Scavenger Receptor Class B Type 1 Research Articles

PAR4 Inhibition Reduces Coronary Artery Atherosclerosis and Myocardial Fibrosis in SR-B1/LDLR Double Knockout Mice.

SR-B1 (scavenger receptor class B type 1)/LDLR (low-density lipoprotein receptor) double knockout mice fed a high-fat, high-cholesterol diet containing cholate exhibit coronary artery disease characterized by occlusive coronary artery atherosclerosis, platelet accumulation in coronary arteries, and myocardial fibrosis. Platelets are involved in atherosclerosis development, and PAR (protease-activated receptor) 4 has a prominent role in platelet function in mice. However, the role of PAR4 on coronary artery disease in mice has not been tested. We tested the effects of a PAR4 inhibitory pepducin (RAG8) on diet-induced aortic sinus and coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis in SR-B1/LDLR double knockout mice. SR-B1/LDLR double knockout mice were fed a high-fat, high-cholesterol diet containing cholate and injected daily with 20 mg/kg of either the RAG8 pepducin or a control reverse-sequence pepducin (SRQ8) for 20 days. Platelets from the RAG8-treated mice exhibited reduced thrombin and PAR4 agonist peptide-mediated activation compared with those from control SRQ8-treated mice when tested ex vivo. Although aortic sinus atherosclerosis levels did not differ, RAG8-treated mice exhibited reduced coronary artery atherosclerosis, reduced platelet accumulation in atherosclerotic coronary arteries, and reduced myocardial fibrosis. These protective effects were not accompanied by changes in circulating lipids, inflammatory cytokines, or immune cells. However, RAG8-treated mice exhibited reduced VCAM-1 (vascular cell adhesion molecule 1) protein levels in nonatherosclerotic coronary artery cross sections and reduced leukocyte accumulation in atherosclerotic coronary artery cross sections compared with those from SRQ8-treated mice. The PAR4 inhibitory RAG8 pepducin reduced coronary artery atherosclerosis and myocardial fibrosis in SR-B1/LDLR double knockout mice fed a high-fat, high-cholesterol diet containing cholate. Furthermore, RAG8 reduced VCAM-1 in nonatherosclerotic coronary arteries and reduced leukocyte and platelet accumulation in atherosclerotic coronary arteries. These findings identify PAR4 as an attractive target in reducing coronary artery disease development, and the use of RAG8 may potentially be beneficial in cardiovascular disease.

Association of cluster determinant 36, scavenger receptor class B type 1, and major facilitator superfamily domain containing the 2a genetic polymorphism with serum lipid profile in aging population with type 2 diabetes mellitus.

BackgroundLipid metabolism disorder commonly happens in subjects with Type 2 diabetes mellitus (T2DM) which may be linked to genetic variants of lipid metabolism-related genes. However, few studies have explored the relationship between lipid metabolism-related gene polymorphism and serum lipid profile in aging subjects with T2DM. The present study was designed to explore the impact of genetic polymorphism of cluster determinant 36 (CD36) (rs1049673, rs1054516, rs2151916), scavenger receptor class B type 1 (SCARB1) (rs5888), and major facilitator superfamily domain containing the 2a (MFSD2A) (rs12083239, rs4233508, rs12072037) on the relationship between circulating lipids in aging subjects with T2DM.Methods205 T2DM patients and 205 age and gender matched control subjects were recruited. Information on demographic characteristics was collected by using a self-administered questionnaire. Fasting venous blood samples were taken for lipid-related gene genotyping and serum lipid profile measurement. The Chi-square test was used to compare percentage differences and to calculate P-value for Hardy-Weinberg equilibrium. Logistic regression and multiple linear regression were used to explore the risk or correlation between variables, and general linear model (GLM) was used to compare the means of serum lipids between the groups.ResultsIn T2DM group, CD36 rs1054516 and MFSD2A rs12072037 were correlated with serum TC level. In control group, CD36 rs1049673 was correlated with serum HDL-C level. Meanwhile, T2DM subjects with MFSD2A rs12083239 (CG), MFSD2A rs4233508 (TT), and MFSD2A rs12072037 (AA) had higher TG level than control subjects. T2DM subjects with CD36 rs1049673 (CG, GG), CD36 rs1054516 (CT), CD36 rs2151916 (TT, CT), SCARB1 rs5888 (GG), MFSD2A rs12083239 (GG, CG), MFSD2A rs4233508 (TT), and MFSD2A rs12072037 (CA, AA) had lower HDL-C level than control subjects. T2DM subjects with MFSD2A rs12072037 (AA) had lower LDL-C level than control subjects. In dominant model, major genotype (GG) of SCARB1 gene was associated with the risk of T2DM (OR = 0.636, P = 0.032).ConclusionThe genetic polymorphism of CD36 (rs1049673, rs1054516, rs2151916), SCARB1 (rs5888), and MFSD2A (rs12083239, rs4233508, rs12072037) were associated with serum lipids in T2DM subjects. The SCARB1 rs5888 major genotype (GG) was a protective factor for T2DM. Large scale cohort study is required to determine the relationship between lipid metabolism-related gene polymorphism, serum lipid profile and T2DM in aging subjects.

Abstract 375: SR-B1-targeted nanoparticle delivery of novel anthracyclines to Ewing's Tumors

Abstract Purpose: Anthracyclines effectively treat many pediatric cancers, but their use is limited by cardiotoxicity and new approaches to mitigate anthracycline-induced cardiac damage are urgently needed. Nanoparticle drug delivery is one solution to maintain anticancer efficacy while mitigating both acute and long-term cardiac complications. Additionally, novel treatments are needed to improve cure rates in certain cancer diagnoses that have not seen advancements in decades, particularly Ewing Sarcoma (EWS). Experimental Design: We investigated the use of a self-assembling micelle structure composed of myristic acid conjugated to an Apo-A1 mimetic 5A peptide, termed Myr5A nanoparticles (Myr5A NPs). These nanoparticles are transported into cells via the cholesterol scavenger receptor class B type-1 (SR-B1). Doxorubicin (DOX) and the Myr5A NP cannot form a stable micelle due to the hydrophilic nature of DOX, which results in preferential binding to the peptide shell, as opposed to the hydrophobic core. To favor micelle stability, we opted to use the novel, highly hydrophobic anthracyclines valrubicin and AD198 to test the nanoparticle delivery system. The potency of these anthracyclines encapsulated in Myr5A NPs were evaluated in human EWS cell lines with high and low SR-B1 expression via MTT assay. Additionally, 5 mg/kg intraperitoneal injections were administered weekly to 4-week-old wild type C57BL6/J mice and immune compromised homozygous null forkhead box N1 mice (Foxn1null/null mice) over 5 weeks, to assess by echocardiography, acute and long-term cardiac dysfunction. Results: Treatment with Myr5A-encapsulated AD198 and Myr5A-encapsulated valrubicin significantly inhibited EWS cell proliferation at concentrations comparable to conventional anthracyclines. Moreover, compared to unencapsulated valrubicin and AD198, encapsulation resulted in a lower IC50 in EWS lines with higher SR-B1 surface expression. By 19 weeks of age, DOX-treated C57BL6/J mice exhibited significantly decreased ejection fraction (EF) compared to PBS control and Myr5A-encapsulated anthracyclines (p<0.05). Additionally, an increase in Left Ventricular Mass (LVM) was observed in all groups except DOX by 19 weeks (p<0.05). Lastly, DOX-treated Foxn1null/null mice showed diminished survival rate compared to all treatment groups, and similar results to C57BL6/J mice in EF and LVM. Conclusions: Our results indicate that AD198 and valrubicin, when encapsulated in Myr5A NPs, induce minimal cardiac dysfunction while maintaining antitumor efficacy in EWS tumors. Myr5A NP drug delivery may be a viable option for the treatment of high SR-B1 expressing tumors with a decreased risk of acute and long-term cardiac complications. Future studies will evaluate the drug potency in non-cancer cell lines, such as cardiac fibroblasts and myocytes, and the effects of Myr5A-encaspulated anthracyclines on EWS xenografts and other pediatric tumors. Citation Format: Kathryn Crouch, Logan Davis, Nirupama Sabnis, Alexander Pertsemlidis, Laura Rutledge, James Graham, Jason Yustein, Gregory J. Aune. SR-B1-targeted nanoparticle delivery of novel anthracyclines to Ewing's Tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 375.

Characterization and functional analysis of BmSR-B1 for phytosterol uptake

Insects cannot synthesize sterols, such as cholesterol, and require sterols in their diet. Phytophagous insects use dietary phytosterols as a source of cholesterol. Sterols are transported from the midgut by the insect lipoprotein, lipophorin (Lp), although mechanisms for uptake of phytosterols into tissues are unclear. This study characterizes Scavenger Receptor class B type1 (SR-B1) from Bombyx mori (BmSR-B1) as molecules related to phytosterol uptake. According to sterol quantification using LC-MS/MS analysis, the midgut and fat body were phytosterol-rich relative to cholesterol-rich brain and prothoracic glands. Gene expression analysis of Bmsr-b1 in silkworm tissues showed that the genes Bmsr-b1_2, 3, 4, 6, and 10 were expressed in the midgut and fat body. To characterize the function of BmSR-B1, 11 BmSR-B1 homologs expressed in Bombyx ovary-derived BmN cells and Drosophila melanogaster embryo-derived Schneider 2 (S2) cells were incubated with purified Lp. Our analysis showed that BmSR-B1_3 induced the accumulation of campesterol and BmSR-B1_4 induced the accumulation of β-sitosterol and campesterol in culture cells. BmSR-B1 incorporated specific phytosterols into insect cells by selective uptake across the cell membrane where BmSR-B1 was localized. In conclusion, our study demonstrated that one function of BmSR-B1 is the uptake of phytosterols into silkworm tissues.

A Tale of Two Scavenger Receptors: Structure‐Function Relationships of Purified SR‐B1 and CD36

Both CD36 and SR‐B1 are glycosylated integral membrane proteins belonging to the class B scavenger receptor family and are known to play roles in cardiovascular and atherosclerotic disease. CD36 serves as the receptor for oxidized low density lipoprotein (oxLDL) and facilitates cholesterol accumulation in macrophages and development of atherosclerotic plaques. SR‐B1 (scavenger receptor class B type 1) is the primary receptor for high density lipoprotein (HDL), which removes cholesterol from the peripheral atherosclerotic plaques and delivers it to the liver for excretion. Current structural information about class B scavenger receptors is limited to only purified extracellular regions, transmembrane segments, or transient transfection studies in cultured cells, and remains a roadblock to studying the isolated functions of these lipid and cholesterol transporters. Recently, we have successfully expressed and purified full‐length human SR‐B1 and CD36 using an Sf9 insect cell/baculoviral infection system, which allows for the expression of glycosylated proteins. Purified full‐length receptors are a valuable addition to our scientific toolbox and allow us to ask novel questions about the structure‐function relationships of scavenger receptors. To verify function within Sf9 cell membranes, we expressed human full‐length constructs in plated Sf9 cells and observed significantly increased binding of DiI‐HDL and DiI‐oxLDL, as well as increased DiI‐lipid uptake when comparing SR‐B1 and CD36 to empty vector infected cells, respectively. When purified and solubilized in detergent micelles, both receptors remain stable over time as shown by Prometheus thermal shift assays. We have also demonstrated that purified proteins are able to bind to their native ligands (HDL to SR‐B1 and oxLDL to CD36) with high affinity by microscale thermophoresis (MST). However, as SR‐B1 and CD36 are both scavenger receptors, they are able to bind to a variety of lipoprotein ligands and we have demonstrated these interactions with varying binding affinities by MST. Glycosylation of both CD36 and SR‐B1 has been shown to be important for cell surface expression, but the role of glycosylation in ligand binding has remained uncharacterized. We are the first to demonstrate that the glycosylation status of CD36 and SR‐B1 does not alter binding affinities or protein stability. These purified receptors and functional assays provide promise for understanding the ways in which class B scavenger receptors perform their critical functions and lay the groundwork for future structure‐function studies.

Calcifediol During Pregnancy Improves Maternal and Fetal Availability of Vitamin D Compared to Vitamin D3 in Rats and Modifies Fetal Metabolism.

The fetus depends on the transplacental transfer of vitamin D. Calcifediol (25-OH-D3) is the vitamin D metabolite that crosses the placenta. Previously, oral 25-OH-D3 improved serum 25-OH-D3 compared to vitamin D3 in non-pregnant subjects, although no studies are available in pregnant women. We evaluated the availability of oral 25-OH-D3 compared to vitamin D3 during pregnancy, as well as, their levels in the fetus and effect on metabolism-related proteins. Twenty female rats per group were fed with 25 μg/kg of diet of vitamin D3 (1,000 UI vitamin D/kg diet) or with 25 μg/kg diet of 25-OH-D3. We analyzed 25-OH-D3 levels in maternal and fetal plasma; protein levels of vitamin D receptor (VDR), fatty acid translocase (FAT), and scavenger-receptor class B type-1 (SR-B1) in both maternal liver and placenta; and protein levels of VDR and Glutamate decarboxylase (GAD67) in fetal brain. 25-OH-D3 doubled the concentration of 25-OH-D3 in both maternal and fetal plasma compared to vitamin D3. In addition, maternal liver VDR, FAT, and SR-BI increased significantly in the 25-OH-D3 group, but no changes were found in the placenta. Interestingly, 25-OH-D3 decreased GAD67 expression in the fetal brain and it also tended to decrease VDR (P = 0.086). In conclusion, 25-OH-D3 provided better vitamin D availability for both mother and fetus when administered during pregnancy compared to vitamin D3. No adverse effects on pregnancy outcomes were observed. The effects of 25-OH-D3 on the expression of VDR and GAD67 in fetal brain require further investigation.

Circ_0003146 upregulates SCARB1 expression by acting as a miR-1272 sponge to promote malignant behaviors of clear cell renal cell carcinoma.

Circular RNAs (circRNAs) exhibit essential regulation in the malignant development of clear cell renal cell carcinoma (ccRCC). The aims of this study were to investigate the role and mechanism of circ_0003146 in the biologic behaviors of ccRCC. RNA level analysis was performed through reverse transcription-quantitative PCR assay. Cell proliferation was measured by EdU assay and cell counting kit-8 assay. The protein expression was analyzed using a western blot. Flow cytometry and caspase 3 activity assay were used to assess cell apoptosis. Cell migration and invasion were evaluated via wound healing assay and transwell assay. Circ_0003146 function in vivo was determined by xenograft tumor assay. Dual-luciferase reporter assay was applied for target relation analysis. Circ_0003146 upregulation was detected in ccRCC tissues and cells. Downregulation of circ_0003146 induced inhibition of proliferation, migration, invasion and EMT but the promotion of apoptosis in ccRCC cells. Tumor growth in vivo was inhibited after knockdown of circ_0003146. Circ_0003146 directly interacted with miR-1272, and the miR-1272 sponging effect was responsible for the function of circ_0003146. Scavenger receptor class B type 1 (SCARB1) was a target of miR-1272, and circ_0003146 regulated SCARB1 level by absorbing miR-1272. The regulation of circ_0003146 in ccRCC progression was achieved by upregulating SCARB1 in part. The current findings demonstrated that circ_0003146 contributed to the malignant progression of ccRCC via inducing SCARB1 upregulation by targeting miR-1272.

Expression Levels and Genetic Polymorphism of Scavenger Receptor Class B Type 1 as a Biomarker of Type 2 Diabetes Mellitus

ObjectivesThis study aimed to determine whether the expression level and genetic polymorphism scavenger receptor class B type 1 (SCARB1) rs5888 may be used as biological markers in type 2 diabetes mellitus (T2DM).MethodsThis case-control study was conducted at King George’s Medical University, Lucknow, India, from September 2018 to December 2019. Blood samples were collected from each individual with T2DM and each healthy individual. Total proteins were determined using western blot analysis. Additionally, restriction fragment length polymorphism analysis was achieved to detect the incidence of genetic polymorphisms.ResultsA total of 600 individuals, including 300 individuals with T2DM and 300 healthy individuals, were enrolled in the study. Western blot analysis results revealed that the protein expression of SRB1 was significantly decreased in T2DM of SCARB1 CC variant when compared with controls (P = 0.007). The genotype distribution and the allelic frequencies for the SRB1 polymorphism were significantly different between T2DM and controls (P = 0.03). The CC genotype of the SCARB1 polymorphism showed a potential association with the incidence of T2DM (odds ratio = 1.19, 95% confidence interval = 0.63–2.25; P = 0.577).ConclusionThe expression levels and genetic polymorphisms of the SCARB1 CC variant may be potential biomarkers for the occurrence of T2DM.

Functional Deletion/Insertion Promoter Variants in SCARB1 Associated With Increased Susceptibility to Lipid Profile Abnormalities and Coronary Heart Disease.

Background: Genetic variants in Scavenger receptor Class B Type 1 (SCARB1) influencing high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) risk were identified by recent genome-wide association studies. Further study of potential functional variants in SCARB1 may provide new ideas of the complicated relationship between HDL-C and CHD.Methods: 2000 bp in SCARB1 promoter region was re-sequenced in 168 participants with extremely high plasma HDL-C and 400 control subjects. Putative risk alleles were identified using bioinformatics analysis and reporter-gene assays. Two indel variants, rs144334493 and rs557348251, respectively, were genotyped in 5,002 CHD patients and 5,175 control subjects. The underlying mechanisms were investigated.Results: Through resequencing, 27 genetic variants were identified. Results of genotyping in 5,002 CHD patients and 5,175 control subjects revealed that rs144334493 and rs557348251 were significantly associated with increased risk of CHD [odds ratio (OR): 1.28, 95% confidence interval (CI): 1.09 to 1.52, p = 0.003; OR: 2.65, 95% CI: 1.66–4.24, p = 4.4 × 10−5). Subsequent mechanism experiments demonstrated that rs144334493 deletion allele attenuated forkhead box A1 (FOXA1) binding to the promoter region of SCARB1, while FOXA1 overexpression reversely increased SR-BI expression.Conclusion: Genetic variants in SCARB1 promoter region significantly associated with the plasma lipid levels by affecting SR-BI expression and contribute to the susceptibility of CHD.

Association between a genetic variant in scavenger receptor class B type 1 and its role on codon usage bias with increased risk of developing coronary artery disease

ObjectiveCoronary artery disease (CAD) as an important cause of morbidity and mortality globally. The scavenger receptor class B type 1 (SCARB1) plays an essential role in the reverse cholesterol transport. We have explored the association between a genetic variant, rs5888, in the SCARB1 gene with CAD and serum HDL-C levels. MethodsPatients were categorized into two groups' angiogram positive (>50% coronary stenosis) and angiogram negative (<50% coronary stenosis). Genotyping was carried out using polymerase chain reaction-amplification refractory mutation system. The association between the SNP rs5888 and serum HDL-C was analyzed using a logistic regression model. ResultsThe results showed that the subjects carrying a T allele was associated with a decreased serum HDL-C levels compared to the C allele in total population (p < 0.001). The risk of angiogram positivity in subjects carrying a T allele was 3.1-fold higher than for the control group (p < 0.001). ConclusionCVD patients carrying the T allele of rs5888 variant in the SCARB1 gene was associated with decreased serum level of HDL.

SR-B1 and CD10 combined immunoprofile for differential diagnosis of metastatic clear cell renal cell carcinoma and clear cell carcinoma of the ovary

Both clear cell renal carcinoma (ccRCC) and clear cell carcinoma of the ovary (CCOC) have a clear cytoplasmic morphological feature, hence it is difficult to identify metastatic ccRCC and CCOC by morphology alone. At present, there are no effective immunohistochemical markers to distinguish between these two tumors. Studies have shown that the clear cytoplasm of ccRCC is mainly caused by cholesterol-rich lipids in the cytoplasm, while that of CCOC is due to the accumulation of cytoplasmic glycogen. Objective: to hypothesize that the scavenger receptor class B-type 1 (SR-B1) protein responsible for HDL cholesterol uptake may be differentially expressed in ccRCC and CCOC, and high CD10 expression in the renal tubular epithelium may assist in distinguishing between ccRCC and CCOC. Methods: effective immunohistochemical markers were applied in 90 cases of renal clear cell carcinoma and 31 cases of ovarian cancer to distinguish between the two types of tumors.Result: SR-B1 and CD10 expression is significantly higher in ccRCC than CCOC. Both SR-B1 and CD10 exhibited focal weak-medium intensity staining in CCOC, and their staining extent and intensity were significantly lower than ccRCC. The sensitivity and specificity of SR-B1 for identifying ccRCC were 74.4% and 83.9%, respectively. The sensitivity and specificity of CD10 for identifying CCOC were 93.3% and 80.6%, respectively. The combined SR-B1( +) CD10( +) immunoprofile supports the diagnosis of ccRCC with a specificity of 93.5%. The combined SR-B1(-) CD10(-) immunoprofile supports the diagnosis of CCOC with a specificity of 93.3%. Conclusions: our findings demonstrate that the combination of SR-B1 and CD10 immunoprofiling is a valuable tool for differential diagnosis of ccRCC and CCOC.

Hepatic Scavenger Receptor Class B Type 1 Knockdown Reduces Atherosclerosis and Enhances the Antiatherosclerotic Effect of Brown Fat Activation in APOE*3-Leiden.CETP Mice.

[Figure: see text].

HDL (High-Density Lipoprotein) and ApoA-1 (Apolipoprotein A-1) Potentially Modulate Pancreatic α-Cell Glucagon Secretion.

Subjects with low levels of HDL (high-density lipoprotein) and ApoA-1 (apolipoprotein A-1) have increased risk to develop type 2 diabetes. HDL levels are an independent predictor of β-cell function and positively modulate it. Type 2 diabetes is characterized by defects in both β and α-cell function, but the effect of HDL and ApoA1 on α-cell function is unknown. Approach and Results: We observed a significant negative correlation (r=-0.422, P<0.0001) between HDL levels and fasting glucagon in a cohort of 132 Italian subjects. In a multivariable regression analysis including potential confounders such as age, sex, BMI, triglycerides, total cholesterol, fasting and 2-hour postload glucose, and fasting insulin, the association between HDL and fasting glucagon remained statistically significant (β=-0.318, P=0.006). CD1 mice treated with HDL or ApoA-1 for 3 consecutive days showed a 32% (P<0.001) and 23% (P<0.05) reduction, respectively, in glucagon levels following insulin-induced hypoglycemia, compared with controls. Treatment of pancreatic αTC1 clone 6 cells with HDL or ApoA-1 for 24 hours resulted in a significant reduction of glucagon expression (P<0.04) and secretion (P<0.01) after an hypoglycemic stimulus and increased Akt (RAC-alpha serine/threonine-protein kinase) and FoxO1 (forkhead/winged helix box gene, group O-1) phosphorylation. Pretreatment with Akt inhibitor VIII, PI3K (phosphatidylinositol 3-kinase) inhibitor LY294002, and HDL receptor SCARB-1 (scavenger receptor class B type 1) inhibitor BLT-1 (block lipid transport-1) restored αTC1 cell response to low glucose levels. These results support the notion that HDL and ApoA-1 modulate glucagon expression and secretion by binding their cognate receptor SCARB-1, and activating the PI3K/Akt/FoxO1 signaling cascade in an in vitro α-cell model. Overall, these results raise the hypothesis that HDL and ApoA-1 may have a role in modulating glucagon secretion.

Sex-Specific Influence of the SCARB1 Rs5888 SNP on the Serum Lipid Response to Atorvastatin in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

BackgroundEpidemiological studies have shown that there are sex differences in blood lipid levels and lipid responses to statins. Previous studies have shown that the rs5888 single nucleotide polymorphism (SNP) in the scavenger receptor class B type 1 (SCARB1) gene is associated with serum lipid levels in a sex-specific manner. The present study was undertaken to detect the sex-specific influence of the SCARB1 rs5888 SNP on the serum lipid response to atorvastatin in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).MethodsA total of 158 unrelated ACS patients (108 males, 50 females) were enrolled, and all patients received atorvastatin 20 mg/daily after PCI. Genotyping of the rs5888 SNP was performed by polymerase chain reaction and direct sequencing. Serum lipid profiles were determined before treatment and after an average follow-up time of one year.ResultsThe baseline serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo)AI levels were higher in females than in males (P<0.05). After treatment with atorvastatin, serum TC, LDL-C, and ApoB were decreased, and ApoAI was increased (P<0.05). The effects of atorvastatin on serum lipid levels were different between males and females, and females had greater decreases in TC, LDL-C and ApoB levels than males (P<0.05). The genotypic frequencies of the rs5888 SNP were not different between males and females. The atorvastatin response was not associated with the rs5888 SNP in males (P > 0.05). Nonetheless, in female individuals carrying the rs5888 T-allele, we observed a greater reduction in TC, LDL-C, and ApoB levels after the use of 20 mg/day atorvastatin (P<0.05).ConclusionThis study indicates that the SCARB1 rs5888 T-allele was associated with a greater reduction in serum TC, LDL-C, and ApoB after atorvastatin treatment in female patients with ACS undergoing PCI.

Effects of dietary supplementation of natural astaxanthin from Haematococcus pluvialis on antioxidant capacity, lipid metabolism, and accumulation in the egg yolk of laying hens

The present study evaluated the effects of natural astaxanthin (ASTA) from Haematococcus pluvialis on the antioxidant capacity, lipid metabolism, and ASTA accumulation in the egg yolk of laying hens. Hy-Line Brown layers (n = 288, 50 wk old) were randomly assigned to 1 of 4 dietary treatment groups. Each group had 6 replicates of 12 hens each. All birds were given a corn-soybean meal–based diet containing 0, 25, 50, or 100 mg/kg ASTA for 6 wk. The results showed that the total antioxidant capacity, superoxide dismutase level, and glutathione peroxidase level in the plasma, livers, and egg yolks were significantly increased in the ASTA groups compared with those of the control group (P < 0.05), whereas the content of malondialdehyde linearly decreased (P < 0.05). The plasma levels of high-density and very-low-density lipoprotein cholesterol in the ASTA groups were significantly higher than those in the control group (P < 0.05). In addition, ASTA supplementation decreased low-density lipoprotein cholesterol and triglyceride plasma levels (P < 0.05). However, there were no significant differences in the other lipid metabolism parameters among the ASTA-supplemented groups relative to the control group except for an increase in high-density lipoprotein cholesterol in the liver. Compared with the control, dietary ASTA supplementation significantly increased the enrichment of ASTA in egg yolks at the end of week 2, 4, and 6 (P < 0.05). The mRNA expression of scavenger receptor class B type 1 (SCARB1) and very-low-density lipoprotein receptor (VLDLR) in the ASTA groups was markedly higher (P < 0.05) than that in the control group in the liver and ovaries, respectively. In conclusion, these results suggest that dietary ASTA enhances the antioxidant capacity and regulates lipid metabolism in laying hens. ASTA enrichment in egg yolks may be closely related to the upregulation of SCARB1 and VLDLR gene expression.

DNA methylation at LRP1 gene locus mediates the association between maternal total cholesterol changes in pregnancy and cord blood leptin levels.

Placental lipids transfer is essential for optimal fetal development, and alterations of these mechanisms could lead to a higher risk of adverse birth outcomes. Low-density lipoprotein receptor (LDLR), LDL receptor-related protein 1 (LRP1), and scavenger receptor class B type 1 (SCARB1) genes are encoding lipoprotein receptors expressed in the placenta where they participate in cholesterol exchange from maternal to fetal circulation. The aim of this study was thus to investigate the association between maternal lipid changes occurring in pregnancy, placental DNA methylation (DNAm) variations at LDLR, LRP1, and SCARB1 gene loci, and newborn's anthropometric profile at birth. Sixty-nine normoglycemic women were followed from the first trimester of pregnancy until delivery. Placental DNAm was quantified at 43 Cytosine-phosphate-Guanines (CpGs) at LDLR, LRP1, and SCARB1 gene loci using pyrosequencing: 4 CpGs were retained for further analysis. Maternal clinical data were collected at each trimester of pregnancy. Newborns' data were collected from medical records. Statistical models included minimally newborn sex and gestational and maternal age. Maternal total cholesterol changes during pregnancy (ΔT3-T1) were correlated with DNAm variations at LDLR (r = -0.32, p = 0.01) and LRP1 (r = 0.34, p = 0.007). DNAm at these loci was also correlated with newborns' cord blood triglyceride and leptin levels. Mediation analysis supports a causal relationship between maternal cholesterol changes, DNAm levels at LRP1 locus, and cord blood leptin concentration (pmediation = 0.02). These results suggest that LRP1 DNAm link maternal blood cholesterol changes in pregnancy and offspring adiposity at birth, which provide support for a better follow-up of blood lipids in pregnancy.

Identifying and targeting angiogenesis-related microRNAs in ovarian cancer.

Current anti-angiogenic therapy for cancer is based mainly on inhibition of the vascular endothelial growth factor pathway. However, due to the transient and only modest benefit from such therapy, additional approaches are needed. Deregulation of microRNAs (miRNAs) has been demonstrated to be involved in tumor angiogenesis and offers opportunities for a new therapeutic approach. However, effective miRNA-delivery systems are needed for such approaches to be successful. In this study, miRNA profiling of patient data sets, along with in vitro and in vivo experiments, revealed that miR-204-5p could promote angiogenesis in ovarian tumors through THBS1. By binding with scavenger receptor class B type 1 (SCARB1), reconstituted high-density lipoprotein-nanoparticles (rHDL-NPs) were effective in delivering miR-204-5p inhibitor (miR-204-5p-inh) to tumor sites to suppress tumor growth. These results offer a new understanding of miR-204-5p in regulating tumor angiogenesis.

Prenatal ethanol exposure-induced a low level of foetal blood cholesterol and its mechanism of IGF1-related placental cholesterol transport dysfunction

Clinical researches showed that intrauterine growth retardation (IUGR) foetus had decreased blood cholesterol levels. The present study aimed to confirm that prenatal ethanol exposure (PEE) caused decreased blood cholesterol levels in IUGR foetal rats and elucidate its placental mechanism. Pregnant Wistar rats were intragastrically administrated with ethanol (4 g/kg.d) on gestational days 9–20 (GD9–20). in vivo, PEE increased the levels of total cholesterol (TCH), high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) in maternal serum, whereas decreased them in both female and male foetal serum. Moreover, the expression of cholesterol transport genes, scavenger receptor class B type 1 (SCARB1), low-density lipoprotein receptor (LDLR), ATP binding cassette subfamily A member 1 (ABCA1) and ATP binding cassette subfamily G member 1 (ABCG1) was reduced in female and male placentas in the PEE group. Meanwhile, the proliferation decreased and the apoptosis increased in female and male placentas, and the insulin like growth factor 1 (IGF1) signal pathway was inhibited. in vitro, after being treated with ethanol (15, 30, 60, 120 mM) for 72 h, the expression of cholesterol transport genes was decreased, the apoptosis was increased, the proliferation was decreased and the IGF1 signal pathway was inhibited in BeWo cells, whereas exogenous IGF1 reversed these changes. In conclusion, by inhibiting the IGF1 signal pathway in placentas, PEE induced apoptosis and inhibited proliferation, thus decreased the cholesterol transport in placentas, and eventually leading to low blood cholesterol levels in foetal rats.

Single Nucleotide Polymorphisms in β-Carotene Oxygenase 1 are Associated with Plasma Lycopene Responses to a Tomato-Soy Juice Intervention in Men with Prostate Cancer

Human plasma and tissue lycopene concentrations are heterogeneous even when consuming controlled amounts of tomato or lycopene. Our objective is to determine whether single nucleotide polymorphisms (SNPs) in or near known or putative carotenoid metabolism genes [β-carotene 15,15' monooxygenase 1 (BCO1), scavenger receptor class B type 1 (SCARB1), ATP-binding cassette transporter subfamily A member 1 (ABCA1), microsomal triglyceride transfer protein (MTTP), apolipoprotein B-48, elongation of very long chain fatty acids protein 2 (ELOVL2), and ATP-binding cassette subfamily B member 1 (ABCB1), and an intergenic superoxide dismutase 2, mitochondrial-associated SNP] are predictive of plasma lycopene responses to steady state tomato juice consumption. Secondary linear regression analyses of data from a dose-escalation study of prostate cancer patients [n=47; mean ± SEM age: 60±1 y; BMI (in kg/m2): 32±1] consuming 0, 1, or 2 cans of tomato-soy juice/d (163 mL/can; 20.6 mg lycopene 1.2 mg β-carotene/can) for 24±0.7 d before prostatectomy were conducted to explore 11 SNP genotype effects on the change in plasma lycopene and plasma and prostate tissue concentrations of lycopene, β-carotene, phytoene, and phytofluene. Two BCO1 SNP genotypes were significant predictors of the change in plasma lycopene, with SNP effects differing in magnitude and direction, depending on the level of juice intake (rs12934922×diet group P=0.02; rs6564851×diet group P=0.046). Further analyses suggested that plasma β-carotene changes were predicted by BCO1 rs12934922 (P<0.01), prostate lycopene by trending interaction and main effects of BCO1 SNPs (rs12934922×diet group P=0.09; rs12934922 P=0.02; rs6564851 P=0.053), and prostate β-carotene by BCO1 SNP interaction and main effects (rs12934922×diet group P=0.01; rs12934922 P<0.01; rs7501331 P=0.02). In conclusion, SNPs in BCO1 and other genes may modulate human plasma and prostate tissue responses to dietary lycopene intake and warrant validation in larger, human controlled feeding intervention and cohort studies. Genetic variants related to carotenoid metabolism may partially explain heterogeneous human blood and tissue responses and may be critical covariates for population studies and clinical trials. This trial was registered at clinicaltrials.gov as NCT01009736.

Association of Scavenger Receptor Gene with Premature Coronary Artery Disease

Background: Coronary artery disease (CAD) is one of the greatest causes of morbidity and mortality worldwide. It is the principal threat to health in countries in Africa and the Middle East and one of the leading causes of disease burden in developing countries. Scavenger receptor class B type1 (SCARB1) is a multi-ligand cell surface receptor. This membrane protein facilitates the uptake of cholesterol esters from high-density lipoprotein cholesterol (HDL-C) and drives cholesterol from tissues to the liver in the various stages of reverse cholesterol transport pathway. Aim: The aim of this work is to study the association of rs5888 polymorphism of SCARB1 gene and premature coronary artery disease. Patients and Methods: PCAD group included 20 patients newly diagnosed angiographically with premature coronary artery disease, and non-PCAD group that included 20 age and sex matched non-CAD individuals who showed no luminal stenosis in coronary angiographic results. Results: The frequency of the wild type (CC) was higher in the control group (60%) than patients’ group (25%) and it can be considered as a negative risk factor for PCAD (OR: 0.71, 95% CI [0.60-0.82], p < 0.01). The homozygous and heterozygous mutations (TT & CT) were statistically more frequently distributed in PCAD patients compared to control subjects (30 % and 45 % respectively), however only the CT genotype was considered as positive risk factor for PCAD (OR: 4.02, 95% CI[1.96-10.54], p= 0.01). Conclusion: Allele frequencies of studied SCARB 1 SNP revealed a higher frequency of distribution of T alleles in patients' group when compared with control group; on the other hand it shows the higher frequency of distribution of C alleles in control group when compared to patients' group.