Lipid metabolism and TNF-alpha secretion in response to dietary sterols in human monocyte derived macrophages (original) (raw)
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Experimental Biology and Medicine, 2013
The potential link between the inflammatory effects of postprandial lipemia and the induction of macrophage foam cell formation by triacylglycerol-rich lipoproteins (TGRL) was studied using postprandial triacylglycerol-rich lipoproteins ( ppTGRL) derived from human volunteers and primary human monocyte-derived macrophages (HMDM). Subjects were fed a test meal high in dairy fat, followed three hours later by isolation of serum ppTGRL. Pro-inflammatory (M1) and antiinflammatory (M2) phenotypes were induced in HMDM by treatment with lipopolysaccharide (LPS) or dexamethasone (DEX), respectively. ppTGRL caused a dose-dependent increase in both triacylglycerol (TG) and cholesterol (CH) accumulation in the cells. TG accumulation was unaffected by LPS or DEX treatment, but LPS as compared with DEXtreated HMDM were found to accumulate more CH, and this effect was greater than that induced by ppTGRL in untreated cells. LPS-treatment had no effect on lipid uptake from ppTGRL (via the LDLr, scavenger receptors or SR-B1) or on CH efflux, but the CH synthesis inhibitor mevinolin abolished the difference between CH accumulation in LPS-and DEX-treated cells, suggesting that CH synthesis is enhanced in the inflammatory state. Phospholipid (PL) synthesis was increased in inflammatory M1 as compared with anti-inflammatory M2 HMDM. Moreover, TG synthesis was decreased by ppTGRL in DEX-treated as compared with untreated cells. We conclude, therefore, inflammation causes a greater increase in the accumulation of neutral lipids than ppTGRL in macrophages, and that this effect is related to modulation of PL metabolism and possibly also CH synthesis. Thus, the inflammatory phenotype of macrophages influences their lipid metabolism, and is, therefore, likely to modulate the induction of macrophage lipid accumulation by lipoproteins associated with foam cell formation.
Experimental Biology and Medicine, 2004
The effects of low-density lipoprotein (LDL) and chylomicron remnants on lipid accumulation in human monocyte-derived macrophages (HMDMs) and in macrophages derived from the human monocyte cell line THP-1 were compared. The HMDMs or THP-1 macrophages were incubated with LDL, oxidized LDL (oxLDL), chylomicron remnant-like particles (CMR-LPs), or oxidized CMR-LPs (oxCMR-LPs), and the amount and type of lipid accumulated were determined. As expected, the lipid content of both cell types was increased markedly by oxLDL but not LDL, and this was due to a rise in cholesterol, cholesteryl ester (CE), and triacylglycerol (TG) levels. In contrast, both CMR-LPs and oxCMR-LPs caused a considerable increase in cellular lipid in HMDMs and THP-1 macrophages, but in this case there was a greater rise in the TG than in the cholesterol or CE content. Lipid accumulation in response to oxLDL, CMR-LPs, and oxCMR-LPs was prevented by the ACAT inhibitor CI976 in HMDMs but not in THP-1 macrophages, where TG levels remained markedly elevated. The rate of incorporation of [ 3 H]oleate into CE and TG in THP-1 macrophages was increased by oxLDL, CMR-LPs, and oxCMR-LPs, but incorporation into TG was increased to a greater extent with CMR-LPs and oxCMR-LPs compared with oxLDL. These results demonstrate that both CMR-LPs and oxCMR-LPs cause lipid accumulation in human macrophages comparable to that seen with oxLDL and that oxidation of the remnant particles does not enhance this effect. They also demonstrate that a greater proportion of the lipid accumulated in response to CMR-LPs compared with oxLDL is TG rather than cholesterol or CE and that this is associated with a higher rate of TG synthesis. This study, therefore, provides further evidence to suggest that chylomicron remnants have a role in foam cell formation that is distinct from that of oxLDL.
Exogenously Added Oxyphytosterols Do Not Affect Macrophage-Mediated Inflammatory Responses
Lipids
Although phytosterols, plant-derived sterol-like components, are well known for their cholesterol-lowering properties, their atherogenic potential is still under debate. Although they are known to share structural similarities with cholesterol, it is unclear whether their oxidized forms (oxyphytosterols) have the capacity to mediate proinflammatory responses in macrophages. In the present study, bone marrow-derived macrophages were treated with oxidized low-density lipoproteins, oxyphytosterols (7keto-sito/ campesterol [7keto-sit/camp] or 7-beta-hydroxy-sito/campesterol [7βOH-sit/camp]), nonoxidized phytosterol (β-sitosterol), or carrier-control (cyclodextrin) in a doseand time-dependent manner. Inflammatory cytokine release, activity, and the corresponding mRNA expression levels were analyzed. 7βOH-sit/camp, rather than 7keto-sit/camp, induced a modest proinflammatory response in wild-type cells derived from C57Bl/6 mice. The observed mild inflammatory effects are independent of the low-density lipoprotein receptor and Cluster of differentiation 36/Scavenger receptor-a. These data suggest that exogenously added oxyphytosterols do not affect macrophage-mediated inflammatory responses, at least in vitro.
Data in Brief, 2016
This article supports experimental evidence on the timedependent effect on gene expression related to inflammation and cholesterol deposition in lipid-loaded cells. The cells employed were human monocytes THP1 line transformed into macrophages by treatment with phorbol esters. Macrophages were treated at different times with oxidized low density lipoprotein (Ox-LDL) and then gene expression was measured. We also include data about the different types of oxidized lipoprotein obtained (low, media or high oxidation) for differential exposure with Cu ions. These data include characterization to lipid and protein peroxidative damage and also quantification of cell viability by exposure to native and modified LDL. The present article complements data published in "Decreased OxLDL uptake and cholesterol efflux in THP1 cells elicited by cortisol and by cortisone through 11β-hydroxysteroid dehydrogenase type 1" Ledda et al.
British Journal of Nutrition, 2009
Dietary long-chain PUFA, both n-3 and n-6, have unique benefits with respect to CVD risk. The aim of the present study was to determine the mechanisms by which n-3 PUFA (EPA, DHA) and n-6 PUFA (linoleic acid (LA), arachidonic acid (AA)) relative to SFA (myristic acid (MA), palmitic acid (PA)) alter markers of inflammation and cholesterol accumulation in macrophages (MΦ). Cells treated with AA and EPA elicited significantly less inflammatory response than control cells or those treated with MA, PA and LA, with intermediate effects for DHA, as indicated by lower levels of mRNA and secretion of TNFα, IL-6 and monocyte chemoattractant protein-1. Differences in cholesterol accumulation after exposure to minimally modified LDL were modest. AA and EPA resulted in significantly lower MΦ scavenger receptor 1 mRNA levels relative to control or MA-, PA-, LA-and DHA-treated cells, and ATP-binding cassette A1 mRNA levels relative to control or MA-, PA-and LA-treated cells. These data suggest changes in the rate of bidirectional cellular cholesterol flux. In summary, individual long-chain PUFA have differential effects on inflammatory response and markers of cholesterol flux in MΦ which are not related to the n position of the first double bond, chain length or degree of saturation.
The Journal of Steroid Biochemistry and Molecular Biology, 2001
The importance of the interactions of modified lipids and macrophages in foam cell generation is clear; however, little attention has been paid to the role of intra-macrophagic redox potential as a modulator of their lipid synthesis and metabolism. In this study, the effects of previously induced non-toxic manipulations of intracellular redox balance on lipid synthesis in human monocyte-derived macrophages (HMDM) was evaluated. Cells, pre-treated with 2.5 mM of the pro-oxidising agent CuSO 4 or with 5 mM of the antioxidant and thiol supplier N-acetylcysteine (NAC), were exposed to radiolabelled oleic acid alone or in combination with native low density lipoprotein (LDL) or modified LDL to evaluate the incorporation of radioactivity into cholesteryl ester, triacylglycerols and phospholipids. CuSO 4 -treated macrophages synthesised more lipids than NAC-treated cells in absence of exogenous lipid, and, generally, in the presence of native or acetylated, but oxidised LDL. In addition, the activities of the enzymes involved in cholesteryl ester storage were also influenced by the pro-oxidant condition. The ratio values between acyl-coenzyme A:cholesterol acyl transferase and cholesteryl ester hydrolase activity suggest that in CuSO 4 -treated macrophages the hydrolysis of cholesteryl ester is favoured with respect to esterification. The interaction of HMDM with oxidised LDL showed a significant different pattern in term of lipid synthesis with respect to those induced by native or acetylated LDL, disrespectful of the initial redox profile of the cells. On the whole, these results suggest that the pre-existing internal redox condition is a further parameter able to modulate the effects of native or acetylated LDL-cell interaction, influencing both HMDM lipid synthesis profile and cholesterol storage. Moreover, oxidised LDL represent a carrier of additional factor(s) able per se to introduce perturbation in the synthetic pathway of lipids, which is not influenced by the redox potential of the macrophage.
Lipids in Health and Disease, 2011
Background: Advanced glycation end products (AGE) alter lipid metabolism and reduce the macrophage expression of ABCA-1 and ABCG-1 which impairs the reverse cholesterol transport, a system that drives cholesterol from arterial wall macrophages to the liver, allowing its excretion into the bile and feces. Oxysterols favors lipid homeostasis in macrophages and drive the reverse cholesterol transport, although the accumulation of 7-ketocholesterol, 7alphahydroxycholesterol and 7beta-hydroxycholesterol is related to atherogenesis and cell death. We evaluated the effect of glycolaldehyde treatment (GAD; oxoaldehyde that induces a fast formation of intracellular AGE) in macrophages overloaded with oxidized LDL and incubated with HDL alone or HDL plus LXR agonist (T0901317) in: 1) the intracellular content of oxysterols and total sterols and 2) the contents of ABCA-1 and ABCG-1.
Journal of Vascular Research, 2006
Background: Though it is now clear that chylomicron remnants are pro-atherogenic lipoproteins, events leading to their incorporation by macrophages are poorly understood. Methods: This study investigates, in human macrophages, the fate of either [3H]cholesteryl oleate or [3H]triacylglycerol carried by human apolipoprotein-E-containing chylomicron remnant-like particles (CRLP) and the influence of CRLP containing trilinolein, (18:2)CRLP, or triolein, (18:1)CRLP, on lipid accumulation, newly synthesized cholesteryl ester (CE) and triacylglycerol (TG). Results: Labelled fatty acids from TG were markedly incorporated into TG and phospholipid and, to a lesser extent, into free fatty acids and were scarcely recovered in cholesteryl esters. [3H]CE from CRLP accumulated in cells in a dose-dependent manner with a significant difference between concentrations of 10 and 40 µg cholesterol/ml with (18:2)CRLP. In the same concentration range, TG synthesis was enhanced by about 46 and 30% by (18:2...
Efflux of lipid from macrophages after induction of lipid accumulation by chylomicron remnants
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2005
The fate of cholesterol and triacylglycerol taken up and accumulated by macrophages after exposure to chylomicron remnants was investigated using macrophages derived from the human monocyte cell line THP-1 and chylomicron remnant-like particles containing human apolipoprotein (apo) E (CRLPs) as the experimental model. In THP-1 macrophages lipid loaded with CRLPs and incubated with various cholesterol acceptors for 24 h, the mass of cholesterol and cholesteryl ester found in the cells was not changed by HDL, HDL 3 or lipid-free ApoA-I, although it was decreased by 38% by ApoA-I-phosphatidylcholine vesicles (ApoA-I-PC). After loading of the macrophages with [ 3 H]cholesterol-labelled CRLPs, only about 5% of the label was effluxed in 24 h in the absence of cholesterol acceptors, and this increased to about 10% with ApoA-I or PC only, and to about 30% with apoA-I-PC. In similar experiments with [ 3 H]triolein, only about 4% of the labelled triacylglycerol taken up by the cells was released into the medium in 24 h, and a large (>60%) and consistent proportion of the intracellular radioactivity remained associated with the triacylglycerol throughout this period. These results suggest that cholesterol and triacylglycerol derived from chylomicron remnants are not readily cleared from macrophages, and this is likely to contribute to the atherogenicity of the remnant lipoproteins. D