156 Regulation of LDL-cholesterol Associated Gene Expression by Iron Responsive Elements and Iron

Heart ◽  
2014 ◽  
Vol 100 (Suppl 3) ◽  
pp. A91.1-A91
Author(s):  
Dan Yin ◽  
Jutta Palmen ◽  
Anastasia Kalea ◽  
Andrew Smith ◽  
Philippa Talmud ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ldl Cholesterol ◽  
Iron Responsive Elements

scholarly journals Reduced oxidized LDL in T2D plaques is associated with a greater statin usage but not with future cardiovascular events

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Pratibha Singh ◽  
Isabel Goncalves ◽  
Christoffer Tengryd ◽  
Mihaela Nitulescu ◽  
Ana F. Persson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Events ◽  
Ldl Cholesterol ◽  
Oxidized Ldl ◽  
Receptor Gene ◽  
Clinical Information ◽  
Endothelial Activation ◽  
Statin Treatment ◽  
Plasma Lipoproteins ◽  
Statin Usage

Abstract Background Type 2 diabetes (T2D) patients are at a greater risk of cardiovascular events due to aggravated atherosclerosis. Oxidized LDL (oxLDL) has been shown to be increased in T2D plaques and suggested to contribute to plaque ruptures. Despite intensified statin treatment during the last decade the higher risk for events remains. Here, we explored if intensified statin treatment was associated with reduced oxLDL in T2D plaques and if oxLDL predicts cardiovascular events, to elucidate whether further plaque oxLDL reduction would be a promising therapeutic target. Methods Carotid plaque OxLDL levels and plasma lipoproteins were assessed in 200 patients. Plaque oxLDL was located by immunohistochemistry. Plaque cytokines, cells and scavenger receptor gene expression were quantified by Luminex, immunohistochemistry and RNA sequencing, respectively. Clinical information and events during follow-up were obtained from national registers. Results Plaque oxLDL levels correlated with markers of inflammatory activity, endothelial activation and plasma LDL cholesterol (r = 0.22-0.32 and p ≤ 0.01 for all). T2D individuals exhibited lower plaque levels of oxLDL, sLOX-1(a marker of endothelial activation) and plasma LDL cholesterol (p = 0.001, p = 0.006 and p = 0.009). No increased gene expression of scavenger receptors was identified in T2D plaques. The lower oxLDL content in T2D plaques was associated with a greater statin usage (p = 0.026). Supporting this, a linear regression model showed that statin treatment was the factor with the strongest association to plaque oxLDL and plasma LDL cholesterol (p < 0.001 for both). However, patients with T2D more frequently suffered from symptoms and yet plaque levels of oxLDL did not predict cardiovascular events in T2D (findings are summarized in Fig. 1a). Conclusions This study points out the importance of statin treatment in affecting plaque biology in T2D. It also implies that other biological components, beyond oxLDL, need to be identified and targeted to further reduce the risk of events among T2D patients receiving statin treatment.

Iron Responsive Element-Mediated Responses to Iron Dyshomeostasis in Alzheimer’s Disease

2021 ◽  
pp. 1-34
Author(s):  
Nhi Hin ◽  
Morgan Newman ◽  
Stephen Pederson ◽  
Michael Lardelli
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cultured Cells ◽  
Transcript Abundance ◽  
Untranslated Regions ◽  
Gene Sets ◽  
The Stability ◽  
Responsive Element ◽  
Iron Responsive Elements

Background: Iron trafficking and accumulation is associated with Alzheimer’s disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterized, making it difficult to explore these in existing datasets. Objective: To identify sets of genes predicted to contain iron responsive elements (IREs) and use these to explore possible iron dyshomeostasis-associated gene expression responses in AD. Methods: Comprehensive sets of genes containing predicted IRE or IRE-like motifs in their 3′ or 5′ untranslated regions (UTRs) were identified in human, mouse, and zebrafish reference transcriptomes. Further analyses focusing on these genes were applied to a range of cultured cell, human, mouse, and zebrafish gene expression datasets. Results: IRE gene sets are sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, changes in IRE transcript abundance are among the earliest observable changes in zebrafish familial AD (fAD)-like brains, preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some IREs in the 3′ untranslated regions of transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead display decreased stability, indicating that this is not a generalizable paradigm. Conclusion: Our results reveal IRE gene expression changes as early markers of the pathogenic process in fAD and are consistent with iron dyshomeostasis as an important driver of this disease. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis-associated gene expression responses across different species, tissues, and conditions.

scholarly journals Using metabolic profiling and gene expression analyses to explore molecular effects of replacing saturated fat with polyunsaturated fat—a randomized controlled dietary intervention study

2019 ◽  
Vol 109 (5) ◽  
pp. 1239-1250 ◽  
Author(s):  
Stine M Ulven ◽  
Jacob J Christensen ◽  
Ottar Nygård ◽  
Asbjørn Svardal ◽  
Lena Leder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dietary Fat ◽  
Metabolic Profiling ◽  
Dietary Intervention ◽  
Ldl Cholesterol ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Randomized Controlled ◽  
Fat Quality ◽  
Molecular Effects

ABSTRACT Background Replacing dietary saturated fatty acids (SFAs) with polyunsaturated fatty acids (PUFA) reduces the plasma low-density lipoprotein (LDL) cholesterol and subsequently the risk of cardiovascular disease. However, beyond changes in LDL cholesterol, we lack a complete understanding of the physiologic alterations that occur when improving dietary fat quality. Objectives The aim of this study was to gain knowledge of metabolic alterations paralleling improvements in the fat quality of the diet. Methods We recently conducted an 8-wk, double-blind, randomized controlled trial replacing SFAs with PUFAs in healthy subjects with moderate hypercholesterolemia (n = 99). In the present substudy, we performed comprehensive metabolic profiling with multiple platforms (both nuclear magnetic resonance- and mass spectrometry-based technology) (n = 99), and analyzed peripheral blood mononuclear cell gene expression (n = 95) by quantitative real-time polymerase chain reaction. Results A large number of lipoprotein subclasses, myristoylcarnitine and palmitoylcarnitine, and kynurenine were reduced when SFAs were replaced with PUFAs. In contrast, bile acids, proprotein convertase subtilisin/kexin type 9, acetate, and acetoacetate were increased by the intervention. Some amino acids were also altered by the intervention. The mRNA levels of LXRA and LDLR were increased, in addition to several liver X receptor α target genes and genes involved in inflammation, whereas the mRNA levels of UCP2 and PPARD were decreased in peripheral blood mononuclear cells after replacing SFAs with PUFAs. Partial least squares-discriminant analysis showed that the 30 most important variables that contributed to class separation spanned all classes of biomarkers, and was in accordance with the univariate analysis. Conclusions Applying metabolomics in randomized controlled dietary intervention trials has the potential to extend our knowledge of the biological and molecular effects of dietary fat quality. This study was registered at clinicaltrials.gov as NCT 01679496.

scholarly journals Docosahexaenoic Acid and Eicosapentaenoic Acid Supplementation Differentially Modulate Pro- and Anti-inflammatory Cytokines in Subjects with Chronic Inflammation (OR29-02-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jisun So ◽  
Dayong Wu ◽  
Alice Lichtenstein ◽  
Stefania Lamon-Fava
Keyword(s):  
Gene Expression ◽  
Docosahexaenoic Acid ◽  
Eicosapentaenoic Acid ◽  
Chronic Inflammation ◽  
Inflammatory Cytokines ◽  
Ldl Cholesterol ◽  
Serum Concentrations ◽  
Blood Monocytes ◽  
Control Phase ◽  
Anti Inflammatory

Abstract Objectives Despite extensive works on the cardioprotective effects of fish oil containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the distinct mechanisms by which DHA and EPA modulate inflammation and plasma lipids are not well characterized. We compared the effects of DHA and EPA supplementation on serum cytokines and blood monocyte inflammatory response and on blood lipids in subjects with chronic inflammation. Methods Twenty-one subjects (9 men and 12 women, 50–75 y) with chronic inflammation (CRP > 2 µg/mL) were enrolled in a randomized, controlled crossover trial consisting of a 4-week lead-in control phase (high oleic sunflower oil, 3 g/d) followed by two sequential 10-week supplementation phases with pure DHA or EPA (3 g/d each) with a 10-week washout in between. Serum concentrations of cytokines were determined by electrochemiluminescence (ECL) assay. Following lipopolysaccharides (LPS) stimulation of blood monocytes, gene expression and secretion of cytokines were assessed by qPCR and ECL. Plasma lipid concentrations were measured by enzymatic assays. Results Relative to the control phase, DHA reduced the LPS-induced gene expression of pro-inflammatory TNFA (median % change: −45%, P < 0.001), IL6 (−51%, P < 0.05), MCP1 (−28%, P < 0.04) as well as anti-inflammatory IL10 (−33%, P < 0.02) and the secretion of TNF-α (−41%, P < 0.02), MCP-1 (−29%, P < 0.01), and IL-10 (−47%, P < 0.05) in monocytes. On the other hand, EPA increased serum concentrations of IL-10 (+14%, P < 0.05) and lowered only TNFAexpression (−20%, P < 0.03) in monocytes. When compared to EPA supplementation, DHA decreased serum concentrations of MCP-1 (P < 0.03), and monocyte MCP-1 secretion (P < 0.05) and IL10 expression (P < 0.04). Regarding plasma concentrations of lipids, relative to the control phase, both DHA (−16%, P < 0.001) and EPA decreased triglycerides (−22%, P < 0.001) while only DHA increased LDL-cholesterol (+7%, P < 0.02). Conclusions DHA and EPA differently modulate the balance between pro- and anti-inflammatory cytokines in serum and blood monocytes in subjects with chronic inflammation. While DHA inhibits a broad range of pro- and anti-inflammatory cytokines, EPA has a relatively minor role in lowering pro-inflammatory cytokines but preserves the anti-inflammatory IL-10. DHA, but not EPA, increases LDL-cholesterol. Funding Sources Funded by USDA/NIFA.

Molecular and Microscopic Analysis of Altered Gene Expression in Transgenic and Gene Targeted Mice

1996 ◽  
Vol 54 ◽  
pp. 12-13
Author(s):  
W. K. Jones ◽  
J. Robbins
Keyword(s):  
Gene Expression ◽  
Pulmonary Veins ◽  
Microscopic Analysis ◽  
Mouse Tissue ◽  
Adult Heart ◽  
Heavy Chains ◽  
Altered Gene Expression ◽  
Altered Gene ◽  
Pulmonary Myocardium

Two myosin heavy chains (MyHC) are expressed in the mammalian heart and are differentially regulated during development. In the mouse, the α-MyHC is expressed constitutively in the atrium. At birth, the β-MyHC is downregulated and replaced by the α-MyHC, which is the sole cardiac MyHC isoform in the adult heart. We have employed transgenic and gene-targeting methodologies to study the regulation of cardiac MyHC gene expression and the functional and developmental consequences of altered α-MyHC expression in the mouse.We previously characterized an α-MyHC promoter capable of driving tissue-specific and developmentally correct expression of a CAT (chloramphenicol acetyltransferase) marker in the mouse. Tissue surveys detected a small amount of CAT activity in the lung (Fig. 1a). The results of in situ hybridization analyses indicated that the pattern of CAT transcript in the adult heart (Fig. 1b, top panel) is the same as that of α-MyHC (Fig. 1b, lower panel). The α-MyHC gene is expressed in a layer of cardiac muscle (pulmonary myocardium) associated with the pulmonary veins (Fig. 1c). These studies extend our understanding of α-MyHC expression and delimit a third cardiac compartment.

Sign in / Sign up

Export Citation Format

Share Document