Effect of diet and genotype on the lipidome of mice with altered lipoprotein metabolism.

The present study describes and compares the impact of PCSK9 and LDLR, two pivotal players in cholesterol metabolism, on the whole lipidome of plasma, liver and aorta in different dietary conditions. This issue is relevant, since several lipid species, circulating at very low concentrations, have the ability to impair lipid metabolism and promote atherosclerosis development. To this aim, wild-type, hypercholesterolemic Ldlr-KO, and hypocholesterolemic Pcsk9-KO mice were fed a standard chow or a Western-type diet up to 30 and 16 weeks of age, respectively.

Effect of diet and genotype on the miRNome of mice with altered lipoprotein metabolism.

The molecular mechanism by which lipid/lipoprotein biosynthesis is regulated in mammals involves a very large number of genes that are subject to multiple levels of regulation. miRNAs are recognized contributors to lipid homeostasis at the post-transcriptional level, although the elucidation of their role is made difficult by the multiplicity of their targets and the ability of more miRNAs to affect the same mRNAs. In this study, an evaluation of how miRNA expression varies in organs playing a key role in lipid/lipoprotein metabolism was conducted in control mice and in two mouse models carrying genetic ablations which differently affect low-density lipoprotein metabolism.

Autism-linked NLGN3 is a key regulator of gonadotropin-releasing hormone deficiency.

Gonadotropin-releasing hormone (GnRH) deficiency (GD) is a disorder characterized by absent or delayed puberty, with largely unknown genetic causes. The purpose of this study was to obtain and exploit gene expression profiles of GnRH neurons during development to unveil novel biological mechanisms and genetic determinants underlying GD. Here, we combined bioinformatic analyses of immortalized and primary embryonic GnRH neuron transcriptomes with exome sequencing from GD patients to identify candidate genes implicated in the pathogenesis of GD.

Effect of Diets on Plasma and Aorta Lipidome: A Study in the apoE Knockout Mouse Model.

Scope: Specific lipid molecules circulating in plasma at low concentrations have emerged as biomarkers of atherosclerotic risk. The aim of the present study is that of evaluating, in an athero-prone mouse model, how different diets can affect plasma and aorta lipidome.

Methods And Results: Thirty-six apoE knockout mice are divided in three groups and feed 12 weeks with diets differing for cholesterol and fatty acid content.

Lack of ApoA-I in ApoEKO Mice Causes Skin Xanthomas, Worsening of Inflammation, and Increased Coronary Atherosclerosis in the Absence of Hyperlipidemia.

Background: HDL (high-density lipoprotein) and its major protein component, apoA-I (apolipoprotein A-I), play a unique role in cholesterol homeostasis and immunity. ApoA-I deficiency in hyperlipidemic, atheroprone mice was shown to drive cholesterol accumulation and inflammatory cell activation/proliferation. The present study was aimed at investigating the impact of apoA-I deficiency on lipid deposition and local/systemic inflammation in normolipidemic conditions.

reString: an open-source Python software to perform automatic functional enrichment retrieval, results aggregation and data visualization.

Functional enrichment analysis is an analytical method to extract biological insights from gene expression data, popularized by the ever-growing application of high-throughput techniques. Typically, expression profiles are generated for hundreds to thousands of genes/proteins from samples belonging to two experimental groups, and after ad-hoc statistical tests, researchers are left with lists of statistically significant entities, possibly lacking any unifying biological theme. Functional enrichment tackles the problem of putting overall gene expression changes into a broader biological context, based on pre-existing knowledge bases of reference: database collections of known expression regulation, relationships and molecular interactions.

Aortic Gene Expression Profiles Show How ApoA-I Levels Modulate Inflammation, Lysosomal Activity, and Sphingolipid Metabolism in Murine Atherosclerosis.

Objective: HDL (high-density lipoprotein) particles are known to possess several antiatherogenic properties that include the removal of excess cholesterol from peripheral tissues, the maintenance of endothelial integrity, antioxidant, and anti-inflammatory activities. ApoA-I overexpression in apoE-deficient (EKO) mice has been shown to increase HDL levels and to strongly reduce atherosclerosis development. The aim of the study was to investigate gene expression patterns associated with atherosclerosis development in the aorta of EKO mice and how HDL plasma levels relate to gene expression patterns at different stages of atherosclerosis development and with different dietary treatments.

liputils: a Python module to manage individual fatty acid moieties from complex lipids.

Lipidomic analyses address the problem of characterizing the lipid components of given cells, tissues and organisms by means of chromatographic separations coupled to high-resolution, tandem mass spectrometry analyses. A number of software tools have been developed to help in the daunting task of mass spectrometry signal processing and cleaning, peak analysis and compound identification, and a typical finished lipidomic dataset contains hundreds to thousands of individual molecular lipid species. To provide researchers without a specific technical expertise in mass spectrometry the possibility of broadening the exploration of lipidomic datasets, we have developed liputils, a Python module that specializes in the extraction of fatty acid moieties from individual molecular lipids.

Fat-Shaped Microbiota Affects Lipid Metabolism, Liver Steatosis, and Intestinal Homeostasis in Mice Fed a Low-Protein Diet.

Scope: Protein malnutrition is characterized by stunted growth, hepatic steatosis and a damaged gut mucosal architecture. Since high-fat shaped gut microbiota (HFM) has an increased ability in providing nutrients and energy from food to the host, the aim of this study is to determine whether such a microbiota could beneficially impact on the consequences of malnutrition.

Methods And Results: The cecal content of specific pathogen free C57Bl/6J mice fed a high-fat diet or a low-protein diet is transplanted in two groups of germ-free C57Bl/6J recipient mice, which are subsequently fed a low-protein diet for 8 weeks.

The Gut Microbiota Affects Host Pathophysiology as an Endocrine Organ: A Focus on Cardiovascular Disease.

It is widely recognized that the microorganisms inhabiting our gastrointestinal tract-the gut microbiota-deeply affect the pathophysiology of the host. Gut microbiota composition is mostly modulated by diet, and gut microorganisms communicate with the different organs and tissues of the human host by synthesizing hormones and regulating their release. Herein, we will provide an updated review on the most important classes of gut microbiota-derived hormones and their sensing by host receptors, critically discussing their impact on host physiology.

Myocardial overexpression of ANKRD1 causes sinus venosus defects and progressive diastolic dysfunction.

Aims: Increased Ankyrin Repeat Domain 1 (ANKRD1) levels linked to gain of function mutations have been associated to total anomalous pulmonary venous return and adult cardiomyopathy occurrence in humans. The link between increased ANKRD1 level and cardiac structural and functional disease is not understood. To get insight into this problem, we have generated a gain of function ANKRD1 mouse model by overexpressing ANKRD1 in the myocardium.

Fenretinide treatment accelerates atherosclerosis development in apoE-deficient mice in spite of beneficial metabolic effects.

Background And Purpose: Fenretinide, a synthetic retinoid derivative first investigated for cancer prevention and treatment, has been shown to ameliorate glucose tolerance, improve plasma lipid profile and reduce body fat mass. These effects, together with its ability to inhibit ceramide synthesis, suggest that fenretinide may have an anti-atherosclerotic action.

Experimental Approach: To this aim, nine-week-old apoE-knockout (EKO) female mice were fed for twelve weeks a Western diet, without (control) or with (0.

Infusions of Large Synthetic HDL Containing Trimeric apoA-I Stabilize Atherosclerotic Plaques in Hypercholesterolemic Rabbits.

Background: Among strategies to reduce the remaining risk of cardiovascular disease, interest has focused on using infusions of synthetic high-density lipoprotein (sHDL).

Methods: New Zealand rabbits underwent a perivascular injury at both carotids and were randomly allocated into 2 protocols: (1) a single-dose study, where rabbits were treated with a single infusion of sHDL containing a trimeric form of human apoA-I (TN-sHDL, 200 mg/kg) or with Placebo; (2) a multiple-dose study, where 4 groups of rabbits were treated 5 times with Placebo or TN-sHDL at different doses (8, 40, 100 mg/kg). Plaque changes were analysed in vivo by intravascular ultrasound.

MEN1309/OBT076, a First-In-Class Antibody-Drug Conjugate Targeting CD205 in Solid Tumors.

CD205 is a type I transmembrane glycoprotein and is a member of the C-type lectin receptor family. Analysis by mass spectrometry revealed that CD205 was robustly expressed and highly prevalent in a variety of solid malignancies from different histotypes. IHC confirmed the increased expression of CD205 in pancreatic, bladder, and triple-negative breast cancer (TNBC) compared with that in the corresponding normal tissues.

Effects of Vegetable Proteins on Hypercholesterolemia and Gut Microbiota Modulation.

Risk assessment tools, i.e., validated risk prediction algorithms, to estimate the patient's 10-year risk of developing cardiovascular disease (CVD) should be used to identify high-risk people for primary prevention.

Lipid phosphate phosphatase 3 in vascular pathophysiology.

LPP3 is an integral membrane protein belonging to a family of enzymes (LPPs) that display broad substrate specificity and catalyse dephosphorylation of several lipid substrates, including lysophosphatidic acid and sphingosine-1-phosphate. In mammals, the LPP family consists of three enzymes named LPP1, LPP2 and LPP3, which are encoded by three independent genes, PLPP1, PLPP2 and PLPP3, respectively (formerly known as PPAP2A, PPAP2C, PPAP2B). These three enzymes, in vitro, do not seem to differ for catalytic activities and substrate preferences.

Effect of Dietary Components from Antarctic Krill on Atherosclerosis in apoE-Deficient Mice.

Scope: Antarctic krill is a great source of n-3 fatty acids and high-quality proteins. Aim of the study was to evaluate the effect of Antarctic krill components on plasma lipids and atherosclerosis development.

Methods And Results: Sixty apoEKO mice were divided into four groups and fed Western diet (CONTROL) or Western-like diets, differing for protein or fat content.

Liver-specific deletion of the Plpp3 gene alters plasma lipid composition and worsens atherosclerosis in apoE mice.

The PLPP3 gene encodes for a ubiquitous enzyme that dephosphorylates several lipid substrates. Genome-wide association studies identified PLPP3 as a gene that plays a role in coronary artery disease susceptibility. The aim of the study was to investigate the effect of Plpp3 deletion on atherosclerosis development in mice.

Nutraceuticals and Bioactive Components from Fish for Dyslipidemia and Cardiovascular Risk Reduction.

Cardiovascular disease remains the most common health problem in developed countries, and residual risk after implementing all current therapies is still high. Permanent changes in lifestyle may be hard to achieve and people may not always be motivated enough to make the recommended modifications. Emerging research has explored the application of natural food-based strategies in disease management.

A Comparative View on Easy to Deploy non-Integrating Methods for Patient-Specific iPSC Production.

Induced pluripotent stem cells (iPSCs) are routinely produced from dermal fibroblasts, with potential applications ranging from in vitro disease models to drug discovery and regenerative medicine. The need of eliminating the remaining reprogramming factors after iPSC production spurred the development of non-integrating viruses such as Sendai and other methods to deliver episomal vectors, which are progressively lost upon cell division. We compared four widespread methods (Sendai virus, Nucleofector, Neon transfection system and Lipofectamine 3000) to generate integration-free iPSC lines from primary human dermal fibroblasts (hDF) of three patients.

High-density lipoprotein deficiency in genetically modified mice deeply affects skin morphology: A structural and ultrastructural study.

Cutaneous lipids, endogenously synthetized and transported by lipoproteins, play a pivotal role in maintaining skin barrier. An impairment of extracutaneous lipid trafficking leads to the development of xanthomas, mostly arising in hyperlipidemic patients, but also in subjects with high-density lipoprotein (HDL) deficiency. The aim of this work was to evaluate, in a genetically modified mouse model, lacking two protein components of HDL particles, apolipoprotein(apo)E and apoA-I, the effect of HDL deficiency on skin morphology.