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Jacqueline C Silva, Edson M de Oliveira, Walter M Turato, Gustavo H G Trossini, Vinícius G Maltarollo, Marina G R Pitta, Ivan R Pitta, Beatriz de Las Heras, Lisardo Boscá, Martina Rudnicki, Dulcineia S P Abdalla
BACKGROUND: Obesity and insulin resistance/diabetes are important risk factors for cardiovascular diseases and demand safe and efficacious therapeutics. OBJECTIVE: To assess the effects of a new thiazolidine compound-GQ-11-on obesity and insulin resistance induced by a diabetogenic diet in LDL receptor-deficient (LDLr -/- ) mice. METHODS: Molecular docking simulations of GQ-11, PPARα and PPARγ structures were performed. Male C57BL/6J LDLr -/- mice fed a diabetogenic diet for 24 weeks were treated with vehicle, GQ-11 or pioglitazone or (20 mg/kg/day) for 28 days by oral gavage...
January 30, 2018: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Nitika Setia, Renu Saxena, J P S Sawhney, Ishwar C Verma
OBJECTIVE: Familial Hypercholesterolemia (FH) is an inherited disorder of lipid metabolism characterized by very high low density lipoprotein (LDL) cholesterol since birth, resulting in premature atherosclerosis and coronary artery disease (CAD). Cascade screening of children and family members of proven FH individuals can identify more subjects who have high LDL cholesterol or the family mutation and appropriate intervention can reduce their risk of atherosclerosis and prevent its complications...
February 15, 2018: Indian Journal of Pediatrics
Amy C Burke, Dawn E Telford, Brian G Sutherland, Jane Y Edwards, Cynthia G Sawyez, P Hugh R Barrett, Roger S Newton, J Geoffrey Pickering, Murray W Huff
OBJECTIVE: Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. In phase 2 studies, BemA lowers elevated low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. In the present study, we tested the ability of BemA to decrease plasma cholesterol and LDL-C and attenuate atherosclerosis in a large animal model of familial hypercholesterolemia. APPROACH AND RESULTS: Gene targeting has been used to generate Yucatan miniature pigs heterozygous ( LDLR +/- ) or homozygous ( LDLR -/- ) for LDL receptor deficiency (ExeGen)...
February 15, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Jennifer M Rutkowsky, Linda L Lee, Michelle Puchowicz, Mari S Golub, Douglas E Befroy, Dennis W Wilson, Steven Anderson, Gary Cline, Jason Bini, Kamil Borkowski, Trina A Knotts, John C Rutledge
Recent work suggests that diet affects brain metabolism thereby impacting cognitive function. Our objective was to determine if a western diet altered brain metabolism, increased blood-brain barrier (BBB) transport and inflammation, and induced cognitive impairment in C57BL/6 (WT) mice and low-density lipoprotein receptor null (LDLr -/-) mice, a model of hyperlipidemia and cognitive decline. We show that a western diet and LDLr -/- moderately influence cognitive processes as assessed by Y-maze and radial arm water maze...
2018: PloS One
Yang Shen, Bin Cao, Noah R Snyder, Kevin M Woeppel, James R Eles, Xinyan Tracy Cui
BACKGROUND: Oxidative stress acts as a trigger in the course of neurodegenerative diseases and neural injuries. An antioxidant-based therapy can be effective to ameliorate the deleterious effects of oxidative stress. Resveratrol (RSV) has been shown to be effective at removing excess reactive oxygen species (ROS) or reactive nitrogen species generation in the central nervous system (CNS), but the delivery of RSV into the brain through systemic administration is inefficient. Here, we have developed a RSV delivery vehicle based on polylactic acid (PLA)-coated mesoporous silica nanoparticles (MSNPs), conjugated with a ligand peptide of low-density lipoprotein receptor (LDLR) to enhance their transcytosis across the blood-brain barrier (BBB)...
February 13, 2018: Journal of Nanobiotechnology
Jiawei Liao, Xuejing Liu, Mingming Gao, Mengyu Wang, Yuhui Wang, Feng Wang, Wei Huang, George Liu
SEIPIN is an integral membrane protein located in the endoplasmic reticulum, regulating adipocytes differentiation and lipolysis. Deficiency of Seipin in mice causes severe general lipodystrophy, accompanied by insulin resistance, postprandial hypertriglyceridemia and steatohepatitis. In atherosclerosis-prone Ldlr null (Ldlr -/- ) mice, lipodystrophy caused by Seipin deletion even led to severe hypercholesteremia and accelerated atherogenesis, when challenged with an atherogenic diet. However, whether the phenotypes observed in Seipin -/- Ldlr -/- mice were a common consequence due to lipodystrophy, rather than genetic background restricted or diet dependent, was unknown...
March 30, 2018: Gene
Tomás Zambrano, Rosario D C Hirata, Mario H Hirata, Álvaro Cerda, Luis A Salazar
AIM: Although statins are considered a cornerstone for the treatment of high cholesterol levels due to their powerful cholesterol-lowering effects, response to drug administration is still one of the main pitfalls of statin treatment. So far, the reasons underlying this undesired outcome are still poorly understood, but recently, various studies have suggested that miRNAs may be involved. Therefore, we aimed at evaluating the effect of short-term low-dose treatment with 2 statins on miRNAs expression in patients with hypercholesterolemia...
February 7, 2018: European Journal of Pharmaceutical Sciences
Savitha Subramanian, Leela Goodspeed, Shari Wang, Yilei Ding, Kevin D O'Brien, Godfrey S Getz, Alan Chait, Catherine A Reardon
Obesity is a chronic inflammatory state characterized by altered levels of adipose tissue immune cell populations. Natural killer T (NKT) cells are CD1d restricted lymphocyte subsets that recognize lipid antigens whose level decreases in obese adipose tissue. However, studies in mice with deficiency or increased levels of NKT cells have yielded contradictory results, so the exact role of these cells in obesity and adipose tissue inflammation is not yet established. We previously showed that Ldlr-/- mice with excess invariant NKT (iNKT) cells demonstrate significant weight gain, adiposity, metabolic abnormalities, and atherosclerosis...
February 8, 2018: International Journal of Molecular Sciences
Geralda Gillian Silva-Sena, Maressa Malini, Juliana Macedo Delarmelina, Jean Carlos Vencioneck Dutra, Suiany Vitorino Gervásio, Marcos André Soares Leal, Thiago de Melo Costa Pereira, Aneli M Barbosa-Dekker, Robert F H Dekker, Flavia de Paula, Maria do Carmo Pimentel Batitucci
The antimutagenic effect of botryosphaeran, an exocellular (1 → 3)(1 → 6)-β-d-glucan, from the ascomyceteous and plant-borne endophytic fungus, Botryosphaeria rhodina MAMB-05, was evaluated in young (6-8 weeks) and elderly (18 months) Swiss albino mice of both genders. The hypolipidemic, hypoglycemic and antiatherogenic potential was also evaluated in 18-month old male LDL receptor knockout (LDLr-/-) mice. Administration of botryosphaeran by gavage (doses: 7.5, 15, 30 mg/kg b.w./day) in a 30-day pretreatment protocol (young mice), or 15-day protocol (older mice), did not cause genotoxicity as assessed by the micronucleus test in peripheral blood (PB) and bone marrow cells (BMCs)...
February 2018: Mutation Research
Weichun Yang, Ziyi Shen, Sixian Wen, Wei Wang, Minyu Hu
BACKGROUND: Lycopene is a kind of carotenoid, with a strong capacity of antioxidation and regulating the bloodlipid. There has been some evidence that lycopene has protective effects on the central nervous system, but few studies have rigorously explored the role of neurotransmitters in it. Therefore, the present study was designed to investigate the effects of several neurotransmitters as lycopene exerts anti-injury effects induced by hyperlipidemia. METHODS: Eighty adult SD rats, half male and half female, were randomly divided into eight groups on the basis of serum total cholesterol (TC) levels and body weight...
February 7, 2018: Lipids in Health and Disease
Hee Nam Kim, Sun-Seog Kweon, Min-Ho Shin
We aimed to evaluate the prevalence of familial hypercholesterolaemia (FH) in a subject with hypercholesterolaemia from two population-based cohorts in South Korea. A total of 283 subjects with total cholesterol levels of 290 mg/dL (7.5 mmol/L) or higher were selected from the Namwon and Dong-gu Studies. We used next generation sequencing (NGS) to detect mutations in low-density lipoprotein receptors (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. We have confirmed 17 different mutations of the LDLR, APOB and PCSK9 in 23 subjects (8...
January 2018: Chonnam Medical Journal
Luis Masana, Josefa Girona, Daiana Ibarretxe, Ricardo Rodríguez-Calvo, Roser Rosales, Joan-Carles Vallvé, Cèlia Rodríguez-Borjabad, Montserrat Guardiola, Marina Rodríguez, Sandra Guaita-Esteruelas, Iris Oliva, Neus Martínez-Micaelo, Mercedes Heras, Raimon Ferré, Josep Ribalta, Núria Plana
While the impact of very low concentrations of low-density lipoprotein cholesterol (LDL-C) on cardiovascular prevention is very reassuring, it is intriguing to know what effect these extremely low LDL-C concentrations have on lipid homoeostasis. The evidence supporting the safety of extremely low LDL levels comes from genetic studies and clinical drug trials. Individuals with lifelong low LDL levels due to mutations in genes associated with increased LDL-LDL receptor (LDLR) activity reveal no safety issues...
January 8, 2018: Journal of Clinical Lipidology
Majambu Mbikay, Janice Mayne, Francine Sirois, Olesya Fedoryak, Angela Raymond, Jennifer Noad, Michel Chrétien
SCOPE: Hepatic LDL receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) regulate the clearance of plasma LDL-cholesterol (LDL-C): LDLR promotes it, and PCSK9 opposes it. These proteins also expressed in pancreatic β cells. Using cultured hepatocytes, we previously showed that the plant flavonoid quercetin-3-glucoside (Q3G) inhibited PCSK9 secretion, stimulated LDLR expression, and enhanced LDL-C uptake. Here, we examined whether Q3G supplementation could reverse the hyperlipidemia and hyperinsulinemia of mice fed a high-cholesterol diet, and how it affected hepatic and pancreatic LDLR and PCSK9 expression...
February 3, 2018: Molecular Nutrition & Food Research
Chiara Ricci, Massimiliano Ruscica, Marina Camera, Laura Rossetti, Chiara Macchi, Alessandra Colciago, Ilaria Zanotti, Maria Giovanna Lupo, Maria Pia Adorni, Arrigo F G Cicero, Federica Fogacci, Alberto Corsini, Nicola Ferri
Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250 ÷ 2.5 µg/ml) of human recombinant PCSK9 (hPCSK9)...
February 2, 2018: Scientific Reports
Merel L Hartgers, Joep C Defesche, Gisle Langslet, Paul N Hopkins, John J P Kastelein, Marie T Baccara-Dinet, Werner Seiz, Sara Hamon, Poulabi Banerjee, Claudia Stefanutti
BACKGROUND: Mutations in the genes for the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). OBJECTIVE: The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. METHODS: Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR, apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 genes...
December 28, 2017: Journal of Clinical Lipidology
Aline D de Lima, Maria C Guido, Elaine R Tavares, Priscila O Carvalho, Alyne F Marques, Marcelo D T de Melo, Vera M C Salemi, Roberto Kalil-Filho, Raul C Maranhão
Left ventricular (LV) remodeling after myocardial infarction constitutes the structural basis for ventricular dysfunction and heart failure. The characterization underlying the expression of lipoprotein receptors in cardiac dysfunction is scarcely explored. The aim of this study was to analyze the status of lipoprotein receptors on the infarcted and noninfarcted areas of LV and to verify whether nanoparticles that mimic the lipid structure of low-density lipoprotein (LDL) and have the ability to bind to LDL receptors (LDE) are taken up more avidly by the noninfarcted LV...
February 2, 2018: Lipids
Jean-Pierre Rabès, Sophie Béliard, Alain Carrié
PURPOSE OF REVIEW: We provide an overview of molecular diagnosis for familial hypercholesterolemia in France including descriptions of the mutational spectrum, polygenic susceptibility and perspectives for improvement in familial hypercholesterolemia diagnosis. RECENT FINDINGS: Molecular testing for familial hypercholesterolemia is recommended for patients with a LDL-cholesterol level above 190 mg/dl (adults) associated with criteria related to personal and family history of hypercholesterolemia and premature cardiovascular disease...
January 31, 2018: Current Opinion in Lipidology
Sandy Elbitar, Delia Susan-Resiga, Youmna Ghaleb, Petra El Khoury, Gina Peloso, Nathan Stitziel, Jean-Pierre Rabès, Valérie Carreau, Josée Hamelin, Ali Ben-Djoudi-Ouadda, Eric Bruckert, Catherine Boileau, Nabil G Seidah, Mathilde Varret, Marianne Abifadel
Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated LDL-C levels leading to coronary heart disease. Four genes are implicated in ADH: LDLR, APOB, PCSK9 and APOE. Our aim was to identify new mutations in known genes, or in new genes implicated in ADH. Thirteen French families with ADH were recruited and studied by exome sequencing after exclusion, in their probands, of mutations in the LDLR, PCSK9 and APOE genes and fragments of exons 26 and 29 of APOB gene. We identified in one family a p...
January 31, 2018: Scientific Reports
Mehri Jamilian, Mansooreh Samimi, Naghmeh Mirhosseini, Faraneh Afshar Ebrahimi, Esmat Aghadavod, Mohsen Taghizadeh, Zatollah Asemi
Gestational diabetes mellitus (GDM) is a common complication of pregnancy, and it is mostly associated with postpartum diabetes, insulin resistance, and dyslipidemia. Fish oil (omega-3) supplementation has been shown to reduce the risk of different chronic diseases such as cardiovascular disease, type 2 diabetes, and cancers, though the evidence of its impact on gestational diabetes is scarce. Our goal in this study was to determine the effect of fish oil administration on gene expression related to insulin action, blood lipids, and inflammation in women with GDM...
January 31, 2018: Nutrients
Rie Harada, Masako Kimura, Yasushi Sato, Tatsuya Taniguchi, Tetsu Tomonari, Takahiro Tanaka, Hironori Tanaka, Naoki Muguruma, Hirohiko Shinomiya, Hirohito Honda, Issei Imoto, Masahiro Sogabe, Toshiya Okahisa, Tetsuji Takayama
BACKGROUND: It has been reported that some single-nucleotide polymorphisms (SNPs) in lipid regulators such as apolipoproteins and cell surface molecules for hepatitis C virus (HCV) entry into hepatocytes are associated with HCV infection. However, it is unknown how HCV infection is affected by altered lipid metabolism resulting from the SNPs. We investigated the relationship between these SNPs and HCV infection status, and also analyzed the mechanism by which these SNPs mediate HCV infection via lipid metabolism alterations...
January 30, 2018: BMC Gastroenterology
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