Increased susceptibility to activation and increased uptake of low density lipoprotein by cholesterol-loaded macrophages.

Abstract

Inflammation is associated with macrophage activation, and this process has been shown to occur during atherogenesis. Macrophages (J774A.1) that were activated with either lipopolysaccharide (LPS), zymosan, or phorbol ester demonstrated a 30-35% increased uptake and degradation of low density lipoprotein (LDL) in comparison with nonactivated cells. This phenomenon was also shown for LDL cellular binding, and it resulted in macrophage cholesterol accumulation, as evidenced by cholesterol mass determination and flow cell cytometric analysis. Enhanced uptake of LDL was also obtained with two other types of macrophages: mouse peritoneal macrophages and human monocyte-derived macrophages. In LPSstimulated macrophages, high density lipoprotein-mediated cholesterol efflux was not different from that shown in nonstimulated cells. Cellular cholesterol synthesis, however, was increased by 25% in the activated macrophages. Macrophage activation, measured as cellular procoagulant activity, was higher in cholesterol-loaded than in nonloaded cells. On stimulation of cholesterol-loaded macrophages, cellular uptake and degradation of LDL were increased by 3.3-fold in comparison with nonactivated cholesterolloaded cells. Human monocyte-derived macrophages from hypercholesterolemic patients were found to contain 52% more cholesterol mass than macrophages derived from normal healthy donors. These cells demonstrated increased activation (twofold) in response to LPS stimulation and also showed 25% enhanced cellular degradation of LDL. We conclude that activation of macrophages during atherogenesis can lead to foam cell formation, and this mechanism is probably operative in hypercholesterolemic

Adipocyte Fatty Acid–Binding Protein Expression and Lipid Accumulation Are Increased During Activation of Murine Macrophages by Toll-Like Receptor Agonists

“…1 Activation of macrophages by TLR ligands has been shown to induce foam cell formation in murine macrophages by our laboratory and others. 13,14 We now extend these findings to show LPS-mediated increases in mRNA and protein levels of aP2, an FABP found in macrophages that has been shown recently to have an important role in atherosclerosis. This intracellular transport protein is present at extremely low levels in macrophages at baseline, and its expression is dramatically increased on exposure to LPS and zymosan.…”

“…13,14 In addition, our laboratory has reported an increase in intracellular triglyceride with LPS stimulation of murine macrophages in the absence of exogenous lipid. 14 In vivo studies have also documented an increase in atherosclerotic lesion size with LPS administration.…”

Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host

“…In the presence of LPS, macrophages accumulated more TG and cholesterol (286,287). VLDL produced during endotoxemia also provided more TG to macrophages compared with control VLDL, and these TGs were selectively stored as cellular lipids (375).…”

“…LPS and cytokines (TNF and IL-1) activate macrophages to accumulate lipids (286)(287)(288). LPS-stimulated macrophages accumulate more TGs and cholesteryl ester from lipoproteins than do unstimulated cells.…”

Pycnogenol, an extract from French maritime pine, suppresses Toll-like receptor 4-mediated expression of adipose differentiation-related protein in macrophages

“…Because of the broad capacity of ligands and the ubiquitous expression of TLRs, TLRs are involved in various phases of inflammatory and immune diseases (3). Activation of macrophages by TLR ligands, such as bacterial lipopolysaccharide (LPS) increased LDL uptake and cholesterol content, leading to foam cell formation (12,21,34). Activation of TLR2 and TLR4 stimulated formation of lipid bodies in leukocytes (9,37).…”