scholarly journals TNF-α interferes with lipid homeostasis and activates acute and proatherogenic processes

2007 ◽  
Vol 31 (2) ◽  
pp. 216-227 ◽  
Author(s):  
Klementina Fon Tacer ◽  
Drago Kuzman ◽  
Matej Seliškar ◽  
Denis Pompon ◽  
Damjana Rozman
Keyword(s):  
Regulatory Element ◽  
Hdl Cholesterol ◽  
Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Lipid Homeostasis ◽  
Transcriptional Level ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Element Binding Protein ◽  
Cytokine Tumor Necrosis Factor

The interaction between disrupted lipid homeostasis and immune response is implicated in the pathogenesis of several diseases, but the molecular bridges between the major players are still a matter of controversy. Our systemic study of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in the livers of mice exposed to 20-h cytokine/fasting for the first time shows that TNF-α interferes with adaptation to fasting and activates harmful proatherogenic pathways, partially through interaction with the insulin-Insig-sterol regulatory element binding protein (Srebp) signaling pathway. In addition to the increased expression of acute-phase inflammatory genes, the most prominent alterations represent modified lipid homeostasis observed on the gene expression and metabolite levels. These include reduction of HDL-cholesterol, increase of LDL-cholesterol, and elevated expression of cholesterogenic genes, accompanied by increase of potentially harmful precholesterol metabolites and suppression of cholesterol elimination through bile acids, likely by farnesoid X receptor-independent mechanisms. On the transcriptional level, a shift from fatty oxidation toward fatty acid synthesis is observed. The concept of the influence of TNF-α on the Srebp regulatory network, followed by downstream effects on sterol metabolism, is novel. Observed acute alterations in lipid metabolism are in agreement with chronic disturbances found in patients.

scholarly journals CRISPR/Cas9-mediated editing of Δ5 and Δ6 desaturases impairs Δ8-desaturation and docosahexaenoic acid synthesis in Atlantic salmon (Salmo salar L.)

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Alex K. Datsomor ◽  
Rolf E. Olsen ◽  
Nikola Zic ◽  
Angelico Madaro ◽  
Atle M. Bones ◽  
...  
Keyword(s):  
Atlantic Salmon ◽  
Regulatory Element ◽  
Acid Synthesis ◽  
Fatty Acyl ◽  
Chain Polyunsaturated Fatty Acid ◽  
Pufa Diet ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
High Degree

AbstractThe in vivo functions of Atlantic salmon fatty acyl desaturases (fads2), Δ6fads2-a, Δ6fads2-b, Δ6fads2-c and Δ5fads2 in long chain polyunsaturated fatty acid (LC-PUFA) synthesis in salmon and fish in general remains to be elucidated. Here, we investigate in vivo functions and in vivo functional redundancy of salmon fads2 using two CRISPR-mediated partial knockout salmon, Δ6abc/5Mt with mutations in Δ6fads2-a, Δ6fads2-b, Δ6fads2-c and Δ5fads2, and Δ6bcMt with mutations in Δ6fads2-b and Δ6fads2-c. F0 fish displaying high degree of gene editing (50–100%) were fed low LC-PUFA and high LC-PUFA diets, the former containing reduced levels of eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acids but higher content of linoleic (18:2n-6) and alpha-linolenic (18:3n-3) acids, and the latter containing high levels of 20:5n-3 and 22:6n-3 but reduced compositions of 18:2n-6 and 18:3n-3. The Δ6abc/5Mt showed reduced 22:6n-3 levels and accumulated Δ6-desaturation substrates (18:2n-6, 18:3n-3) and Δ5-desaturation substrate (20:4n-3), demonstrating impaired 22:6n-3 synthesis compared to wildtypes (WT). Δ6bcMt showed no effect on Δ6-desaturation compared to WT, suggesting Δ6 Fads2-a as having the predominant Δ6-desaturation activity in salmon, at least in the tissues analyzed. Both Δ6abc/5Mt and Δ6bcMt demonstrated significant accumulation of Δ8-desaturation substrates (20:2n-6, 20:3n-3) when fed low LC-PUFA diet. Additionally, Δ6abc/5Mt demonstrated significant upregulation of the lipogenic transcription regulator, sterol regulatory element binding protein-1 (srebp-1) in liver and pyloric caeca under reduced dietary LC-PUFA. Our data suggest a combined effect of endogenous LC-PUFA synthesis and dietary LC-PUFA levels on srebp-1 expression which ultimately affects LC-PUFA synthesis in salmon. Our data also suggest Δ8-desaturation activities for salmon Δ6 Fads2 enzymes.

scholarly journals Matrix Metalloproteinases Contribute to Brain Damage in Experimental Pneumococcal Meningitis

2000 ◽  
Vol 68 (2) ◽  
pp. 615-620 ◽  
Author(s):  
Stephen L. Leib ◽  
David Leppert ◽  
John Clements ◽  
Martin G. Täuber
Keyword(s):  
Matrix Metalloproteinases ◽  
Bacterial Meningitis ◽  
Brain Damage ◽  
Neuronal Injury ◽  
Housekeeping Gene ◽  
Close Correlation ◽  
Necrosis Factor Alpha ◽  
Mmp Inhibitor ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor

ABSTRACT The present study was performed to evaluate the role of matrix metalloproteinases (MMP) in the pathogenesis of the inflammatory reaction and the development of neuronal injury in a rat model of bacterial meningitis. mRNA encoding specific MMPs (MMP-3, MMP-7, MMP-8, and MMP-9) and the inflammatory cytokine tumor necrosis factor alpha (TNF-α) were significantly (P< 0.04) upregulated, compared to the β-actin housekeeping gene, in cortical homogenates at 20 h after infection. In parallel, concentrations of MMP-9 and TNF-α in cerebrospinal fluid (CSF) were significantly increased in rats with bacterial meningitis compared to uninfected animals (P = 0.002) and showed a close correlation (r = 0.76; P < 0.001). Treatment with a hydroxamic acid-type MMP inhibitor (GM6001; 65 mg/kg intraperitoneally every 12 h) beginning at the time of infection significantly lowered the MMP-9 (P< 0.02) and TNF-α (P < 0.02) levels in CSF. Histopathology at 25.5 ± 5.7 h after infection showed neuronal injury (median [range], 3.5% [0 to 17.5%] of the cortex), which was significantly (P < 0.01) reduced to 0% (0 to 10.8%) by GM6001. This is the first report to demonstrate that MMPs contribute to the development of neuronal injury in bacterial meningitis and that inhibition of MMPs may be an effective approach to prevent brain damage as a consequence of the disease.

scholarly journals PCSK9: A Key Target for the Treatment of Cardiovascular Disease (CVD)

2020 ◽  
Vol 10 (4) ◽  
pp. 502-511
Author(s):  
Saeideh Sobati ◽  
Amir Shakouri ◽  
Mahdi Edalati ◽  
Daryoush Mohammadnejad ◽  
Reza Parvan ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Gene Silencing ◽  
Regulatory Element ◽  
New Method ◽  
Lipid Homeostasis ◽  
Transcriptional Level ◽  
Ldl Receptors ◽  
Sterol Regulatory Element ◽  
Pcsk9 Inhibition

Proprotein convertase subtilisin/kexin type 9 (PCSK9), as a vital modulator of low-densitylipoprotein cholesterol (LDL-C) , is raised in hepatocytes and released into plasma where it bindsto LDL receptors (LDLR), leading to their cleavage. PCSK9 adheres to the epidermal growthfactor-like repeat A (EGF-A) domain of the LDLR which is confirmed by crystallography. LDLRexpression is adjusted at the transcriptional level through sterol regulatory element bindingprotein 2 (SREBP-2) and at the post translational stages, specifically through PCSK9, and theinducible degrader of the LDLR PCSK9 inhibition is an appealing new method for reducing theconcentration of LDL-C. In this review the role of PCSK9 in lipid homeostasis was elucidated, theeffect of PCSK9 on atherosclerosis was highlighted, and contemporary therapeutic techniquesthat focused on PCSK9 were summarized. Several restoration methods to inhibit PCSK9 havebeen proposed which concentrate on both extracellular and intracellular PCSK9, and theyinclude blockage of PCSK9 production by using gene silencing agents and blockage of it’sbinding to LDLR through antibodies and inhibition of PCSK9 autocatalytic processes by tinymolecule inhibitors.

scholarly journals The Flavonoid Quercetin Inhibits Proinflammatory Cytokine (Tumor Necrosis Factor Alpha) Gene Expression in Normal Peripheral Blood Mononuclear Cells via Modulation of the NF-κβ System

2006 ◽  
Vol 13 (3) ◽  
pp. 319-328 ◽  
Author(s):  
Madhavan P. Nair ◽  
Supriya Mahajan ◽  
Jessica L. Reynolds ◽  
Ravikumar Aalinkeel ◽  
Harikrishnan Nair ◽  
...  
Keyword(s):  
Gene Expression ◽  
Proinflammatory Cytokine ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

ABSTRACT The flavonoids comprise a large class of low-molecular-weight plant metabolites ubiquitously distributed in food plants. These dietary antioxidants exert significant antitumor, antiallergic, and anti-inflammatory effects. The molecular mechanisms of their biological effects remain to be clearly understood. We investigated the anti-inflammatory potentials of a safe, common dietary flavonoid component, quercetin, for its ability to modulate the production and gene expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) by human peripheral blood mononuclear cells (PBMC). Our results showed that quercetin significantly inhibited TNF-α production and gene expression in a dose-dependent manner. Our results provide direct evidence of the anti-inflammatory effects of quercetin by PBMC, which are mediated by the inhibition of the proinflammatory cytokine TNF-α via modulation of NF-κβ1 and Iκβ.

Effect of Polysaccharide from Tricholoma Matsutake on TNF-α and IL-2

2014 ◽  
Vol 644-650 ◽  
pp. 5435-5438
Author(s):  
Tan Li ◽  
Ming Zhu ◽  
Ming Yue Zhai ◽  
Ye Shen ◽  
Gang Lv ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Tricholoma Matsutake ◽  
Control Group ◽  
Transcriptional Level ◽  
Mrna Transcription ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Model Control ◽  
Model Control Group ◽  
Factor Alpha

The effects of the polysaccharide extracted from Tricholoma matsutake on the immune response of Sarcoma180 bearing mice were evaluated. Mice were treated with two doses of polysaccharideL-2(1,10mg/kgbodyweight) for 10 days. The concentration of tumor necrosis factor-alpha (TNF-α), interferon-2(IL-2) in mice serum and TNF-α mRNA expression were determined. The concentration of TNF-α in serum increased significantly in two doses groups compared to the model control group, but IL-2 not. The level of TNF-α mRNA transcription increased significantly in two doses groups to the model control group. Results of these studies demonstrated the polysaccharide significantly promoted TNF-α production, immunity potentiating and anti-tumor effects of the polysaccharide were associated with its potentiation of TNF-α mRNA expression at the transcriptional level.

scholarly journals Progesterone Stimulates Adipocyte Determination and Differentiation 1/Sterol Regulatory Element-binding Protein 1c Gene Expression

2001 ◽  
Vol 276 (15) ◽  
pp. 11512-11516 ◽  
Author(s):  
Danièle Lacasa ◽  
Xavier Le Liepvre ◽  
Pascal Ferre ◽  
Isabelle Dugail
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid Synthase ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cancer Cell Line ◽  
Dominant Negative ◽  
Transcriptional Level ◽  
Dominant Negative Form ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Fatty acid synthase (FAS), a nutritionally regulated lipogenic enzyme, is transcriptionally controlled by ADD1/SREBP1c (adipocyte determination and differentiation 1/sterol regulatory element-binding protein 1c), through insulin-mediated stimulation of ADD1/SREBP1c expression. Progesterone exerts lipogenic effects on adipocytes, and FAS is highly induced in breast tumor cell lines upon progesterone treatment. We show here that progesterone up-regulates ADD1/SREBP1c expression in the MCF7 breast cancer cell line and the primary cultured preadipocyte from rat parametrial adipose tissue. In MCF7, progesterone induced ADD1/SREBP1c and Metallothionein II (a well known progesterone-regulated gene) mRNAs, with comparable potency. In preadipocytes, progesterone increased ADD1/SREBP1c mRNA dose-dependently, but not SREBP1a or SREBP2. Run-on experiments demonstrated that progesterone action on ADD1/SREBP1c was primarily at the transcriptional level. The membrane-bound and mature nuclear forms of ADD1/SREBP1 protein accumulated in preadipocytes cultured with progesterone, and FAS induction could be abolished by adenovirus-mediated overexpression of a dominant negative form of ADD1/SREBP1 in these cells. Finally, in the presence of insulin, progesterone was unable to up-regulate ADD1/SREBP1c mRNA in preadipocytes, whereas its effect was restored after 24 h of insulin deprivation. Together these results demonstrate that ADD1/SREBP1c is controlled by progesterone, which, like insulin, acts by increasing ADD1/SREBP1c gene transcription. This provides a potential mechanism for the lipogenic actions of progesterone on adipose tissue.

scholarly journals Endothelial cell apicobasal polarity coordinates distinct responses to luminally versus abluminally delivered TNF-α in a microvascular mimetic

2020 ◽  
Vol 12 (11) ◽  
pp. 275-289
Author(s):  
Alec T Salminen ◽  
Jeffrey Tithof ◽  
Yara Izhiman ◽  
Elysia A Masters ◽  
Molly C McCloskey ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Systemic Inflammation ◽  
Polymorphonuclear Neutrophil ◽  
Apical Surface ◽  
Necrosis Factor Alpha ◽  
Apicobasal Polarity ◽  
Tnf Α ◽  
Luminal Side ◽  
Cytokine Tumor Necrosis Factor ◽  
Key Barrier

Abstract Endothelial cells (ECs) are an active component of the immune system and interact directly with inflammatory cytokines. While ECs are known to be polarized cells, the potential role of apicobasal polarity in response to inflammatory mediators has been scarcely studied. Acute inflammation is vital in maintaining healthy tissue in response to infection; however, chronic inflammation can lead to the production of systemic inflammatory cytokines and deregulated leukocyte trafficking, even in the absence of a local infection. Elevated levels of cytokines in circulation underlie the pathogenesis of sepsis, the leading cause of intensive care death. Because ECs constitute a key barrier between circulation (luminal interface) and tissue (abluminal interface), we hypothesize that ECs respond differentially to inflammatory challenge originating in the tissue versus circulation as in local and systemic inflammation, respectively. To begin this investigation, we stimulated ECs abluminally and luminally with the inflammatory cytokine tumor necrosis factor alpha (TNF-α) to mimic a key feature of local and systemic inflammation, respectively, in a microvascular mimetic (μSiM-MVM). Polarized IL-8 secretion and polymorphonuclear neutrophil (PMN) transmigration were quantified to characterize the EC response to luminal versus abluminal TNF-α. We observed that ECs uniformly secrete IL-8 in response to abluminal TNF-α and is followed by PMN transmigration. The response to abluminal treatment was coupled with the formation of ICAM-1-rich membrane ruffles on the apical surface of ECs. In contrast, luminally stimulated ECs secreted five times more IL-8 into the luminal compartment than the abluminal compartment and sequestered PMNs on the apical EC surface. Our results identify clear differences in the response of ECs to TNF-α originating from the abluminal versus luminal side of a monolayer for the first time and may provide novel insight into future inflammatory disease intervention strategies.

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