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J C Cohen
Genetic variation arises through multiple different alleles that vary in frequency and severity of effect. Mutations that give rise to Mendelian disorders, such as the LDL receptor (LDLR) mutations that result in familial hypercholesterolaemia, are efficiently winnowed from the population by purifying selection and are almost inevitably rare. Conversely, alleles that are common in the population (such that homozygotes for the minor allele are present even in modest sample sizes) typically have very modest phenotypic effects...
October 14, 2016: Journal of Internal Medicine
Zuhal Eroglu, Ece Harman, Egemen Vardarli, Meral Kayikcioglu, Asli Tetik Vardarli
BACKGROUND: Dyslipidemia has a substantial role in the development of cardiovascular diseases in patients with type 2 diabetes mellitus (T2DM). Determining the genetic profile of T2DM patients with dyslipidemia is important in order to reduce the risk of microvascular and macrovascular complications. Low-density lipoprotein receptor (LDLR) plays a critical role in plasma lipoprotein hemostasis. LDLR mutations/polymorphisms cause changes at the lipoprotein level. The objective of this study is to determine the frequency of LDLR (rs179989) polymorphisms in Turkish T2DM patients with dyslipidemia...
November 2016: Journal of Clinical Medicine Research
Dongyan Shao, Yilin Wang, Qingsheng Huang, Junling Shi, Hui Yang, Zhongli Pan, Mingliang Jin, Haobin Zhao, Xiaoguang Xu
Resveratrol (Res) was previously reported to be capable of lowering plasma TC and LDL-C. The mechanism behind Res is not clearly understood, although it is presumed to have an effect on bile acid metabolism in the liver: a significant way in eliminating cholesterol from the body. As one of the major metabolites of Res in the liver, resveratrol glucuronides (Gres) is suspected to also contribute to the overall cholestrol-lowering activity of Res, which needs to be studied. In this research, when HepG2 steatosis hepatic cells were treated with Res and Gres at different concentration levels, Res and Gres showed similar activity in lowering cellular TC content...
October 13, 2016: Journal of Food Science
Johanna M U Silvola, Helena Virtanen, Riikka Siitonen, Sanna Hellberg, Heidi Liljenbäck, Olli Metsälä, Mia Ståhle, Tiina Saanijoki, Meeri Käkelä, Harri Hakovirta, Seppo Ylä-Herttuala, Pekka Saukko, Matti Jauhiainen, Tibor Z Veres, Sirpa Jalkanen, Juhani Knuuti, Antti Saraste, Anne Roivainen
Given the important role of inflammation and the potential association of the leukocyte trafficking-associated adhesion molecule vascular adhesion protein 1 (VAP-1) with atherosclerosis, this study examined whether functional VAP-1 is expressed in atherosclerotic lesions and, if so, whether it could be targeted by positron emission tomography (PET). First, immunohistochemistry revealed that VAP-1 localized to endothelial cells of intra-plaque neovessels in human carotid endarterectomy samples from patients with recent ischemic symptoms...
October 12, 2016: Scientific Reports
Mai Yamashita, Motofumi Kumazoe, Yuki Nakamura, Yeong Seon Won, Jaehoon Bae, Shuya Yamashita, Hirofumi Tachibana
Western diets induce obesity associated with an increased risk of hypercholesterolaemia. Indeed, obesity-induced hypercholesterolaemia is correlated with increased coronary cardiovascular disease (CVD) risk. Male C57BL/6J mice were fed a normal diet, high-fat and high-sucrose diet (HF/HS), HF/HS with green tea extract powder diet (HF/HS+GT), HF/HS with eriodictyol diet (HF/HS+Eri), or HF/HS with green tea extract powder and eriodictyol diet (HF/HS+GT+Eri) for 8 wk. Body weight was lower in the HF/HS+GT+Eri group than in the HF/HS group (-8...
2016: Journal of Nutritional Science and Vitaminology
Mattia Stucchi, Giovanni Grazioso, Carmen Lammi, Silvia Manara, Chiara Zanoni, Anna Arnoldi, Giordano Lesma, Alessandra Silvani
Herein we report on the multicomponent synthesis of a novel imidazole-based compound, able to act efficiently as a minimalist β-strand mimic. Biological evaluation proved its ability to impair the LDLR-PCSK9 protein-protein interaction, disclosing it as the first small molecule exerting a PCSK9-mediated hypocholesterolemic effect.
October 18, 2016: Organic & Biomolecular Chemistry
Xiaoyue Pan, Christopher A Bradfield, M Mahmood Hussain
Circadian rhythms controlled by clock genes affect plasma lipids. Here we show that global ablation of Bmal1 in Apoe(-/-) and Ldlr(-/-) mice and its liver-specific ablation in Apoe(-/-) (L-Bmal1(-/-)Apoe(-/-)) mice increases, whereas overexpression of BMAL1 in L-Bmal1(-/-)Apoe(-/-) and Apoe(-/-)mice decreases hyperlipidaemia and atherosclerosis. Bmal1 deficiency augments hepatic lipoprotein secretion and diminishes cholesterol excretion to the bile. Further, Bmal1 deficiency reduces expression of Shp and Gata4...
October 10, 2016: Nature Communications
Jing Leng, Mei-Hong Chen, Zhi-Hui Zhou, Ya-Wen Lu, Xiao-Dong Wen, Jie Yang
Adipose tissue inflammation and macrophage polarization are tightly associated with the development of obesity-associated insulin resistance. Our previous studies have demonstrated the triterpenoids-enriched extract from the aerial parts of Salvia miltiorrhiza (TTE) could significantly improve atherosclerosis in LDLR(-/-) mice. However, its molecular mechanisms of TTE ameliorating insulin resistance remain unclear. In the present study, obesity model with insulin resistance induced by feeding high-fat diet (HFD) was established...
October 6, 2016: Phytotherapy Research: PTR
Yue Wang, Yulong Han, Fangni Chai, Hongmei Xiang, Tao Huang, Shuming Kou, Bing Han, Xiaobao Gong, Xiaoli Ye
The aim of this study was to investigate the antihypercholesterolemic activity and potential molecular mechanism of columbamine (COL) that was prepared by extraction from Rhizoma Coptidis in hamsters and HepG2 cells. The results displayed that the COL from Rhizoma Coptidis was a safe natural compound with a LD50 0f 1524.6mg/kg and no detectable toxic symptoms during the observation of chronic toxicity. COL dose-dependently reversed the abnormal lipid levels induced by HFHC diet. Specifically, COL(M) and COL(H) significantly reduced the blood lipid levels(TC, TG and LDL-c) and enhanced the fecal contents of TBA by 21...
October 3, 2016: Fitoterapia
Kristian K Jensen, Marija Tadin-Strapps, Sheng-Ping Wang, James Hubert, Yanqing Kan, Yong Ma, David G McLaren, Stephen F Previs, Kithsiri B Herath, Ablatt Mahsut, Andy Liaw, Shubing Wang, Steven J Stout, CarolAnn Keohan, Gail Forrest, David Coelho, Satya Yendluri, Stephanie Williams, Martin Koser, Steven Bartz, Karen O Akinsanya, Shirly Pinto
SREBP cleavage-activating protein (SCAP) is a key protein in the regulation of lipid metabolism and a potential target for treatment of dyslipidemia. SCAP is required for activation of the transcription factors SREBP-1 and -2. SREBPs regulate the expression of genes involved in fatty acid and cholesterol biosynthesis, and LDL-C clearance through the regulation of LDLR and PCSK9 expression. To further test the potential of SCAP as a novel target for treatment of dyslipidemia, we used short interfering RNAs (siRNA) to inhibit hepatic SCAP expression and assess the effect on PCSK9, LDLR and lipids in mice and rhesus monkeys...
October 5, 2016: Journal of Lipid Research
Luca A Lotta, Stephen J Sharp, Stephen Burgess, John R B Perry, Isobel D Stewart, Sara M Willems, Jian'an Luan, Eva Ardanaz, Larraitz Arriola, Beverley Balkau, Heiner Boeing, Panos Deloukas, Nita G Forouhi, Paul W Franks, Sara Grioni, Rudolf Kaaks, Timothy J Key, Carmen Navarro, Peter M Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, Jose-Ramón Quirós, Elio Riboli, Olov Rolandsson, Carlotta Sacerdote, Elena Salamanca-Fernandez, Nadia Slimani, Annemieke M W Spijkerman, Anne Tjonneland, Rosario Tumino, Daphne L van der A, Yvonne T van der Schouw, Mark I McCarthy, Inês Barroso, Stephen O'Rahilly, David B Savage, Naveed Sattar, Claudia Langenberg, Robert A Scott, Nicholas J Wareham
Importance: Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes...
October 4, 2016: JAMA: the Journal of the American Medical Association
Amanda Karolina Soares E Silva, Fabiana Oliveira Dos Santos Gomes, Bruna Dos Santos Silva, Edlene Lima Ribeiro, Amanda Costa Oliveira, Shyrlene Meyre da Rocha Araújo, Ingrid Tavares de Lima, Anne Gabrielle Vasconcelos Oliveira, Martina Rudnicki, Dulcineia S P Abdalla, Maria do Carmo Alves de Lima, Ivan da Rocha Pitta, Christina Alves Peixoto
BACKGROUND: Atherosclerosis is a complex disorder with a multifactorial pathogenesis. We previously indicated that the new TZD LPSF/GQ-02 inhibits hepatic steatosis and inflammation, which are reported as risk factors for atherosclerosis development. Here, we explored the effects of LPSF/GQ-02 on atherosclerosis in LDLr-/- mice comparing two treatment periods. METHODS AND RESULTS: LDLr(-/-) mice were fed a high-fat diet for 10 and 12 weeks and received oral treatment with LPSF/GQ-02 (30mg/kg/day) or pioglitazone (20mg/kg/day) for 15 and 30 days, respectively...
September 29, 2016: European Journal of Pharmacology
Luisa Pozzo, Andrea Vornoli, Ilaria Coppola, Clara Maria Della Croce, Lucia Giorgetti, Pier Giovanni Gervasi, Vincenzo Longo
AIMS: The aim of the study was to evaluate lipid, cholesterol and glucose metabolism in a novel rat model of non-alcoholic fatty liver disease (NAFLD). MAIN METHODS: Rats (Wistar) were fed high fat/cholesterol diet (HFD) and a single low dose (35mg/kg) of streptozotocin (STZ). Collagen and glycogen content, oxidative stress and glucokinase activity were measured using biochemical assays. Other metabolic pathway were assessed by qRT-PCR. KEY FINDINGS: HFD/STZ treated rats, compared to control ones, showed an increase in expression of biomarkers of inflammation (TNFα, IL6), fibrosis (TGFβ), mitochondrial stress (UCP2) and oxidative stress (GSH and carbonylated proteins) but not of ER stress (CHOP, XBP1)...
September 28, 2016: Life Sciences
Fang Zhang, Catherine Sodroski, Helen Cha, Qisheng Li, T Jake Liang
BACKGROUND & AIMS: The signaling molecule and transcriptional regulator SMAD6, which inhibits the transforming growth factor beta (TGFB) signaling pathway, is required for infection of hepatocytes by hepatitis C virus (HCV). We investigated the mechanisms by which SMAD6, and another inhibitory SMAD (SMAD7), promote HCV infection in human hepatoma cells and hepatocytes. METHODS: We infected Huh7 and Huh7.5.1 cells and primary human hepatocytes with JFH1 HCVcc; we measured HCV binding, intracellular levels of HCV RNA, and expression of target genes...
September 29, 2016: Gastroenterology
Xiaoxia Shi, Dangdang Li, Qinghua Deng, Zhicheng Peng, Chenxu Zhao, Xiaobing Li, Zhe Wang, Xinwei Li, Guowen Liu
Dairy cows with fatty liver or ketosis exhibit hyperketonemia, oxidative stress, and a low rate of very low density lipoprotein (VLDL) assembly, and there may be a potential link among these characteristics. Therefore, the objective of this study was to determine the effect of acetoacetic acid (AcAc) on the assembly of VLDL in cow hepatocytes. Cultured cow hepatocytes were treated with different concentrations of AcAc with or without N-acetylcysteine (NAC, an antioxidant). AcAc treatment decreased the mRNA expression and activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and significantly increased malondialdehyde (MDA) content, indicative of oxidative stress...
October 3, 2016: Journal of Dairy Research
Jieyi Li, Dipanjan Chanda, Patrick J van Gorp, Mike L J Jeurissen, Tom Houben, Sofie M A Walenbergh, Jacques Debets, Yvonne Oligschlaeger, Marion J J Gijbels, Dietbert Neumann, Ronit Shiri-Sverdlov
Non-alcoholic steatohepatitis (NASH) is a common liver disease characterized by hepatic lipid accumulation (steatosis) and inflammation. Currently, therapeutic options are poor and the long-term burden to society is constantly increasing. Previously, macrophage stimulating protein (MSP)-a serum protein mainly secreted by liver-was shown to inhibit oxidized low-density lipoprotein (OxLDL)/lipopolysaccharides (LPS)-induced inflammation in mouse macrophages. Additionally, MSP could reduce palmitic acid (PA)-induced lipid accumulation and lipogenesis in the HepG2 cell line...
2016: PloS One
Rafael Escate, Teresa Padro, Maria Borrell-Pages, Rosa Suades, Rosa Aledo, Pedro Mata, Lina Badimon
Familial hypercholesterolaemia (FH) is a major risk for premature coronary heart disease due to severe long-life exposure to high LDL levels. Accumulation of LDL in the vascular wall triggers atherosclerosis with activation of the innate immunity system. Here, we have investigated (i) gene expression of LDLR and LRPs in peripheral blood cells (PBLs) and in differentiated macrophages of young FH-patients; and (ii) whether macrophage from FH patients have a differential response when exposed to high levels of atherogenic LDL...
September 29, 2016: Journal of Cellular and Molecular Medicine
Rosalind Martin, Mark Latten, Padraig Hart, Helena Murray, Deborah A Bailie, Martin Crockard, John Lamont, Peter Fitzgerald, Colin A Graham
BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) leads to a lifelong increase in plasma LDL levels with subsequent increase in premature vascular disease. Early diagnosis and treatment is the key to effective management of this condition. This research aims to produce a simple and cost effective genetic test which could identify the majority (71%) of mutations causing FH in the UK and Ireland. METHODS: The Randox Biochip Array Technology was used to detect 40 point mutations in LDLR, APOB and PCSK9 genes, over two 5 × 5 arrays...
September 17, 2016: Atherosclerosis
Mu-En Lin, Theodore M Chen, Mary C Wallingford, Ngoc B Nguyen, Shunsuke Yamada, Chenphop Sawangmake, Jaimei Zhang, Mei Y Speer, Cecilia M Giachelli
AIMS: Vascular smooth muscle cells (SMCs) are major precursors contributing to osteochondrogenesis and calcification in atherosclerosis. Runt-related transcription factor-2 (Runx2) has been found essential for SMC differentiation to an osteochondrogenic phenotype and subsequent calcification in vitro A recent study using a conditional targeting allele that produced a truncated Runx2 protein in SMCs of ApoE(-/-) mice showed reduced vascular calcification, likely occurring via reduction of receptor activator of nuclear factor-κB ligand (RANKL), macrophage infiltration, and atherosclerotic lesion formation...
September 26, 2016: Cardiovascular Research
Xiang Chen, Chunyu Wang, Kun Zhang, Ying Xie, Xiao Ji, Hui Huang, Xijie Yu
Growing evidence argues for a relationship between lipid and bone metabolisms with inconsistent conclusions. Sphingosine-1-phosphate (S1P) has been recognized as a suitable candidate for possible link between lipid metabolism and bone metabolism. This study was designed to investigate the effects of hyperlipidemia on bone metabolism using diet-induced and genetic-induced hyperlipidemia animal models and to explore whether S1P is involved. Wild-type mice and low-density lipoprotein receptor gene deficient (LDLR(-/-)) mice at age of 8weeks were placed on either control diet or high-fat diet (HFD) for 12weeks...
September 23, 2016: Bone
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