounced when the density of the BBB-specific ligands on the mf-LIPs is 0.1mol%, compared to 0.2%, highlighting the importance of this parameter. When a high lipid dose (4mg/mouse) is injected in WT and APP/PS1 mice, the head-signals of mf-LIPs are significantly higher than those of BBB-LIPs, but no differences are observed between WT and APP/PS1 mice. However, after administration of a low liposome dose (0.05mg/mouse) of mf-LIPs, significant differences in the head-signals are found between WT and transgenic mice, highlighting the AD theranostic potential of the multifunctional liposomes, as well as the importance of the experimental parameters used in such in vivo screening studies.

Correlation of soluble thrombomodulin and high sensitive C reactive protein with hypercoagulability in children with primary nephrotic syndrome

Objective To explore the correlations of soluble thrombomodulin(sTM) and high sensitive C reactive protein(hs-CRP) levels with the hypercoagulable state and indicators of predicting thrombosis in children with primary nephrotic syndrome(PNS). Methods Sixty-four PNS patients who had primary clinical diagnosis or recurrence after hormone withdrawal for 6 months or more hospitalized in Department of Urology, the Second Children′s Hospital of Tianjin from January 2010 to January 2014 were selected as PNS group.Thirty patients with inguinal hernia undergoing elective surgery hospitalized in Department of Surgery, the Second Children′s Hospital of Tianjin from January 2010 to January 2014 were selected as control group.All the selected patients were extracted for venous blood samples, and the double-antibody sandwich enzyme-linked immunosorbent assay was used to detect plasma sTM levels, while immunoturbidimetric assay was used to detect plasma hs-CRP levels; the indicators of predicting thrombosis as blood lipid and fibrinogen(Fb)etc.were simultaneously detected.Inspection results were compared and the correlation was analyzed by using statistical methods. Results The level of plasma sTM in children with PNS was significantly higher than that in the control group[(1.63±0.68) μg/L vs.(0.30±0.24) μg/L], and the difference was statistically significant between the 2 groups(t=12.545, P<0.05). The level of plasma sTM in PNS group with urine protein negative was significantly lower than that before hormone treatment[(1.05±0.56) μg/L vs.(1.63±0.68) μg/L], and there was a statistically significant difference(t=6.298, P<0.05). The level of plasma sTM in children with PNS had positive correlation with 24 h urinary protein, low density lipoprotein, apolipoprotein B, lipoprotein a and Fb(r=0.379, 0.203, 0.184, 0.177, 0.224, all P<0.05). The level of plasma hs-CRP in children with PNS was significantly higher than that in the control group[(1.9±1.7) mg/L vs.(0.7±0.6) mg/L], and the difference was statistically significant between the 2 groups(t=3.487, P<0.05). In PNS group, the level of plasma hs-CRP with urine protein negative was significantly lower than that before hormone treatment[(0.4±0.3) mg/L vs.(1.9±1.7) mg/L], and there was a statistically significant difference(t=5.473, P<0.05). The level of plasma hs-CRP in children with PNS was negatively correlated with plasma albumin(r=-0.194, P<0.05), but positively correlated with Fb(r=0.257, P<0.01). Plasma sTM and hs-CRP levels in children with PNS were positively correlated(r=0.395, P<0.05). Conclusions sTM involves in the formation process of PNS hypercoagulable state possibly through dual influencing by blood coagulation process and blood lipids.sTM may be used as one of the reference indicators for PNS activity and prediction of thrombosis.Plasma hs-CRP reflects the micro-inflammatory state in children with PNS, and involves in the formation of hypercoagulability by effecting blood coagulation process, and should be used as indicators for monitoring the hypercoagulability of active PNS. Key words: Nephrotic syndrome, primary; Thrombomodulin; High sensitivity C reactive protein; Child

LIPID PROFILE AND GENETIC MARKERS ASSOCIATED WITH THE LEVEL OF OXIDIzED LOW DENSITY LIPOPROTEIDES

Aim. To assess biochemical and genetic markers associated with the level of oxidized low density lipoproteides (oxLDL). Material and methods. Patients with various cardiovascular risk according to the SCORE scale were included in this study. Biochemical parameters were measured in blood serum with automatic analyzer Architect C8000 (Abbott, USA). OxLDL level was measured with the hard-phase immune-enzyme assay Oxidized LDL ELIsA (Mercodia, sweden). Genotyping was performed via the Cardio-MetaboChip microarrays (Illumina, USA). Seventeen single-nucleotide polymorphisms (SNP) of the APOB gene were included into analysis: rs676210, rs1042034, rs6728178, rs6754295, rs673548, rs6711016, rs11902417, rs10184054, rs6544366, rs4564803, rs7557067, rs2678379, rs533617, rs679899, rs1801695, rs1367117, rs1042031. The association study between SNP and oxLDL level was performed by the ROC-analysis. Based on results, the group of SNP was selected. According to this group, the total SCORE (TS) showing the level of genetic susceptibility to an increased oxLDL level was calculated. Results. The present study included 717 patients ranging from 28 to 84 years old (with the median of 57), 204 men (28.45%). The oxLDL level varied from 21,03 to 163,72 U/dL (median 68,5) and correlated with the levels of total cholesterol (TC), triglycerides (TG), low density cholesterol (LDL-C), C-reactive protein (C-RP) and apolipoprotein B-100 (ApoB-100). The highest coefficients of correlations (p 3 (p<10 ),and the patients with the same LDL-C level by 5 units, respectively (p<10 ). Conclusion. The oxLDL level depends on the level of LDL-C and ApoB-100 in blood, as well as on the genetic susceptibility — a combination of the SNP of APOB gene.

The blood lipid status study of the healthy check-up crowd in the People's Hospital of Gaoqing county, Shandong province

Objective To know the blood lipid status and its influencing factors of the healthy check-up crowd in the People's Hospital of Gaoqing County, Shandong, and to provide theoretical basis for a healthy lifestyle. Methods 367 cases for medical health examination were collected as the study subjects from September 2013 to August 2015 in our hospital.The concentrations of total cholesterol(TC), triglyceride(TG), high-density lipoprotein cholesterol(HDL-C), low density lipoprotein cholesterol(LDL-C), apolipoprotein A(ApoA) and apolipoprotein B(ApoB) in serum of the study subjects were detected with automatic biochemical analyzer.And then, the study subjects were grouped according to the age, gender and the possible risk factors.The results were analyzed. Results The concentrations of TC, TG, HDL-C, LDL-C and ApoB had increasing trends with age(F=48.121, 51.343, 46.873, 47.342, 12.865, 53.012, all P<0.05). The levels of TC, HDL-C and ApoA in serum of women were significantly higher than those in men(t=2.143, 1.669, 0.979, all P<0.05). The levels of TC, HDL-C and ApoA in serum of knowledge workers were significantly higher than the manual workers(t=2.143, P<0.05). TC, TG, LDL-C and ApoB had the trends of increase gradually with the increase of the body mass index(BMI)(F=3.142, 7.355, 6.622, 5.012, all P<0.05). HDL-C and ApoA had the trends of reduce gradually with the increase of the BMI(F=4.379, 73.865, all P<0.05). Conclusion There is hyperliplidemia conditions in the health check-up crowd in the People's Hospital of Gaoqing County, especially in the elderly, women, mental workers, and the high BMI should be pay more attention. Key words: Dyslipidemias; Health surveys; Risk factors

Abstract 545: Differential mRNA Expression is Influenced by Apolipoprotein A-I in Order to Promote Foam Cell Regression

Atherosclerosis is a disease of both lipids and inflammatory immune cells. More specifically, elevated plasma levels of low-density lipoproteins (LDL) leads to migration of circulating monocytes into the artery wall. Lipid loaded monocyte cells subsequently proliferate in the arterial walls becoming macrophage foam cells; a hallmark of atherosclerotic lesions. A proposed mechanism of the protective effects of high-density lipoprotein (HDL) is apolipoprotein A-I (apo A-I) acting as a mediator of cholesterol efflux and subsequent foam cell regression. To better understand the biological changes stimulated by apo A-I treatment, differential expression analysis of microarray data was performed on spleen cells from apo A-I treated mice. LDL receptor null (LDLr -/- ) and LDL receptor and apo A-I null (LDLr -/- , apoA-I -/- ) mice were fed a western diet consisting of 0.2% cholesterol and 42% of calories as fat for 12 weeks. After 6 weeks of diet, a subset of mice for each genotype was subcutaneously injected with 200 micrograms of apo A-I 3 times a week for the remaining 6 weeks. The control group mice were subcutaneously injected with 200 micrograms of saline or BSA. Spleen cell RNA was isolated, purified, and analyzed for differential expression analysis using Illumina BeadArray Microarray Technology Analysis. Individual gene expression analysis for LDLr -/- , apoA-I -/- apo A-I treated mice showed 281 significantly differentially expressed genes compared to BSA treated mice. LDLr -/- A-I treated mice had 1502. Of the significant genes, 189 intersected across both genotypes. LDLr -/- , apoA-I -/- A-I mice showed 73 up-regulated and 116 down-regulated genes. Similarly, LDLr -/- A-I mice had 71 up-regulated and 118 down-regulated. One-directional Gene Set Enrichment Analysis (GSEA) of LDLr -/- , apoA-I -/- A-I mice revealed 49 significant pathways while a total of 63 were found for LDLr -/- . Of these pathways, 21 were up-regulated and 13 were down-regulated in both genotypes. Eight of the top 10 most significant up-regulated pathways in both genotypes were immune cell related. Their functions involve receptor, adhesion, and chemokine signaling. Overall, preliminary analysis suggests A-I treatment induces similar gene expression changes across different genotypes.

Estrogen stimulates expression of chicken hepatic vitellogenin II and very low-density apolipoprotein II through ER-α

Steroid hormones and their receptors play pivotal roles throughout vertebrate reproduction and development. Egg formation in avian species is a prime example. The synthesis of egg yolk proteins by the liver is highly dependent on estrogen. Two major components of the yolk protein precursors, vitellogenin II (VTG II) and very low-density apolipoprotein II (ApoVLDL II), are synthesized in the liver of hens under estrogen stimulation and are subsequently transferred via the blood to the developing oocytes. Estrogen-inducible transcription can be mediated through estrogen receptors (ERs) (ER-α and ER-β) or through G protein–coupled receptor 30 (GPR30), but the exact participation of the individual receptor is not clear. Here, we determine the relative contribution of each transduction pathway in the synthesis of VTG II and ApoVLDL II in the hepatocytes by using selective compounds that are known to specifically interact with each of the ERs and GPR30. 17β-Estradiol and propyl pyrazole triol (PPT, ER-α agonist) induced increase in VTG II and ApoVLDL II mRNA expressions in a dose-dependent manner. A high concentration of diarylpropionitrile (DPN, which preferentially motivates ER-β) slightly stimulated the expression of VTG II and ApoVLDL II mRNAs. However, G-1 (a GPR30 agonist) failed to display any stimulating role. Methyl-piperidino-pyrazole (a highly selective ER-α antagonist) fully blocked the expression of both yolk precursors, which were upregulated by 17β-estradiol, PPT, and DPN. Considering that DPN can also provoke the action of ER-α at high concentration, this excludes the participation of ER-β and supports the role of ER-α. The aforementioned results indicate that estrogen stimulates the expression of VTG II and ApoVLDL II mRNAs predominantly through ER-α in the chicken liver.

Effects of gonadotropin-releasing hormone analog treatment on glucose and lipid metabolism in girls with idiopathic central precocious puberty

Objective To assess the effects of gonadotropin-releasing hormone analog on glucose and lipid metabolism in girls with idiopathic central precocious puberty(ICPP). Methods A total of 26 girls(aged 6-8 years, breast stage B2) with ICPP were followed up in Department of Endocrinology, Shenzhen Children's Hospital from Jan. 2008 to Jun. 2011. Those girls received triptorelin therapy for 12 months. Before and the end of the 6th month, the 12th month of the treatment, body mass index(BMI) was calculated, fasting plasma glucose(FPG), fasting plasma insulin(FPI), total cholesterol, triacylglycerols, high density lipoprotein cholesterol, low density lipoprotein cholesterol, apolipoprotein A, apolipoprotein B and estradiol(E2) were measured. Insulin sensitivity was estimated by homeostasis model assessment of insulin resistance(HOMA-IR). Twenty age-matched prepuberty girls were set as controls. Results 1. Before treatment, BMI, FPG, FPI and HOMA-IR in ICPP girls had no significant difference compared with the controls.2. After 6 months treatment of triptrolin, serum E2 concentration in ICPP girls declined from(30.5±9.8) ng/L at the beginning of treatment to(11.2±4.6) ng/L at the end of 6th month(P<0.01); The end of 12th month of the treatment, FPG and FPI had no significant difference compared with that before of the treatment, but BMI increased from(16.46±1.10) kg/m2 to(18.35±1.30) kg/m2, the difference was significant(P<0.05), HOMA-IR increased from 1.24±0.30 to 2.08±0.40, the difference was significant(P<0.05).3. Lipid metabolism parameters remained unchangeable after 12 months of triptrolin treatment. Conclusion Triptorelin may lead to raise of BMI and HOMA-IR in girls with ICPP at 12 months after treatment. Key words: Idiopathic central precocious puberty; Gonadotropin-releasing hormone analog; Body mass index; Insulin resistance

Expression of Type IIA Secretory Phospholipase A 2 Inhibits Cholesteryl Ester Transfer Protein Activity in Transgenic Mice

High circulating levels of group IIA secretory phospholipase A2 (sPLA2-IIA) activity and mass are independent cardiovascular risk factors. Therefore, inhibition of sPLA2-IIA may be a target for the treatment of atherosclerotic cardiovascular disease. The present study evaluated the effects of sPLA2-IIA inhibition with varespladib acid in a novel mouse model, human apolipoprotein B (apoB)/human cholesteryl ester transfer protein (CETP)/human sPLA2-IIA triple transgenic mice (TTT) fed a Western-type diet. sPLA2-IIA expression increased atherosclerotic lesion formation in TTT compared with human apoB/human CETP double transgenic mice (P<0.01). Varespladib acid effectively inhibited plasma sPLA2-IIA activity. Surprisingly, however, administration of varespladib acid to TTT had no impact on atherosclerosis, which could be attributed to a proatherogenic plasma lipoprotein profile that appears in response to sPLA2-IIA inhibition because of increased plasma CETP activity. In the TTT model, sPLA2-IIA decreased CETP activity by reducing the acceptor properties of sPLA2-IIA-modified very low-density lipoproteins specifically because of a significantly lower apoE content. Increasing very low-density lipoprotein-apoE content by means of adenovirus-mediated gene transfer in sPLA2-IIA transgenic mice restored the acceptor properties for CETP. These data show that in a humanized triple transgenic mouse model with hypercholesterolemia, sPLA2-IIA inhibition increases CETP activity via increasing the very low-density lipoprotein-apoE content, resulting in a proatherogenic lipoprotein profile.

Administration of hydrogen-saturated saline decreases plasma low-density lipoprotein cholesterol levels and improves high-density lipoprotein function in high-fat diet–fed hamsters

Hydrogen (dihydrogen; H2) has an antiatherosclerotic effect in apolipoprotein (apo) E knockout mice. The goals of this study were to further characterize the effects of H2 on the content, composition, and biological activities of plasma lipoproteins in golden hamsters. Plasma analysis by enzymatic method and fast protein liquid chromatography showed that 4-week intraperitoneal injection of hydrogen-saturated saline remarkably decreased plasma total cholesterol and low-density lipoprotein (LDL) cholesterol levels in high-fat diet–fed hamsters. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of apolipoproteins from ultracentrifugally isolated plasma lipoproteins revealed a marked decrease of apo B100 and apo B48 in LDL. A profound decrease of apo E level in very low-density lipoprotein was also observed. Besides, we determined the functional quality of high-density lipoprotein (HDL) particles isolated from H2-treated and control mice. H2 significantly improved HDL functionality assessed in 2 independent ways, namely, (1) stimulation of cholesterol efflux from macrophage foam cells by measuring HDL-induced [3H]cholesterol efflux and (2) protection against LDL oxidation as a measure of Cu2+-induced thiobarbituric acid reactive substances formation. Administration of hydrogen-saturated saline decreases plasma LDL cholesterol and apo B levels and improves hyperlipidemia-injured HDL functions, including the capacity of enhancing cellular cholesterol efflux and playing antioxidative properties, in high-fat diet–fed hamsters.

Hepatic Deficiency of Low Density Lipoprotein Receptor-related Protein-1 Reduces High Density Lipoprotein Secretion and Plasma Levels in Mice

The low density lipoprotein receptor-related protein-1 (LRP1) is known to serve as a chylomicron remnant receptor in the liver responsible for the binding and plasma clearance of apolipoprotein E-containing lipoproteins. Previous in vitro studies have provided evidence to suggest that LRP1 expression may also influence high density lipoprotein (HDL) metabolism. The current study showed that liver-specific LRP1 knock-out (hLrp1(-/-)) mice displayed lower fasting plasma HDL cholesterol levels when compared with hLrp1(+/+) mice. Lecithin:cholesterol acyl transferase and hepatic lipase activities in plasma of hLrp1(-/-) mice were comparable with those observed in hLrp1(+/+) mice, indicating that hepatic LRP1 inactivation does not influence plasma HDL remodeling. Plasma clearance of HDL particles and HDL-associated cholesteryl esters was also similar between hLrp1(+/+) and hLrp1(-/-) mice. In contrast, HDL secretion from primary hepatocytes isolated from hLrp1(-/-) mice was significantly reduced when compared with that observed with hLrp1(+/+) hepatocytes. Biotinylation of cell surface proteins revealed decreased surface localization of the ATP-binding cassette, subfamily A, member 1 (ABCA1) protein, but total cellular ABCA1 level was not changed in hLrp1(-/-) hepatocytes. Finally, hLrp1(-/-) hepatocytes displayed reduced binding capacity for extracellular cathepsin D, resulting in lower intracellular cathepsin D content and impairment of prosaposin activation, a process that is required for membrane translocation of ABCA1 to facilitate cholesterol efflux and HDL secretion. Taken together, these results documented that hepatic LRP1 participates in cellular activation of lysosomal enzymes and through this mechanism, indirectly modulates the production and plasma levels of HDL.

All-trans retinoic acid regulates the expression of apolipoprotein E in rats with glomerulosclerosis induced by Adriamycin

Apolipoprotein E (apoE) is an important plasma protein in cholesterol homeostasis and plays a key role in the progression of glomerulosclerosis (GS). We conducted this investigation to explore whether all-trans retinoic acid (ATRA) could regulate the apoE expression in the pathological process of GS. 120 Wistar rats were divided into three groups at random: sham operation group (SHO), glomerulosclerosis model group without treatment (GS), GS model group treated with ATRA (GA); n = 40, respectively. The disease of GS in rat was established by uninephrectomy and adriamycin (5 mg/kg) injection. At the end of 9 and 13 weeks, 20 rats in each group were killed and the relevant samples were collected. 24-hour urine total protein (24UTP), 24-hour urine excretion for albumin (24Ualb), serum total protein (TP) and serum albumin (Alb), blood urea nitrogen (BUN), serum creatinine (Scr), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), serum and urine apoE and glomerulosclerosis index (GSI) were measured. The protein expressions of collagen IV (Col-IV), fibronectin (FN) and apoE in glomeruli were determined by immunohistochemistry. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was used to detect the expression of apoE mRNA in kidney. TP and Alb in GA group in 9/13-week were increased than those of GS group, however, the differences were not statistically significant. Compared with group GS at 9/13 weeks, values of 24UTP, 24Ualb, BUN, Scr, TC, TG, HDL, LDL, serum and urine apoE, and GSI in GA group that were significantly reduced, and protein expressions of Col-IV, FN and apoE in glomeruli and expression of apoE mRNA in renal tissue were significantly down-regulated by ATRA ( P < 0.01). In conclusion, ATRA can regulate the expression of apoE, reduce the accumulation of extracellular matrix (ECM) and step down the progression of GS.