RISK ASSESSMENT and DIAGNOSIS for EARLY ATHEROSCLEROSIS
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The SCARB1 Rs5888 SNP and Serum Lipid Levels in the Guangxi Mulao and Han Populations
Int. J. Med. Sci. 2012, 9 715 Ivyspring International Publisher International Journal of Medical Sciences 2012; 9(8):715-724. doi: 10.7150/ijms.4815 Research Paper The SCARB1 rs5888 SNP and Serum Lipid Levels in the Guangxi Mulao and Han Populations Dong-Feng Wu1, Rui-Xing Yin1, Ting-Ting Yan1, Lynn Htet Htet Aung1, Xiao-Li Cao1, Lin Miao1, Qing Li1, Xi-Jiang Hu1, Jin-Zhen Wu1, Cheng-Wu Liu2 1. Department of Cardiology, Institute of Cardiovascular Diseases, the First Affiliated Hospital, Guangxi Medical Univer- sity, 22 Shuangyong Road, Nanning 530021, Guangxi, People’s Republic of China 2. Department of Pathophysiology, School of Premedical Sciences, Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China Corresponding author: Prof. Rui-Xing Yin, Department of Cardiology, Institute of Cardiovascular Diseases, the First Affiliated Hospital, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, People’s Republic of China. Tel: +86-771-5326125; Fax: +86-771-5353342; e-mail: [email protected]. © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/ licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Received: 2012.07.04; Accepted: 2012.09.10; Published: 2012.10.13 Abstract Backgroud: The associations of scavenger receptor class B type 1 (SCARB1) rs5888 single nucleotide polymorphism (SNP) and serum lipid levels are inconsistant among diverse ethnic populations. The present study was undertaken to detect the association of rs5888 SNP and serum lipid levels in the Guangxi Mulao and Han populations. -
Harnessing Low-Density Lipoprotein Receptor Protein 6 (LRP6) Genetic Variation and Wnt Signaling for Innovative Diagnostics in Complex Diseases
OPEN The Pharmacogenomics Journal (2018) 18, 351–358 www.nature.com/tpj REVIEW Harnessing low-density lipoprotein receptor protein 6 (LRP6) genetic variation and Wnt signaling for innovative diagnostics in complex diseases Z-M Wang1,2, J-Q Luo1,2, L-Y Xu3, H-H Zhou1,2 and W Zhang1,2 Wnt signaling regulates a broad variety of processes in both embryonic development and various diseases. Recent studies indicated that some genetic variants in Wnt signaling pathway may serve as predictors of diseases. Low-density lipoprotein receptor protein 6 (LRP6) is a Wnt co-receptor with essential functions in the Wnt/β-catenin pathway, and mutations in LRP6 gene are linked to many complex human diseases, including metabolic syndrome, cancer, Alzheimer’s disease and osteoporosis. Therefore, we focus on the role of LRP6 genetic polymorphisms and Wnt signaling in complex diseases, and the mechanisms from mouse models and cell lines. It is also highly anticipated that LRP6 variants will be applied clinically in the future. The brief review provided here could be a useful resource for future research and may contribute to a more accurate diagnosis in complex diseases. The Pharmacogenomics Journal (2018) 18, 351–358; doi:10.1038/tpj.2017.28; published online 11 July 2017 INTRODUCTION signaling pathways and expressed in various target organs.1 LDLR- The Wnt1 gene was identified in 1982. Ensuing studies in related proteins 5/6 (LRP5/6) belong to this large family and Drosophila and Xenopus unveiled a highly conserved Wnt/ function as co-receptors of the Wnt/β-catenin pathway. These β-catenin pathway, namely, canonical Wnt signaling. -
The LRP6 Rs2302685 Polymorphism Is Associated with Increased Risk Of
Xu et al. Lipids in Health and Disease 2014, 13:94 http://www.lipidworld.com/content/13/1/94 RESEARCH Open Access The LRP6 rs2302685 polymorphism is associated with increased risk of myocardial infarction Shun Xu1,2,3, Jie Cheng1,2,3, Yu-ning Chen1,2,3, Keshen Li4, Ze-wei Ma1,2, Jin-ming Cen5, Xinguang Liu1,2,3, Xi-li Yang5, Can Chen6 and Xing-dong Xiong1,2,3* Abstract Background: Abnormal lipids is one of the critical risk factors for myocardial infarction (MI), however the role of genetic variants in lipid metabolism-related genes on MI pathogenesis still requires further investigation. We herein genotyped three SNPs (LRP6 rs2302685, LDLRAP1 rs6687605, SOAT1 rs13306731) in lipid metabolism-related genes, aimed to shed light on the influence of these SNPs on individual susceptibility to MI. Methods: Genotyping of the three SNPs (rs2302685, rs6687605 and rs13306731) was performed in 285 MI cases and 650 control subjects using polymerase chain reaction–ligation detection reaction (PCR–LDR) method. The association of these SNPs with MI and lipid profiles was performed with SPSS software. Results: Multivariate logistic regression analysis showed that C allele (OR = 1.62, P = 0.039) and the combined CT/CC genotype (OR = 1.67, P = 0.035) of LRP6 rs2302685 were associated with increased MI risk, while the other two SNPs had no significant effect. Further stratified analysis uncovered a more evident association with MI risk among younger subjects (≤60 years old). Fascinatingly, CT/CC genotype of rs2302685 conferred increased LDL-C levels compared to TT genotype (3.0 mmol/L vs 2.72 mmol/L) in younger subjects. -
Astrocytic LRP1 Mediates Brain Aßclearance and Impacts Amyloid
The Journal of Neuroscience, April 12, 2017 • 37(15):4023–4031 • 4023 Neurobiology of Disease Astrocytic LRP1 Mediates Brain A Clearance and Impacts Amyloid Deposition Chia-Chen Liu,1 Jin Hu,1,3 Na Zhao,1 XJian Wang,1 Na Wang,1,3 XJohn R. Cirrito,2 Takahisa Kanekiyo,1 David M. Holtzman,2 and Guojun Bu1,3 1Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, 2Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110, and 3Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, 361102 China Accumulation and deposition of amyloid- (A) in the brain represent an early and perhaps necessary step in the pathogenesis of Alzheimer’s disease (AD). A accumulation leads to the formation of A aggregates, which may directly and indirectly lead to eventual neurodegeneration. While A production is accelerated in many familial forms of early-onset AD, increasing evidence indicates that impaired clearance of A is more evident in late-onset AD. To uncover the mechanisms underlying impaired A clearance in AD, we examined the role of low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. Although LRP1 has been shown to play critical roles in brain A metabolism in neurons and vascular mural cells, its role in astrocytes, the most abundant cell type in the brain responsible for maintaining neuronal homeostasis, remains unclear. Here, we show that astrocytic LRP1 plays a critical role in brain A clearance. LRP1 knockdown in primary astrocytes resulted in decreased cellular A uptake and degradation. -
Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis Kaylyn D
Published OnlineFirst February 26, 2019; DOI: 10.1158/1541-7786.MCR-18-1147 Metabolism Molecular Cancer Research Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis Kaylyn D. Tousignant1, Anja Rockstroh1, Atefeh Taherian Fard1, Melanie L. Lehman1, Chenwei Wang1, Stephen J. McPherson1, Lisa K. Philp1, Nenad Bartonicek2,3, Marcel E. Dinger2,3, Colleen C. Nelson1, and Martin C. Sadowski1 Abstract De novo lipogenesis is a well-described androgen receptor delineates the lipid transporter landscape in prostate cancer (AR)–regulated metabolic pathway that supports prostate cell lines and patient samples by analysis of transcriptomics cancer tumor growth by providing fuel, membrane material, and proteomics data, including the plasma membrane prote- and steroid hormone precursor. In contrast, our current under- ome. We show that androgen exposure or deprivation regu- standing of lipid supply from uptake of exogenous lipids and lates the expression of multiple lipid transporters in prostate its regulation by AR is limited, and exogenous lipids may play a cancer cell lines and tumor xenografts and that mRNA and much more significant role in prostate cancer and disease protein expression of lipid transporters is enhanced in bone progression than previously thought. By applying advanced metastatic disease when compared with primary, localized automated quantitative fluorescence microscopy, we provide prostate cancer. Our findings provide a strong rationale to the most comprehensive functional analysis of lipid uptake in investigate lipid uptake as a therapeutic cotarget in the fight cancer cells to date and demonstrate that treatment of AR- against advanced prostate cancer in combination with inhi- positive prostate cancer cell lines with androgens results in bitors of lipogenesis to delay disease progression and significantly increased cellular uptake of fatty acids, cholester- metastasis. -
Adiponectin Regulates Expression of Hepatic Genes Critical for Glucose and Lipid Metabolism
Adiponectin regulates expression of hepatic genes critical for glucose and lipid metabolism Qingqing Liua, Bingbing Yuana, Kinyui Alice Loa,b, Heide Christine Pattersona,c,d, Yutong Sune, and Harvey F. Lodisha,b,1 aWhitehead Institute for Biomedical Research, Cambridge, MA 02142; bDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; cDepartment of Pathology, Brigham and Women’s Hospital, Boston, MA 02115; dInstitut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany; and eDepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 Contributed by Harvey F. Lodish, July 23, 2012 (sent for review May 30, 2012) The effects of adiponectin on hepatic glucose and lipid metabolism mediated by a master regulator of hepatic gene expression, the at transcriptional level are largely unknown. We profiled hepatic transcription factor (TF) Hnf4a. gene expression in adiponectin knockout (KO) and wild-type (WT) mice by RNA sequencing. Compared with WT mice, adiponectin KO Results mice fed a chow diet exhibited decreased mRNA expression of rate- Rate-limiting enzymes catalyze the slowest or irreversible steps limiting enzymes in several important glucose and lipid metabolic in metabolic pathways, which makes them the targets of tran- pathways, including glycolysis, tricarboxylic acid cycle, fatty-acid scriptional regulation and/or posttranslational modifications activation and synthesis, triglyceride synthesis, and cholesterol such as phosphorylation in the regulation of metabolism (7). synthesis. In addition, binding of the transcription factor Hnf4a to Because adiponectin plays an important role in energy metabo- DNAs encoding several key metabolic enzymes was reduced in KO lism, our analysis on hepatic gene expression in adiponectin KO mice, suggesting that adiponectin might regulate hepatic gene and WT mice was specifically focused on the expression levels of expression via Hnf4a. -
Genetic Contribution of SCARB1 Variants to Lipid Traits in African Blacks: a Candidate Gene Association Study Vipavee Niemsiri1, Xingbin Wang1, Dilek Pirim1, Zaheda H
Niemsiri et al. BMC Medical Genetics (2015) 16:106 DOI 10.1186/s12881-015-0250-6 RESEARCH ARTICLE Open Access Genetic contribution of SCARB1 variants to lipid traits in African Blacks: a candidate gene association study Vipavee Niemsiri1, Xingbin Wang1, Dilek Pirim1, Zaheda H. Radwan1, Clareann H. Bunker2, M. Michael Barmada1, M. Ilyas Kamboh1*† and F. Yesim Demirci1*† Abstract Background: High-density lipoprotein cholesterol (HDL-C) exerts many anti-atherogenic properties including its role in reverse cholesterol transport (RCT). Scavenger receptor class B member 1 (SCARB1) plays a key role in RCT by selective uptake of HDL cholesteryl esters. We aimed to explore the genetic contribution of SCARB1 to affecting lipid levels in African Blacks from Nigeria. Methods: We resequenced 13 exons and exon-intron boundaries of SCARB1 in 95 individuals with extreme HDL-C levels using Sanger method. Then, we genotyped 147 selected variants (78 sequence variants, 69 HapMap tagSNPs, and 2 previously reported relevant variants) in the entire sample of 788 African Blacks using either the iPLEX Gold or TaqMan methods. A total of 137 successfully genotyped variants were further evaluated for association with major lipid traits. Results: The initial gene-based analysis demonstrated evidence of association with HDL-C and apolipoprotein A-I (ApoA-I). The follow-up single-site analysis revealed nominal evidence of novel associations of nine common variants with HDL-C and/or ApoA-I (P < 0.05). The strongest association was between rs11057851 and HDL-C (P = 0.0043), which remained significant after controlling for multiple testing using false discovery rate. Rare variant association testing revealed a group of 23 rare variants (frequencies ≤1%)associatedwithHDL-C(P = 0.0478). -
TRAP1 Regulates Wnt/-Catenin Pathway Through LRP5/6 Receptors
International Journal of Molecular Sciences Article TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation 1, 1, 1 1 Giacomo Lettini y, Valentina Condelli y, Michele Pietrafesa , Fabiana Crispo , Pietro Zoppoli 1 , Francesca Maddalena 1, Ilaria Laurenzana 1 , Alessandro Sgambato 1, Franca Esposito 2,* and Matteo Landriscina 1,3,* 1 Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy; [email protected] (G.L.); [email protected] (V.C.); [email protected] (M.P.); [email protected] (F.C.); [email protected] (P.Z.); [email protected] (F.M.); [email protected] (I.L.); [email protected] (A.S.) 2 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy 3 Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy * Correspondence: [email protected] (F.E.); [email protected] (M.L.); Tel.: +39-081-7463-145 (F.E.); +39-0881-736-426 (M.L.) These authors have contributed equally to this work. y Received: 4 September 2020; Accepted: 10 October 2020; Published: 13 October 2020 Abstract: Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. -
High-Density Lipoprotein-Targeted Therapies for Heart Failure
Review High‐Density Lipoprotein‐Targeted Therapies for Heart Failure Mudit Mishra and Bart De Geest * Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Catholic University of Leuven, 3000 Leuven, Belgium; [email protected] * Correspondence: [email protected]; Tel.: +32‐16‐372059 Received: 31 October 2020; Accepted: 15 December 2020; Published: 16 December 2020 Abstract: The main and common constituents of high‐density lipoproteins (HDLs) are apolipoprotein A‐I, cholesterol, and phospholipids. Biochemical heterogeneity of HDL particles is based on the variable presence of one or more representatives of at least 180 proteins, 200 lipid species, and 20 micro RNAs. HDLs are circulating multimolecular platforms that perform divergent functions whereby the potential of HDL‐targeted interventions for treatment of heart failure can be postulated based on its pleiotropic effects. Several murine studies have shown that HDLs exert effects on the myocardium, which are completely independent of any impact on coronary arteries. Overall, HDL‐targeted therapies exert a direct positive lusitropic effect on the myocardium, inhibit the development of cardiac hypertrophy, suppress interstitial and perivascular myocardial fibrosis, increase capillary density in the myocardium, and prevent the occurrence of heart failure. In four distinct murine models, HDL‐targeted interventions were shown to be a successful treatment for both pre‐existing heart failure with reduced ejection fraction (HFrEF) and pre‐existing heart failure with preserved ejection fraction (HFrEF). Until now, the effect of HDL‐targeted interventions has not been evaluated in randomized clinical trials in heart failure patients. As HFpEF represents an important unmet therapeutic need, this is likely the preferred therapeutic domain for clinical translation. -
Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer
Author Manuscript Published OnlineFirst on February 26, 2019; DOI: 10.1158/1541-7786.MCR-18-1147 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Lipid uptake is an androgen-enhanced lipid supply pathway associated with prostate cancer 2 disease progression and bone metastasis 3 4 Kaylyn D Tousignant1, Anja Rockstroh1, Atefeh Taherian Fard1, Melanie L Lehman1, 5 Chenwei Wang1, Stephen J McPherson1, Lisa K Philp1, Nenad Bartonicek2,3, Marcel E 6 Dinger2,3, Colleen C Nelson1, Martin C Sadowski1 7 1Australian Prostate Cancer Research Centre - Queensland, Institute of Health and 8 Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland 9 University of Technology, Princess Alexandra Hospital, Translational Research Institute 10 2 Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, 11 Australia 12 3 St Vincent’s Clinical School, UNSW Sydney, Sydney, Australia 13 14 15 16 Keywords: lipid uptake, androgen signaling, low-density lipoprotein receptor (LDLR), 17 scavenger receptor class B type 1 (SCARB1), prostate cancer 18 19 Disclosure of Potential Conflicts of Interest 20 No potential conflicts of interest were disclosed. 21 1 Downloaded from mcr.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 26, 2019; DOI: 10.1158/1541-7786.MCR-18-1147 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 22 Abstract 23 De novo lipogenesis is a well-described AR-regulated metabolic pathway that supports 24 prostate cancer tumor growth by providing fuel, membrane material and steroid hormone 25 precursor. -
Modulation of LRP6-Mediated Wnt Signaling by Molecular Chaperone Mesd
FEBS Letters 580 (2006) 5423–5428 Modulation of LRP6-mediated Wnt signaling by molecular chaperone Mesd Yonghe Lia,b,*, Wenyan Lua,b,XiHec, Guojun Bua,d a Department of Pediatrics, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, MO 63110, USA b Department of Biochemistry and Molecular Biology, Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, USA c Division of Neuroscience, Children’s Hospital, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA d Department of Cell Biology and Physiology, Washington University School of Medicine, MO 63110, USA Received 3 May 2006; revised 1 September 2006; accepted 7 September 2006 Available online 18 September 2006 Edited by Lukas Huber ligands for other LDLR family members typically bind to Abstract LRP6 is a Wnt coreceptor at the cell surface. Here, we report that a specialized molecular chaperone Mesd modu- the clusters of ligand-binding repeats [2,3]. lates LRP6-mediated Wnt signaling and how different LRP6 A common feature that is shared by most members of the mutants exhibit differential effects on Wnt signaling. We found LDLR family is their ability to bind the receptor-associated that overexpression of increasing amounts of the full-length protein (RAP) [11]. RAP is an endoplasmic reticulum (ER)- LRP6 enhances Wnt signaling in a dose dependent manner only resident protein that functions in receptor folding and traffick- in the presence of a co-expression of the molecular chaperone ing along the secretory pathway. Upon binding to receptors Mesd, which promotes LRP6 folding and maturation to the cell following their translation, RAP promotes receptor folding. -
Loss of SR-BI Down-Regulates MITF and Suppresses Extracellular Vesicle Release in Human Melanoma
International Journal of Molecular Sciences Article Loss of SR-BI Down-Regulates MITF and Suppresses Extracellular Vesicle Release in Human Melanoma Katharina Kinslechner 1 , Birgit Schütz 1, Martina Pistek 1, Philipp Rapolter 1, Hans P. Weitzenböck 2, Harald Hundsberger 2, Wolfgang Mikulits 3 , Johannes Grillari 4, Clemens Röhrl 1, Markus Hengstschläger 1, Herbert Stangl 1 and Mario Mikula 1,* 1 Center for Pathobiochemistry and Genetics, Medical University of Vienna, 1090 Vienna, Austria; [email protected] (K.K.); [email protected] (B.S.); [email protected] (M.P.); [email protected] (P.R.); [email protected] (C.R.); [email protected] (M.H.); [email protected] (H.S.) 2 Medical and Pharmaceutical Biotechnology, IMC University of Applied Sciences, 3500 Krems, Austria; [email protected] (H.P.W.); [email protected] (H.H.) 3 Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; [email protected] 4 Department of Biotechnology, BOKU -University of Natural Resources and Life Sciences, 1190 Vienna, Austria; [email protected] * Correspondence: [email protected]; Tel.: +43-1-40160-56540; Fax: +43-1-40160-956501 Received: 13 February 2019; Accepted: 26 February 2019; Published: 1 March 2019 Abstract: Melanoma is a skin tumor with a high tendency for metastasis and thus is one of the deadliest cancers worldwide. Here, we investigated the expression of the scavenger receptor class B type 1 (SR-BI), a high-density lipoprotein (HDL) receptor, and tested for its role in melanoma pigmentation as well as extracellular vesicle release.