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https://www.readbyqxmd.com/read/28334946/mutations-affecting-the-transmembrane-domain-of-the-ldl-receptor-impact-of-charged-residues-on-the-membrane-insertion
#1
Thea Bismo Strøm, Jon K Laerdahl, Trond P Leren
Familial hypercholesterolemia (FH) is caused by mutations in the low density lipoprotein receptor (LDLR) gene. To study the impact of mutations affecting the hydrophobic transmembrane domain of the LDLR, each of the 22 amino acids of the transmembrane domain was individually mutated to arginine. The more centrally in the transmembrane domain an arginine was located, the lower amounts of the 120 kDa precursor LDLR in the endoplasmic reticulum were observed. This led to lower amounts of the 160 kDa mature LDLR on the cell surface...
February 22, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28333714/novel-regulators-of-plasma-lipid-levels
#2
Natalia Loaiza, Federico Oldoni, Jan A Kuivenhoven
PURPOSE OF REVIEW: To highlight very recent studies identifying novel regulatory molecules and mechanisms in plasma lipid metabolism. RECENT FINDINGS: Two novel regulatory mechanisms of LDL receptor (LDLR) intracellular trafficking have been described. The "COMMD/CCDC22/CCDC93" and "Wiskott-Aldrich syndrome protein and SCAR homologue" complexes were found to be involved in LDLR endosomal sorting and recycling, whereas the GRP94 was shown to protect LDLR from early degradation within the hepatocyte secretory pathway...
March 22, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28323660/impact-of-rare-variants-in-autosomal-dominant-hypercholesterolemia-causing-genes
#3
Sebastiano Calandra, Patrizia Tarugi, Stefano Bertolini
PURPOSE OF REVIEW: The systematic analysis of the major candidate genes in autosomal dominant hypercholesterolemia (ADH) and the use of next-generation sequencing (NGS) technology have made possible the discovery of several rare gene variants whose pathogenic effect in most cases remains poorly defined. RECENT FINDINGS: One major advance in the field has been the adoption of a set of international guidelines for the assignment of pathogenicity to low-density lipoprotein receptor (LDLR) gene variants based on the use of softwares, complemented with data available from literature and public databases...
March 18, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28319449/non-clinical-study-examining-aav8-tbg-hldlr-vector-associated-toxicity-in-chow-fed-wild-type-and-ldlr-rhesus-macaques
#4
Jenny A Greig, Maria P Limberis, Peter Bell, Shu-Jen Chen, Roberto Calcedo, Daniel J Rader, James M Wilson
Vectors based on adeno-associated virus serotype 8 (AAV8) have been evaluated in several clinical trials of gene therapy for hemophilia B with encouraging results. In preparation for a Phase 1 clinical trial of AAV8 gene therapy for the treatment of homozygous familial hypercholesterolemia (HoFH), the safety of the clinical candidate vector, AAV8.TBG.hLDLR, was evaluated in wild-type rhesus macaques and macaques heterozygous for a nonsense mutation in the low-density lipoprotein receptor (LDLR) gene (LDLR(+/-))...
March 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/28319445/nonclinical-pharmacology-toxicology-study-of-aav8-tbg-mldlr-and-aav8-tbg-hldlr-in-a-mouse-model-of-homozygous-familial-hypercholesterolemia
#5
Jenny A Greig, Maria P Limberis, Peter Bell, Shu-Jen Chen, Roberto Calcedo, Daniel J Rader, James M Wilson
The homozygous form of familial hypercholesterolemia (HoFH) is an excellent model for developing in vivo gene therapy in humans. The success of orthotropic liver transplantation in correcting the metabolic abnormalities in HoFH suggests that the correction of low-density lipoprotein receptor (LDLR) expression in hepatocytes via gene therapy should be sufficient for therapeutic efficacy. Vectors based on adeno-associated virus serotype 8 (AAV8) have been previously developed for liver-targeted gene therapy of a number of genetic diseases, including HoFH...
March 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/28304296/pcsk9-promotes-oxldl-induced-pc12-cell-apoptosis-through-the-bcl-2-bax-caspase-9-3-signaling-pathway
#6
Lu-Shan Liu, Xue-Qin Bai, Ya Gao, Qi Wu, Zhong Ren, Qing Li, Li-Hong Pan, Ni-Ya He, Juan Peng, Zhi-Han Tang
BACKGROUND: Hyperlipidemia is a risk factor for neurodegenerative diseases. Proprotein convertase subtilisin / Kexin type 9 (PCSK9) degrades hepatic low-density lipoprotein receptor (LDLR) to regulate lipid metabolism. It is unclear if PCSK9 plays a role in neurodegenerative diseases. OBJECTIVE: This study was designed to determine whether PCSK9 is crucial between hyperlipidemia and Alzheimer's disease. The interrelationship between PCSK9 and neuronal apoptosis was explored in PC12 cells in response to treatment with oxidized low-density lipoprotein (oxLDL)...
March 10, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28301372/news-on-the-molecular-regulation-and-function-of-hepatic-low-density-lipoprotein-receptor-and-ldlr-related-protein-1
#7
Bart van de Sluis, Melinde Wijers, Joachim Herz
PURPOSE OF REVIEW: Clearing of atherogenic lipoprotein particles by the liver requires hepatic low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1). This review highlights recent studies that have expanded our understanding of the molecular regulation and metabolic functions of LDLR and LRP1 in the liver. RECENT FINDINGS: Various proteins orchestrate the intracellular trafficking of LDLR and LRP1. After internalization, the receptors are redirected via recycling endosomes to the cell surface...
March 15, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28300165/somatic-genome-editing-with-crispr-cas9-generates-and-corrects-a-metabolic-disease
#8
Kelsey E Jarrett, Ciaran M Lee, Yi-Hsien Yeh, Rachel H Hsu, Rajat Gupta, Min Zhang, Perla J Rodriguez, Chang Seok Lee, Baiba K Gillard, Karl-Dimiter Bissig, Henry J Pownall, James F Martin, Gang Bao, William R Lagor
Germline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to avoid developmental phenotypes. We sought to address these experimental limitations by generating somatic mutations in the adult liver using CRISPR/Cas9, as a new strategy to model metabolic disorders. As proof-of-principle, we targeted the low-density lipoprotein receptor (Ldlr), which when deleted, leads to severe hypercholesterolemia and atherosclerosis...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28292942/the-apoe-receptors-vldlr-and-apoer2-in-central-nervous-system-function-and-disease
#9
Courtney Lane-Donovan, Joachim Herz
The low-density lipoprotein receptor (LDLR) family has long been studied for its role in cholesterol transport and metabolism; however, the identification of apolipoprotein E4 (ApoE4), an LDLR ligand, as a genetic risk factor for late-onset Alzheimers disease (AD) has focused attention on the role this receptor family plays in the central nervous system (CNS). Surprisingly, it was discovered that two LDLR family members, Apolipoprotein E receptor 2 (Apoer2) and very-low-density lipoprotein receptor (Vldlr), play key roles in brain development and adult synaptic plasticity, primarily by mediating Reelin signaling...
March 14, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28276564/dietary-fatty-acids-on-aortic-root-calcification-in-mice-with-metabolic-syndrome
#10
Maria C Naranjo, Beatriz Bermudez, Indara Garcia, Sergio Lopez, Rocio Abia, Francisco J G Muriana, Sergio Montserrat-de la Paz
Metabolic syndrome (MetS) is associated with obesity, dyslipidemia, type 2 diabetes, and chronic low-grade inflammation. The aim of this study was to determine the role of high-fat low-cholesterol diets (HFLCDs) rich in SFAs (HFLCD-SFAs), MUFAs (HFLCD-MUFAs) or MUFAs plus omega-3 long-chain PUFAs (HFLCD-PUFAs) on vascular calcification by the modulation of the RANKL/RANK/OPG system in the aortic roots of Lep(ob/ob)LDLR(-/-) mice. Animals fed with HFLCD-SFAs had increased weight and a greater atheroma plaque size, calcification, and RANKL/CATHK expression in the aortic root than mice on MUFA-enriched diets, with an increasing OPG expression in the aortic roots of the latter...
March 9, 2017: Food & Function
https://www.readbyqxmd.com/read/28276521/a-randomized-trial-and-novel-spr-technique-identifies-altered-lipoprotein-ldl-receptor-binding-as-a-mechanism-underlying-elevated-ldl-cholesterol-in-apoe4s
#11
M V Calabuig-Navarro, K G Jackson, C F Kemp, D S Leake, C M Walden, J A Lovegrove, A M Minihane
At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28275068/ccr7-ccl19-ccl21-axis-is-essential-for-effective-arteriogenesis-in-a-murine-model-of-hindlimb-ischemia
#12
A Yaël Nossent, Antonius J N M Bastiaansen, Erna A B Peters, Margreet R de Vries, Zeen Aref, Sabine M J Welten, Saskia C A de Jager, Tineke C T M van der Pouw Kraan, Paul H A Quax
BACKGROUND: In order to identify factors that stimulate arteriogenesis after ischemia, we followed gene expression profiles in two extreme models for collateral artery formation over 28 days after hindlimb ischemia, namely "good-responding" C57BL/6 mice and "poor-responding" BALB/c mice. METHODS AND RESULTS: Although BALB/c mice show very poor blood flow recovery after ischemia, most known proarteriogenic genes were upregulated more excessively and for a longer period than in C57BL/6 mice...
March 8, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28262545/generation-of-human-liver-chimeric-mice-with-hepatocytes-from-familial-hypercholesterolemia-induced-pluripotent-stem-cells
#13
Jiayin Yang, Yu Wang, Ting Zhou, Lai-Yung Wong, Xiao-Yu Tian, Xueyu Hong, Wing-Hon Lai, Ka-Wing Au, Rui Wei, Yuqing Liu, Lai-Hung Cheng, Guichan Liang, Zhijian Huang, Wenxia Fan, Ping Zhao, Xiwei Wang, David P Ibañez, Zhiwei Luo, Yingying Li, Xiaofen Zhong, Shuhan Chen, Dongye Wang, Li Li, Liangxue Lai, Baoming Qin, Xichen Bao, Andrew P Hutchins, Chung-Wah Siu, Yu Huang, Miguel A Esteban, Hung-Fat Tse
Familial hypercholesterolemia (FH) causes elevation of low-density lipoprotein cholesterol (LDL-C) in blood and carries an increased risk of early-onset cardiovascular disease. A caveat for exploration of new therapies for FH is the lack of adequate experimental models. We have created a comprehensive FH stem cell model with differentiated hepatocytes (iHeps) from human induced pluripotent stem cells (iPSCs), including genetically engineered iPSCs, for testing therapies for FH. We used FH iHeps to assess the effect of simvastatin and proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies on LDL-C uptake and cholesterol lowering in vitro...
March 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28251657/hypolipidemic-effect-and-mechanism-of-paprika-seed-oil-on-sprague-dawley-rats
#14
Xuhui Chen, Yongbo Ding, Jiaxin Song, Jianquan Kan
BACKGROUND: The functional properties of paprika seed oil are relatively lack, the hyperlipidemic effects and mechanisms of paprika seed oil on Sprague-Dawley rats are explored, which may improve the usage of paprika seed source and provide a theoretical basis of paprika seed oil for the alleviation of hyperlipidemia. RESULTS: In capsaicin and paprika seed oil (PSO) groups, total cholesterol (TC) and total triglyceride (TG) in serum and liver lipids of rats were significantly decreased (P < 0...
March 2, 2017: Journal of the Science of Food and Agriculture
https://www.readbyqxmd.com/read/28241975/chronic-administration-of-the-soluble-nonbacterial-fraction-of-kefir-attenuates-lipid-deposition-in-ldlr-mice
#15
Adriélly F Santanna, Placielle F Filete, Ewelyne M Lima, Marcella L Porto, Silvana S Meyrelles, Elisardo C Vasquez, Denise C Endringer, Dominik Lenz, Dulcineia S P Abdalla, Thiago M C Pereira, Tadeu U Andrade
OBJECTIVES: Kefir is obtained by the action of acidic bacteria and yeasts that exist in symbiotic association in kefir grains. Recently, this fermented milk drink has been recommended for the treatment of several clinical conditions, such as inflammatory, gastrointestinal, or cardiovascular-related diseases, or a combination of these diseases. However, its effects on atherosclerosis are not yet clear. The aim of this study was to prove that chronic treatment with a soluble, nonbacterial fraction of kefir could reduce the progression of atherosclerosis in low-density lipoprotein receptor-deficient (LDLr(-/-)) mice...
March 2017: Nutrition
https://www.readbyqxmd.com/read/28240002/cholesterol-homeostasis-in-isolated-lymphocytes-a-differential-correlation-between-male-control-and-chronic-lymphocytic-leukemia-subjects
#16
Shrimanjunath Sankanagoudar, Govind Singh, Manaranjan Mahapatra, Lalit Kumar, Nimai Chand Chandra
Background: This study was performed to investigate any association between cellular cholesterol homeostasis and chronic lymphocytic leukemia (CLL). CLL is characterized primarily by an abnormal accumulation of neoplastic B cells in the blood, bone marrow, lymph nodes and spleen. Methods: Men aged >50 years participated in this study. Enzyme-based plasma lipid profile estimations, peripheral blood lymphocyte isolation, lysate preparations, SDS-PAGE, western blotting, dil-LDL uptake and ultracentrifugation were employed...
January 1, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/28239402/high-cholesterol-diet-does-not-alter-gut-microbiota-composition-in-mice
#17
Lidiya G Dimova, Nikola Zlatkov, Henkjan J Verkade, Bernt Eric Uhlin, Uwe J F Tietge
INTRODUCTION: Western diet containing both saturated fat and cholesterol impairs cardio-metabolic health partly by modulating diversity and function of the microbiota. While diet containing only high fat has comparable effects, it is unclear how diets only enriched in cholesterol impact the microbiota. Therefore, we aimed to characterize the response of host and microbiota to a high cholesterol (HC) diet in mice susceptible to cardio-metabolic disease. METHODS: LDLR knockout mice received either 1...
2017: Nutrition & Metabolism
https://www.readbyqxmd.com/read/28235710/the-genetic-spectrum-of-familial-hypercholesterolemia-in-the-central-south-region-of-china
#18
Rong Xiang, Liang-Liang Fan, Min-Jie Lin, Jing-Jing Li, Xiang-Yu Shi, Jie-Yuan Jin, Yu-Xing Liu, Ya-Qin Chen, Kun Xia, Shui-Ping Zhao
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is the most common and severe autosomal dominant lipid metabolism dysfunction, which causes xanthoma, atherosclerosis and coronary heart disease. Earlier studies showed that mutations in LDLR, APOB and PCSK9 cause FH. Although more than 75% of the population in Europe has been scrutinized for FH-causing mutations, the genetic diagnosis proportion among Chinese people remains very low (less than 0.5%). The aim of this study was to perform a survey and mutation detection among the Chinese population...
March 2017: Atherosclerosis
https://www.readbyqxmd.com/read/28225891/soy-milk-versus-simvastatin-for-preventing-atherosclerosis-and-left-ventricle-remodeling-in-ldl-receptor-knockout-mice
#19
L Santos, A P Davel, T I R Almeida, M R Almeida, E A Soares, G J M Fernandes, S F Magalhães, V G Barauna, J A D Garcia
Functional food intake has been highlighted as a strategy for the prevention of cardiovascular diseases by reducing risk factors. In this study, we compared the effects of oral treatment with soy milk and simvastatin on dyslipidemia, left ventricle remodeling and atherosclerotic lesion of LDL receptor knockout mice (LDLr-/-) fed a hyperlipidic diet. Forty 3-month old male LDLr-/- mice were distributed into four groups: control group (C), in which animals received standard diet; HL group, in which animals were fed a hyperlipidic diet; HL+SM or HL+S groups, in which animals were submitted to a hyperlipidic diet plus soy milk or simvastatin, respectively...
February 20, 2017: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/28220743/analysis-of-mutations-causing-familial-hypercholesterolaemia-in-black-south-african-patients-of-different-ancestr
#20
U K Ibe, R Whittall, S E Humphries, G Pilcher, F Raal
BACKGROUND: Familial hypercholesterolaemia (FH) is usually caused by mutations in three genes (LDLR, APOB and PCSK9). OBJECTIVE: To identify the spectrum of FH-causing mutations in black South African (SA) patients. METHODS: DNA samples of 16 unrelated South African FH patients with elevated low-density lipoprotein cholesterol levels, tendon xanthomas and corneal arcus (3 clinically homozygous FH and 13 heterozygous FH) of ethnic African origin were screened for mutations in the LDLR (coding region, promoter and intron/exon boundaries), APOB (part of exon 26) and PCSK9 genes (exon 7), using high-resolution melting...
January 30, 2017: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
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