scholarly journals SUMOylation in the control of cholesterol homeostasis

Open Biology ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 200054 ◽  
Author(s):  
Ana Talamillo ◽  
Leiore Ajuria ◽  
Marco Grillo ◽  
Orhi Barroso-Gomila ◽  
Ugo Mayor ◽  
...  
Keyword(s):  
Vitamin D ◽  
Plasma Membrane ◽  
Cardiovascular Diseases ◽  
Protein Modification ◽  
Cholesterol Homeostasis ◽  
Sumo Modification ◽  
Cellular Processes ◽  
Receptor Signalling ◽  
Cholesterol Levels

SUMOylation—protein modification by the small ubiquitin-related modifier (SUMO)—affects several cellular processes by modulating the activity, stability, interactions or subcellular localization of a variety of substrates. SUMO modification is involved in most cellular processes required for the maintenance of metabolic homeostasis. Cholesterol is one of the main lipids required to preserve the correct cellular function, contributing to the composition of the plasma membrane and participating in transmembrane receptor signalling. Besides these functions, cholesterol is required for the synthesis of steroid hormones, bile acids, oxysterols and vitamin D. Cholesterol levels need to be tightly regulated: in excess, it is toxic to the cell, and the disruption of its homeostasis is associated with various disorders like atherosclerosis and cardiovascular diseases. This review focuses on the role of SUMO in the regulation of proteins involved in the metabolism of cholesterol.

scholarly journals Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Vijay R. Varma ◽  
H. Büşra Lüleci ◽  
Anup M. Oommen ◽  
Sudhir Varma ◽  
Chad T. Blackshear ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Transcriptomic Data ◽  
Brain Cholesterol ◽  
Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

scholarly journals The Role of Vitamin D as a Biomarker in Alzheimer’s Disease

2021 ◽  
Vol 11 (3) ◽  
pp. 334
Author(s):  
Giulia Bivona ◽  
Bruna Lo Sasso ◽  
Caterina Maria Gambino ◽  
Rosaria Vincenza Giglio ◽  
Concetta Scazzone ◽  
...  
Keyword(s):  
Vitamin D ◽  
Risk Factor ◽  
Cognitive Decline ◽  
Immune Cell ◽  
Response To Treatment ◽  
Cellular Processes ◽  
Vitamin D Levels ◽  
The Brain ◽  
Key Questions

Vitamin D and cognition is a popular association, which led to a remarkable body of literature data in the past 50 years. The brain can synthesize, catabolize, and receive Vitamin D, which has been proved to regulate many cellular processes in neurons and microglia. Vitamin D helps synaptic plasticity and neurotransmission in dopaminergic neural circuits and exerts anti-inflammatory and neuroprotective activities within the brain by reducing the synthesis of pro-inflammatory cytokines and the oxidative stress load. Further, Vitamin D action in the brain has been related to the clearance of amyloid plaques, which represent a feature of Alzheimer Disease (AD), by the immune cell. Based on these considerations, many studies have investigated the role of circulating Vitamin D levels in patients affected by a cognitive decline to assess Vitamin D’s eventual role as a biomarker or a risk factor in AD. An association between low Vitamin D levels and the onset and progression of AD has been reported, and some interventional studies to evaluate the role of Vitamin D in preventing AD onset have been performed. However, many pitfalls affected the studies available, including substantial discrepancies in the methods used and the lack of standardized data. Despite many studies, it remains unclear whether Vitamin D can have a role in cognitive decline and AD. This narrative review aims to answer two key questions: whether Vitamin D can be used as a reliable tool for diagnosing, predicting prognosis and response to treatment in AD patients, and whether it is a modifiable risk factor for preventing AD onset.

scholarly journals Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Akash Das ◽  
Michael S Brown ◽  
Donald D Anderson ◽  
Joseph L Goldstein ◽  
Arun Radhakrishnan
Keyword(s):  
Plasma Membrane ◽  
Regulatory Mechanism ◽  
Low Density Lipoprotein ◽  
Human Fibroblasts ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Mutant Form ◽  
Perfringolysin O ◽  
Cholesterol Levels ◽  
Plasma Membrane Cholesterol

When human fibroblasts take up plasma low density lipoprotein (LDL), its cholesterol is liberated in lysosomes and eventually reaches the endoplasmic reticulum (ER) where it inhibits cholesterol synthesis by blocking activation of SREBPs. This feedback protects against cholesterol overaccumulation in the plasma membrane (PM). But how does ER know whether PM is saturated with cholesterol? In this study, we define three pools of PM cholesterol: (1) a pool accessible to bind 125I-PFO*, a mutant form of bacterial Perfringolysin O, which binds cholesterol in membranes; (2) a sphingomyelin(SM)-sequestered pool that binds 125I-PFO* only after SM is destroyed by sphingomyelinase; and (3) a residual pool that does not bind 125I-PFO* even after sphingomyelinase treatment. When LDL-derived cholesterol leaves lysosomes, it expands PM's PFO-accessible pool and, after a short lag, it also increases the ER's PFO-accessible regulatory pool. This regulatory mechanism allows cells to ensure optimal cholesterol levels in PM while avoiding cholesterol overaccumulation.

scholarly journals Proprotein Convertase Subtilisin/Kexin Type 9: From the Discovery to the Development of New Therapies for Cardiovascular Diseases

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-21 ◽  
Author(s):  
Nicola Ferri
Keyword(s):  
Cardiovascular Diseases ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Low Density ◽  
Regulatory Effect ◽  
Proprotein Convertase ◽  
Pharmacological Modulation ◽  
Cholesterol Levels

The identification of the HMG-CoA reductase inhibitors, statins, has represented a dramatic innovation of the pharmacological modulation of hypercholesterolemia and associated cardiovascular diseases. However, not all patients receiving statins achieve guideline-recommended low density lipoprotein (LDL) cholesterol goals, particularly those at high risk. There remains, therefore, an unmet medical need to develop additional well-tolerated and effective agents to lower LDL cholesterol levels. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9), a secretory protein that posttranscriptionally regulates levels of low density lipoprotein receptor (LDLR) by inducing its degradation, has opened a new era of pharmacological modulation of cholesterol homeostasis. This paper summarizes the current knowledge of the basic molecular mechanism underlying the regulatory effect of LDLR expression by PCSK9 obtained fromin vitrocell-cultured studies and the analysis of the crystal structure of PCSK9. It also describes the epidemiological and experimental evidences of the regulatory effect of PCSK9 on LDL cholesterol levels and cardiovascular diseases and summarizes the different pharmacological approaches under development for inhibiting PCSK9 expression, processing, and the interaction with LDLR.

scholarly journals The C99 Fragment Of App Regulates Cholesterol Trafficking

2019 ◽  
Author(s):  
M. Pera ◽  
D. Larrea ◽  
J. Montesinos ◽  
C. Guardia-Laguarta ◽  
R.R. Agrawal ◽  
...  
Keyword(s):  
De Novo ◽  
Amyloid Β ◽  
Cholesterol Homeostasis ◽  
Lipid Homeostasis ◽  
Cholesterol Trafficking ◽  
Cellular Cholesterol ◽  
Binding Peptide ◽  
Cholesterol Levels ◽  
Lipid Sensing

The link between cholesterol homeostasis and the cleavage of the amyloid precursor protein (APP), and their relationship to the pathogenesis of Alzheimer’s disease (AD) is still unknown. Cellular cholesterol levels are regulated by a crosstalk between the plasma membrane (PM), where most of the cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates cholesterol resides. This crosstalk between PM and ER is believed to be regulated by lipid-sensing peptide(s) that can modulate the internalization of extracellular cholesterol and/or its de novo synthesis in the ER. Our data here indicates that the 99-aa C-terminal fragment of APP (C99), a cholesterol-binding peptide, regulates cholesterol trafficking between the PM and the ER. In AD models, increases in C99 provoke the upregulation of cholesterol internalization and its delivery to the ER, which in turn result into the loss of lipid homeostasis and the appearance of AD signatures, such as higher production of longer forms of amyloid β. Our data suggest a novel role of C99 as mediator of cholesterol disturbances in AD, and as a potential early hallmark of the disease.

scholarly journals The role of profilin-1 in cardiovascular diseases

2021 ◽  
Vol 134 (9) ◽  
Author(s):  
Abigail Allen ◽  
David Gau ◽  
Partha Roy
Keyword(s):  
Cardiovascular Diseases ◽  
Actin Cytoskeleton ◽  
Cell Cycle Progression ◽  
Neurological Diseases ◽  
Essential Feature ◽  
Actin Binding ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Damage Response

ABSTRACT Dynamic remodeling of the actin cytoskeleton is an essential feature for virtually all actin-dependent cellular processes, including cell migration, cell cycle progression, chromatin remodeling and gene expression, and even the DNA damage response. An altered actin cytoskeleton is a structural hallmark associated with numerous pathologies ranging from cardiovascular diseases to immune disorders, neurological diseases and cancer. The actin cytoskeleton in cells is regulated through the orchestrated actions of a myriad of actin-binding proteins. In this Review, we provide a brief overview of the structure and functions of the actin-monomer-binding protein profilin-1 (Pfn1) and then discuss how dysregulated expression of Pfn1 contributes to diseases associated with the cardiovascular system.

scholarly journals Corrigendum to “The Role of Parathyroid Hormone and Vitamin D Serum Concentrations in Patients with Cardiovascular Diseases”

2018 ◽  
Vol 2018 ◽  
pp. 1-1
Author(s):  
Agnieszka Kolaszko ◽  
Ewa Nowalany-Kozielska ◽  
Piotr Ceranowicz ◽  
Beata Morawiec ◽  
Grzegorz Kubiak
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Cardiovascular Diseases ◽  
Serum Concentrations

scholarly journals Role of Glutaredoxin-1 and Glutathionylation in Cardiovascular Diseases

2020 ◽  
Vol 21 (18) ◽  
pp. 6803 ◽  
Author(s):  
Mannix Burns ◽  
Syed Husain Mustafa Rizvi ◽  
Yuko Tsukahara ◽  
David R. Pimentel ◽  
Ivan Luptak ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Disulfide Bonds ◽  
Arterial Disease ◽  
Disulfide Bridges ◽  
Myocardial Ischemia And Reperfusion ◽  
Cellular Processes ◽  
Mixed Disulfide ◽  
Peripheral Arterial ◽  
Structure Of Proteins

Cardiovascular diseases are the leading cause of death worldwide, and as rates continue to increase, discovering mechanisms and therapeutic targets become increasingly important. An underlying cause of most cardiovascular diseases is believed to be excess reactive oxygen or nitrogen species. Glutathione, the most abundant cellular antioxidant, plays an important role in the body’s reaction to oxidative stress by forming reversible disulfide bridges with a variety of proteins, termed glutathionylation (GSylation). GSylation can alter the activity, function, and structure of proteins, making it a major regulator of cellular processes. Glutathione-protein mixed disulfide bonds are regulated by glutaredoxins (Glrxs), thioltransferase members of the thioredoxin family. Glrxs reduce GSylated proteins and make them available for another redox signaling cycle. Glrxs and GSylation play an important role in cardiovascular diseases, such as myocardial ischemia and reperfusion, cardiac hypertrophy, peripheral arterial disease, and atherosclerosis. This review primarily concerns the role of GSylation and Glrxs, particularly glutaredoxin-1 (Glrx), in cardiovascular diseases and the potential of Glrx as therapeutic agents.

Role of vitamin D in prophylaxis of cardiovascular diseases

2020 ◽  
Vol 18 (1) ◽  
pp. 50-53
Author(s):  
N. V. RYLOVA ◽  
◽  
A. V. ZHOLINSKIY ◽  
Keyword(s):  
Vitamin D ◽  
Cardiovascular Diseases

The role of diet during development on the regulation of adult cholesterol homeostasis

1985 ◽  
Vol 63 (5) ◽  
pp. 557-564 ◽  
Author(s):  
Sheila M. Innis
Keyword(s):  
Cholesterol Metabolism ◽  
Plasma Cholesterol ◽  
Dietary Cholesterol ◽  
Cholesterol Homeostasis ◽  
Cholesterol Levels ◽  
Effective Training ◽  
Cholesterol Intake ◽  
Lower Plasma Cholesterol ◽  
Altered Metabolism

Atherosclerosis is believed to begin early in life and to develop over several decades. Elevated plasma cholesterol is a major contributing factor. Studies in animals have shown that manipulation of cholesterol metabolism during its development in pre-and early post-natal life can permanently alter cholesterol synthesis and catabolism to favour lower plasma cholesterol levels in the adult faced with a high dietary cholesterol intake. Although the mechanisms and pathways involved are likely to be different, "metabolic training" can occur as a result of both the diet fed to the mother during gestation and lactation and from the diet fed to the animal itself in early life. The presence of cholesterol itself in the suckling diet does not appear to confer any lasting improvement to cholesterol handling in either man or animals. Although much research is still required to define the time in development for effective training of specific steps in cholesterol metabolism and the primary site and mechanism of permanently altered metabolism, significant progress has been made. These studies will form the basis of this review.

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