Modification of very low density lipoproteins leads to macrophage scavenger receptor uptake and cholesteryl ester deposition.

Mazzone, Theodore; López, César A.; Bergstraesser, Lynn M.

doi:10.1161/01.atv.7.2.191

Cited by 22 publications

(8 citation statements)

References 34 publications

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“…Macrophages possess many cell surface receptors offering potential routes of uptake for lipoprotein particles, including the VLDL/apo-E receptor [30], scavenger receptors (e.g. CD36 [31]), documented to assimilate modified lipoproteins [32] (and a potential route of uptake of cVLDL [31]), and the triacylglycerolrich lipoprotein receptor (TGRLP) [33]. VLDL synthesis during sepsis may introduce modifications to apoprotein and/or lipid components which may enhance receptormediated uptake.…”

Section: Discussionmentioning

confidence: 99%

Utilisation of Fatty Acid and Triacylglycerol by Rat Macrophages: the Effect of Endotoxin

Hui‐Kang

Evans²

2002

Cell Physiol Biochem

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Background/Aims: Plasma very-low-density lipoprotein (VLDL) concentrations are increased during sepsis/endotoxaemia and VLDL may be substrates for the activated immune system. Lipid substrate utilisation by quiescent and activated macrophages was therefore examined. Methods: Rat R2 macrophages were incubated with oleate or rat VLDL, with or without lipopolysaccharide (LPS) stimulation. The metabolic fate of the lipids was examined. Results: Macrophages utilised both oleate and (control) VLDL-triacylglycerol (TAG) to a similar extent. Most was deposited as cellular lipid; about 10% of oleate was oxidised compared to 25% of cVLDL-TAG. LPS significantly increased oleate oxidation and its deposition as cellular lipid (mostly as TAG) at 48hrs but abolished both oxidation and storage of VLDL-TAG. VLDL produced during endotoxaemia (eVLDL) was assimilated by the unstimulated macrophage to a greater extent than oleate or cVLDL-TAG and selectively stored as cellular lipids (no oxidation); LPS decreased eVLDL utilisation. VLDL-TAG utilisation was decreased by the lipoprotein lipase (LPL) inhibitor terahydrolipstatin. LPL activity was greater in oleate than in VLDL incubations, but was increased by incubation with eVLDL. LPS had no effect (oleate, cVLDL) or increased (eVLDL) LPL activity. Conclusion: VLDL represented an efficient substrate for the macrophage. However under conditions of sepsis/endotoxaemia eVLDL utilisation was limited and directed away from oxidation, suggesting that the increased plasma TAG (eVLDL) concentrations resulting from sepsis is not a respiratory fuel for the macrophage but may supply cellular lipid.

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Section: Discussionmentioning

confidence: 99%

Utilisation of Fatty Acid and Triacylglycerol by Rat Macrophages: the Effect of Endotoxin

Hui‐Kang

Evans²

2002

Cell Physiol Biochem

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“…Freshly isolated IFPs were washed in PBS and placed in 60-mm dishes at 100 mg total tissue (wet weight) per dish. The fresh tissue was minced into 1-mm pieces and incubated in DMEM with 1% lipoprotein-deficient FBS with or without 100 g/ml apoE-containing VLDL for 48 h. ApoE-containing d Ͻ 1.006 g/l lipoproteins were isolated by density gradient ultracentrifugation of nonfasting human plasma, after a spin at 26,000g at 10°C for 30 min to remove chylomicrons, as previously described (20). The layer containing buoyant triglyceride-rich lipoproteins (TGRLs) was collected and dialyzed against PBS at 4°C for 24 h. Pre-␤ mobility of the isolated fraction was confirmed using a Titan Lipoprotein Gel System (Helena Laboratories, Beaumont, TX), and apoE content in the TGRL fraction was confirmed by Western blotting.…”

Section: Methodsmentioning

confidence: 99%

Endogenous ApoE Expression Modulates Adipocyte Triglyceride Content and Turnover

2006

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Apolipoprotein E (apoE) is highly expressed in adipose tissue and adipocytes in which its expression is regulated by peroxisome proliferator-activated receptor (PPAR)-␥ agonists and tumor necrosis factor-␣. There is, however, no information regarding a role for endogenous apoE in differentiated adipocyte function. In this report, we define a novel role for apoE in modulating adipocyte lipid metabolism. ApoE ؊/؊ mice have less body fat and smaller adipocytes compared with wild-type controls. Freshly isolated adipose tissue from apoE ؊/؊ mice contains lower levels of triglyceride and free fatty acid, and these differences are maintained in cultured adipocytes derived from preadipocytes. Adenoviral expression of apoE in apoE ؊/؊ -cultured adipocytes increases triglyceride and fatty acid content. During incubation with apoE-containing triglyceride-rich lipoproteins, apoE ؊/؊ adipose tissue accumulates less triglyceride than wild type. The absence of apoE expression in primary cultured adipocytes also leads to changes in the expression of genes involved in the metabolism/turnover of fatty acids and the triglyceride droplet. Markers of adipocyte differentiation were lower in freshly isolated and cultured apoE ؊/؊ adipocytes. Importantly, PPAR-␥-mediated changes in lipid content and gene expression are markedly altered in cultured apoE ؊/؊ adipocytes. These results establish a novel role for endogenous apoE in adipocyte lipid metabolism and have implications for constructing an integrated model of adipocyte physiology in health and disease. Diabetes 55:3394 -3402, 2006 O besity and its consequent insulin resistance are major health problems in the U.S., imparting significant risk for diabetes and cardiovascular disease (1-4). The prevalence of obesity is predicted to substantially increase over the next several decades, and there is a need to better understand adipocyte and adipose tissue physiology. In the past several years, it has become apparent that adipocytes and adipose tissue actively modulate systemic substrate availability and produce a number of protein factors with endocrine, paracrine, and autocrine regulatory activity (5,6). Apolipoprotein E (apoE), which was first described as a product of hepatocytes and a surface component of lipoproteins, e.g., in humans, chylomicrons, VLDL, remnant lipoproteins, and HDL, has been shown to be highly expressed in adipocytes and adipose tissue (7). Interestingly, apoE has been shown to be highly expressed in a number of cell types that experience high lipid flux (8 -15). The physiologic role of apoE expression in other cell types has been intensively studied and characterized (8 -15). In macrophages and steroidogenic cells, for example, endogenous apoE expression plays an important role in cellular lipid balance. Adipocytes and adipose tissue, like macrophages and steroidogenic cells, also experience large lipid fluxes integral to their differentiated function, yet there is no information regarding a potential physiologic role of apoE expressed in the adipocyte. Our lab...

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“…LXR agonist affects predominantly fluid-phase pinocytosis rather than receptor-mediated endocytosis To investigate whether the effect of T0901317 is specific for fluid-phase pinocytosis, we examined whether T0901317 has an inhibitory effect on receptor-mediated endocytosis of 125 I-acetylated LDL, known to be taken up by macrophage scavenger receptors (32)(33)(34). First, we examined the concentration dependence of 125 I-acetylated LDL uptake by M-CSF-differentiated macrophages.…”

Section: Ppar Agonists Do Not Decrease Macrophage Uptake Of Ldlmentioning

confidence: 99%

Liver X receptors inhibit human monocyte-derived macrophage foam cell formation by inhibiting fluid-phase pinocytosis of LDL

Buono

Waldo

et al. 2007

Journal of Lipid Research

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Liver X receptors (LXRs) are ligand-activated transcription factors involved in the control of lipid metabolism and inflammation. Several studies have recently shown that LXRs promote reverse cholesterol transport and inhibit atherosclerosis. Our study investigated whether LXRs affect macrophage uptake of LDL by human monocyte-derived macrophages. We have previously shown that human monocytes differentiated into macrophages with macrophagecolony-stimulating factor (M-CSF) constitutively take up large amounts of native LDL by receptor-independent, fluidphase pinocytosis. In the research reported here, human monocytes were differentiated to macrophages in the presence of M-CSF with or without the LXR agonists T0901317 or 22(R)-hydroxycholesterol. Then, macrophages were incubated with native 125 I-LDL to determine LDL uptake. T0901317 and 22(R)-hydroxycholesterol inhibited 125 I-LDL uptake by 68 6 1% and 69 6 2%, respectively, and decreased pinocytotic vacuoles in the macrophages. 125 I-BSA uptake, a measure of fluid-phase pinocytosis, and 125 I-LDL uptake were the same, and T0901317 treatment inhibited uptake of both to the same degree. T0901317 did not affect receptormediated uptake of acetylated LDL, showing that the LXR effect is specific for fluid-phase pinocytosis of lipoproteins. Our results show that LXRs downregulate macrophage pinocytosis of LDL. The findings reveal an additional new mechanism by which LXR agonists may inhibit macrophage cholesterol accumulation and atherosclerosis, namely, by inhibiting macrophage uptake of LDL.-Buono, C., Y. Li, S. W. Waldo, and H. S. Kruth. Liver X receptors inhibit human monocyte-derived macrophage foam cell formation by inhibiting fluid-phase pinocytosis of LDL. J. Lipid Res.

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Modification of very low density lipoproteins leads to macrophage scavenger receptor uptake and cholesteryl ester deposition.

Cited by 22 publications

References 34 publications

Utilisation of Fatty Acid and Triacylglycerol by Rat Macrophages: the Effect of Endotoxin

Utilisation of Fatty Acid and Triacylglycerol by Rat Macrophages: the Effect of Endotoxin

Endogenous ApoE Expression Modulates Adipocyte Triglyceride Content and Turnover

Liver X receptors inhibit human monocyte-derived macrophage foam cell formation by inhibiting fluid-phase pinocytosis of LDL

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