Acat tnf

Excess lipid droplets are frequently observed in arterial endothelial cells at sites of advanced atherosclerotic plaques. Here, the role of tumor necrosis factor alpha (TNFα) in modulating the low-density lipoprotein (LDL) content in confluent primary human aortic endothelial cells (pHAECs) was investigated. TNFα promoted an up to 2 folds increase in cellular cholesterol, which was resistant to ACAT inhibition. The cholesterol increase was associated with increased 125 I-LDL surface binding. Using the non-hydrolysable label, Dil, TNFα could induce a massive increase in Dil-LDL by over 200 folds...

This study investigated the pharmacological inhibition of the toll-like receptor 4 (TLR4) genes as a measure to attenuate microcystin-LR (MC-LR) reproductive toxicity. Bovine Sertoli cells were pretreated with TLR4-IN-C34 (C34) for 1 hour. Thereafter the pretreated and non-pretreated Sertoli cells were cultured in medium containing 10% heat-activated fetal bovine serum + 80 μg/L MC-LR for 24 hours to assess the ability of TLR4-IN-C34 to attenuate the toxic effects of MC-LR. The results showed that TLR4-IN-C34 inhibited MC-LR-induced mitochondria membrane damage, mitophagy and downregulation of blood-testis barrier constituent proteins via TLR4/nuclear factor-kappaB and mitochondria-mediated apoptosis signaling pathway blockage...

BACKGROUND/OBJECTIVES: Corn silk (CS) extract contains large amounts of maysin, which is a major flavonoid in CS. However, studies regarding the effect of CS extract on cholesterol metabolism is limited. Therefore, the purpose of this study was to determine the effect of CS extract on cholesterol metabolism in C57BL/6J mouse fed high-fat diets. MATERIALS/METHODS: Normal-fat group fed 7% fat diet, high-fat (HF) group fed 25% fat diet, and high-fat with corn silk (HFCS) group were orally administered CS extract (100 mg/kg body weight) daily...

Manassantin A, a neolignan isolated from Saururus chinensis, is a major phytochemical compound that has various biological activities, including anti-inflammatory, neuroleptic, and human acyl-CoA : cholesterol acyltransferase (ACAT) inhibitory activities. In this study, we investigated the protective effects of manassantin A against ethanol-induced acute gastric injury in rats. Gastric injury was induced by intragastric administration of 5 mL/kg body weight of absolute ethanol to each rat. The positive control group and the manassantin A group were given oral doses of omeprazole (20 mg/kg) or manassantin A (15 mg/kg), respectively, 1 h prior to the administration of absolute ethanol...

BACKGROUND: Tuberculosis (TB) is a respiratory tract disease caused by Mycobacterium tuberculosis infection. M. tuberculosis exploits immune privilege to grow and divide in pleural macrophages. Fibrates are associated with the immune response and control lipid metabolism through glycolysis with β-oxidation of fatty acids. RESULTS: In this study, we investigated the effect of fibrate pretreatment on the immune response during M. smegmatis infection in U937 cells, a human leukemic monocyte lymphoma cell line...

Fish consumption is considered health beneficial as it decreases cardiovascular disease (CVD)-risk through effects on plasma lipids and inflammation. We investigated a salmon protein hydrolysate (SPH) that is hypothesized to influence lipid metabolism and to have anti-atherosclerotic and anti-inflammatory properties. 24 female apolipoprotein (apo) E(-/-) mice were divided into two groups and fed a high-fat diet with or without 5% (w/w) SPH for 12 weeks. The atherosclerotic plaque area in aortic sinus and arch, plasma lipid profile, fatty acid composition, hepatic enzyme activities and gene expression were determined...

Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors...

Interventions on macrophages/foam cells to redirect intracellular cholesterol towards efflux pathways could become a very valuable addition to our therapeutic arsenal against atherosclerosis. However, certain manipulations of the cholesteryl ester cycle, such as the inhibition of ACAT1, an ER-resident enzyme that re-esterifies cholesterol, are not well tolerated. Previously we showed that targeting perilipin-2 (PLIN2), a major lipid droplet (LD)-associated protein in macrophages, prevents foam cell formation and protects against atherosclerosis...

High levels of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are present in atherosclerotic lesions. TNF-alpha regulates expression of multiple genes involved in various stages of atherosclerosis, and it exhibits proatherosclerotic and antiatherosclerotic properties. ACAT catalyzes the formation of cholesteryl esters (CE) in monocytes/macrophages, and it promotes the foam cell formation at the early stage of atherosclerosis. We hypothesize that TNF-alpha may be involved in regulating the ACAT gene expression in monocytes/macrophages...

AIMS: The aim of this study was to take a combination of animal and cell culture approaches to examine the individual responses of vascular cells to varying inflammatory factors in order to gain insights on the mechanism(s) by which poly(ADP-ribose) polymerase (PARP) inhibition promotes factors of plaque stability. METHODS AND RESULTS: Apolipoprotein (ApoE(-/-)) mice fed a high-fat diet were used as a model of atherosclerosis. Primary endothelial cells, smooth muscle cells (SMCs), and ex-vivo generated foam cells (FCs) were used in our in vitro studies...

In order to explore the effect and mechanisms of tumor necrosis factor-alpha (TNF-alpha) on the activity of the acyl coenzyme A: cholesteryl acyltransferase (ACAT), THP-1 monocytes were cultured and induced to differentiate into macrophages with phorbol ester. TNF-alpha (60 ng/mL) was added at different time points into the macrophage-containing medium and the ACAT enzyme activity was measured by quantifying the incorporation of [1-(14)C] oleoyl CoA into cholesteryl esters. The expression of ACAT-1 protein and mRNA was respectively detected by Western blotting and RT-PCR in THP-1 macrophages 24 h after treatment with TNF-alpha (60 ng/mL)...

F12511(S)-2',3',5'-trimethyl-4'-hydroxy-alpha-dodecylthio-alpha-phenylacetanilide (F12511) is a new Acyl-CoA cholesterol acyltransferase (ACAT) inhibitor that not only reduces the plasma cholesterol levels but also has anti-atherosclerotic actions in animals models. The study's aim was to analyze if F12511 may directly modify the ability of tumor necrosis factor--alpha (TNF-alpha)-incubated bovine aortic endothelial cells (BAEC) to express endothelial nitric oxide synthase (eNOS) protein and inflammatory-related proteins such as platelet endothelial cell adhesion molecule (PECAM) and CD40 ligand (CD40L)...

BACKGROUND: Circulating lipids may initiate and progress atherosclerosis by causing vascular inflammation. Monocytes and tissue macrophages are involved and regulate lipid metabolism in the vascular wall through acetylation of cholesterol by acyl-CoA:cholesterol acyltransferase (ACAT). ACAT inhibition reduces atherosclerosis in animal models by mechanisms that may be independent of their effects on circulating lipids. Because endothelial dysfunction is an important factor in atherosclerosis, we tested the hypothesis that systemic ACAT inhibition would improve endothelial function in hypercholesterolemic humans and assessed its effects on circulating lipids and markers of systemic inflammation...

The effect of the inflammatory cytokins TNF-alpha, oncostatin M and interleukine 1 (IL1) on low density lipoprotein (LDL) oxidative modification have been studied on UNA endothelial cells or U937 monocytes in culture, by measuring the end products of lipid peroxydation (TBARS) and the relative electrophoretic mobility of the particle. TNF-alpha as well as oncostatin M stimulated in a dose-dependent manner the LDL peroxidation induced either by endothelial cells or U937 monocytes, and induced an increase in the uptake of modified LDL by J774 macrophages...

The effects of interleukin 1beta (IL1) in the range of concentration of 10-30 ng/ml on cholesterol metabolism were investigated in the monocyte-macrophage cell line J774. IL1 enhanced cholesterol esterification by [14C]oleic acid and acyl-coenzyme A cholesterol acyl transferase activity in a dose-dependent manner. Incubation of IL1-treated cells with acetylated low density lipoproteins labelled with [3H]cholesteryllinoleate resulted in accumulation of radioactive cholesterol in free and esterified form. Concomitantly, IL1 increased the free and esterified cholesterol intracellular content measured by the cholesterol oxidase technique...

Although we have accumulated few data that would definitely designate the role of N-SMase in modern cell biology, current evidence indicates that N-SMase may play a central role in signal transduction (Fig. 7). Biomodulators such as hormones, antibiotics, drugs, growth factors, and lipoproteins may interact with N-SMase either directly or in combination with other components (receptors) on the cell surface. The cell surface topology would provide easy access for such interactions. According to our hypothetical model shown in Fig...

We have investigated biochemical mechanisms of tumor necrosis factor (TNF)-alpha signaling in cultured human skin fibroblasts. We found that TNF-alpha signaling may involve activation of a cell membrane neutral sphingomyelinase (N-SMase) in that within 2.5-5 min of treatment of cells with TNF-alpha there was a 2-fold increase in the activity of N-SMase compared to control. This reaction led to the hydrolysis of sphingomyelin as evidenced by a decrease in sphingomyelin mass and in the radioactivity associated with [14C]choline-labeled sphingomyelin...

Biosynthesis of apolipoprotein (apo) E has been previously demonstrated to be regulated in macrophages by intracellular free cholesterol levels as well as by macrophage activating factors. In this report, the regulation of apo E secretion by cytokines detected within atherosclerotic lesions has been investigated. Granulocyte macrophage-colony stimulating factor (GM-CSF) stimulated macrophages had a 3-5-fold reduction in apo E secretion, comparable to that observed for gamma interferon (IFN gamma), while tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta) resulted in a 2-fold decrease...