Global epidemiology of dyslipidaemias Pirillo, Angela; Casula, Manuela; Olmastroni, Elena ...
Nature reviews cardiology,
10/2021, Letnik:
18, Številka:
10
Journal Article
Recenzirano
Dyslipidaemias are alterations to the plasma lipid profile that are often associated with clinical conditions. Dyslipidaemias, particularly elevated plasma LDL-cholesterol levels, are major risk ...factors for cardiovascular disease, but some forms, such as hypertriglyceridaemia, are associated with severe diseases in other organ systems, including non-alcoholic fatty liver disease and acute pancreatitis. Dyslipidaemias can be genetically determined (primary or familial dyslipidaemias) or secondary to other conditions (such as diabetes mellitus, obesity or an unhealthy lifestyle), the latter being more common. Hypercholesterolaemia is the most common form of dyslipidaemia and is associated with an increased risk of cardiovascular disease, with elevated plasma LDL-cholesterol levels being the 15th leading risk factor for death in 1990, rising to 11th in 2007 and 8th in 2019. The global burden of dyslipidaemias has increased over the past 30 years. Furthermore, the combination of high triglyceride levels and low HDL-cholesterol levels (together with the presence of small, dense LDL particles), referred to as atherogenic dyslipidaemia, is highly prevalent in patients with diabetes or metabolic syndrome and increases their risk of cardiovascular disease. Given the increasing prevalence of diabetes worldwide, treating lipid abnormalities in these patients might reduce their risk of cardiovascular disease.
Epidemiological data and interventional studies with hormone replacement therapy suggest that women, at least until menopause, are at decreased cardiovascular risk compared to men. Still the ...molecular mechanisms beyond this difference are debated and the investigation in experimental models of atherosclerosis has been pivotal to prove that the activation of the estrogen receptor is atheroprotective, despite not enough to explain the differences reported in cardiovascular disease between male and female.
This casts also for investigating the importance of the sex chromosome complement (genetic sex) beyond the contribution of sex hormones (gonadal sex) on atherosclerosis. Aim of this review is to present the dualism between gonadal sex and genetic sex with a focus on the data available from experimental models. The molecular mechanisms driving changes in lipid metabolism, immuno-inflammatory reactivity and vascular response in males and females that affect atherosclerosis progression will be discussed.
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•Women are at decreased cardiovascular risk compared to men until menopause, an effect not solely explained by estrogens.•Experimental models have deepened our knowledge of atherosclerosis, but sex differences are still underestimated.•Animal models are depicting the impact of sexual hormones (gonadal sex) versus sexual chromosomes (genetic sex).•Both lipid and inflammatory traits can be differently modulated by genetic versus gonadal sex.
Abstract
Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are ...removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular function are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.
Cholesterol homeostasis has a pivotal function in regulating immune cells. Here we show that apolipoprotein E (apoE) deficiency leads to the accumulation of cholesterol in the cell membrane of ...dendritic cells (DC), resulting in enhanced MHC-II-dependent antigen presentation and CD4
T-cell activation. Results from WT and apoE KO bone marrow chimera suggest that apoE from cells of hematopoietic origin has immunomodulatory functions, regardless of the onset of hypercholesterolemia. Humans expressing apoE4 isoform (ε4/3-ε4/4) have increased circulating levels of activated T cells compared to those expressing WT apoE3 (ε3/3) or apoE2 isoform (ε2/3-ε2/2). This increase is caused by enhanced antigen-presentation by apoE4-expressing DCs, and is reversed when these DCs are incubated with serum containing WT apoE3. In summary, our study identifies myeloid-produced apoE as a key physiological modulator of DC antigen presentation function, paving the way for further explorations of apoE as a tool to improve the management of immune diseases.
Cholesterol plays an essential role in determining cell membrane physico-chemical characteristics and functions. A proper membrane structure is critical in pancreatic β-cells for glucose-mediated ...insulin secretion, and alterations in cellular cholesterol content may negatively affect this process, leading to β-cell dysfunction. The low density lipoprotein receptor (LDL-R) appears to play a relevant role in ß-cell dysfunction due to cholesterol accumulation. This observation raised the question of whether hypocholesterolemic drugs which increase LDL-R expression might bear diabetogenic properties, thus increasing the risk of new-onset diabetes or worsen glycaemic parameters in diabetic patients.
Being at higher cardiovascular risk, diabetic patients are usually treated with hypolipidemic drugs to correct the atherogenic dyslipidemia characteristic of this pathological condition. Statin therapy has been associated with an increased incidence of new-onset diabetes (NOD), being the diabetogenic effect depending on the type and dose of statin. However, it is worth noting that the benefits on cardiovascular mortality largely exceed the increased risk associated with the development of diabetes. Although genetic variants associated with lower levels of LDL-C are also associated with an increased NOD risk, clinical trials with lipid-lowering drugs other than statins, namely ezetimibe or monoclonal antibodies against PCSK9, did not observe an increase of developing diabetes.
In summary, molecular evidence clearly points to a key role for cholesterol homeostasis in pancreatic β-cell function which, in humans, is negatively affected by statins. Available data exclude that this could be the case for other hypocholesterolemic approaches, but long-term studies are warranted to explore this critical aspect.
•Cholesterol has a key role in determining structure and function of cell membranes.•Cholesterol accumulation in pancreatic β-cells induces cell dysfunction.•Genetically driven low LDL-C levels associate with higher risk of diabetes.•Statin therapy is associated with increased risk of new-onset diabetes.•Hypocholesterolemic drugs other than statins do not appear to increase the risk of diabetes.
New Pharmacological Approaches to Target PCSK9 Catapano, Alberico L.; Pirillo, Angela; Norata, Giuseppe D.
Current atherosclerosis reports,
06/2020, Letnik:
22, Številka:
7
Journal Article
Recenzirano
Purpose of Review
Proprotein convertase subtilisin kexin 9 (PCSK9) plays a crucial role in regulating circulating levels of LDL-C as a consequence of its ability to inhibit LDL receptor recycling in ...the liver. Loss of function variants in the
PCSK9
gene result in low LDL-C levels and associate with reduced cardiovascular risk, whereas gain of-function variants associate with hypercholesterolemia and increased risk of early cardiovascular events. Thus, PCSK9 inhibition has been established as an additional approach for the treatment of hypercholesterolemia. The aim of this review is to provide a brief overview of current strategies targeting PCSK9 and discuss clinical results of the emerging approaches.
Recent Findings
Two monoclonal antibodies targeting circulating PCSK9 (evolocumab and alirocumab) have been approved for the treatment of hypercholesterolemia and cardiovascular disease. Later, a gene silencing approach (inclisiran), which inhibits hepatic PCSK9 synthesis, was shown to be as effective as monoclonal antibodies but with a twice a year injection and is currently under evaluation for approval. Due to the elevated costs of such therapies, several other approaches have been explored, including peptide-based anti PCSK9 vaccination, and small oral PCSK9 inhibitors, which are still in preclinical phase.
Summary
In the coming years, we will assist to a progressive introduction of novel anti-PCSK9 approaches in the clinical practice for the treatment of patients with hypercholesterolemia as well as patients at high cardiovascular risk.
Abstract
The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. We recently identified SPRING as a post-transcriptional ...regulator of SREBP activation. Constitutive or inducible global ablation of
Spring
in mice is not tolerated, and we therefore develop liver-specific
Spring
knockout mice (LKO). Transcriptomics and proteomics analysis reveal attenuated SREBP signaling in livers and hepatocytes of LKO mice. Total plasma cholesterol is reduced in male and female LKO mice in both the low-density lipoprotein and high-density lipoprotein fractions, while triglycerides are unaffected. Loss of
Spring
decreases hepatic cholesterol and triglyceride content due to diminished biosynthesis, which coincides with reduced very-low-density lipoprotein secretion. Accordingly, LKO mice are protected from fructose diet-induced hepatosteatosis. In humans, we find common genetic
SPRING
variants that associate with circulating high-density lipoprotein cholesterol and ApoA1 levels. This study positions SPRING as a core component of hepatic SREBP signaling and systemic lipid metabolism in mice and humans.
Purpose of Review
Familial hypercholesterolemia (FH) is a monogenic disorder characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C) since birth and a high risk of ...premature cardiovascular disease. The genetic defect is carried in only one allele in heterozygous FH (HeFH) or in both in the most severe homozygous FH (HoFH). Current guidelines recommend to reduce substantially LDL-C levels in these high-risk patients, with the need to use association therapy combining agents with different mechanisms of action. As most cases of FH are attributable to mutations in the gene encoding the low-density lipoprotein receptor (LDLR), statins, even in combination with ezetimibe, are less effective in reducing LDL-C plasma levels in FH patients, who require a more intensive approach with additional lipid-lowering agents. Additional targets playing key roles in regulating LDL-C levels are represented by PCSK9 and ANGPTL3.
Recent Findings
Two monoclonal antibodies (mAbs) targeting PCSK9, evolocumab and alirocumab, significantly reduce LDL-C levels in HeFH patients. In patients with HoFH, the efficacy of mAbs to PCSK9 is strictly related to the presence of a residual LDLR activity; thus, patients carrying null mutations do not respond to the therapy with these mAbs, whereas some effects can be appreciated in HoFH bearing defective mutations. Conversely, evinacumab, the mAb targeting ANGPTL3, is highly effective in reducing LDL-C levels even in HoFH patients carrying null
LDLR
mutations, thanks to its LDLR-independent mechanism of action.
Summary
Monoclonal antibodies inhibiting PCSK9 have shown a robust effect in FH patients presenting a residual LDLR activity, while ANGPTL3 inhibitors appear to be promising even in patients carrying null
LDLR
mutations.
Migration of activated regulatory T (Treg) cells to inflamed tissue is crucial for their immune-modulatory function. While metabolic reprogramming during Treg cell differentiation has been ...extensively studied, the bioenergetics of Treg cell trafficking remains undefined. We have investigated the metabolic demands of migrating Treg cells in vitro and in vivo. We show that glycolysis was instrumental for their migration and was initiated by pro-migratory stimuli via a PI3K-mTORC2-mediated pathway culminating in induction of the enzyme glucokinase (GCK). Subsequently, GCK promoted cytoskeletal rearrangements by associating with actin. Treg cells lacking this pathway were functionally suppressive but failed to migrate to skin allografts and inhibit rejection. Similarly, human carriers of a loss-of-function GCK regulatory protein gene—leading to increased GCK activity—had reduced numbers of circulating Treg cells. These cells displayed enhanced migratory activity but similar suppressive function, while conventional T cells were unaffected. Thus, GCK-dependent glycolysis regulates Treg cell migration.
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•Migration of regulatory T (Treg) cells requires glycolysis•This is mediated by the enzyme glucokinase induced by a PI3K-mTORC2 pathway•Treg cells lacking this pathway are unable to localize to inflammatory sites•A loss-of-function GCK regulator gene causes enhanced motility of human Treg cells
Regulatory T cell localization to inflammatory sites is key to their homeostatic function. Kishore and colleagues demonstrate that Treg cell migration requires the activation of glycolysis by the enzyme glucokinase induced via a Treg cell-selective PI3K-mTORC2 pathway.
Pentraxin 3 (PTX3) is a fluid-phase pattern recognition molecule and a key component of the humoral arm of innate immunity. In four different models of tissue damage in mice, PTX3 deficiency was ...associated with increased fibrin deposition and persistence, and thicker clots, followed by increased collagen deposition, when compared with controls. Ptx3-deficient macrophages showed defective pericellular fibrinolysis in vitro. PTX3-bound fibrinogen/fibrin and plasminogen at acidic pH and increased plasmin-mediated fibrinolysis. The second exon-encoded N-terminal domain of PTX3 recapitulated the activity of the intact molecule. Thus, a prototypic component of humoral innate immunity, PTX3, plays a nonredundant role in the orchestration of tissue repair and remodeling. Tissue acidification resulting from metabolic adaptation during tissue repair sets PTX3 in a tissue remodeling and repair mode, suggesting that matrix and microbial recognition are common, ancestral features of the humoral arm of innate immunity.
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