Lipid synthesis in macrophages during inflammation in vivo: Effect of agonists of peroxisome proliferator activated receptors α and γ and of retinoid X receptors

Abstract

The effects of peroxisome proliferator activated receptors alpha and gamma (PPAR-alpha and PPAR-gamma) and retinoid X receptor (RXR) agonists upon synthesis and accumulation of lipids in murine C57Bl macrophages during inflammation induced by injection of zymosan and Escherichia coli lipopolysaccharide (LPS) have been studied. It is significant that intraperitoneal injection of zymosan (50 mg/kg) or LPS (0.1 mg/kg) in mice led to a dramatic increase of [14C]oleate incorporation into cholesteryl esters and triglycerides and [14C]acetate incorporation into cholesterol and fatty acids in peritoneal macrophages. Lipid synthesis reached its maximum rate 18-24 h after injection and was decreased 5-7 days later to control level after LPS injection or was still heightened after zymosan injection. In macrophages obtained in acute phase of inflammation (24 h), degradation of 125I-labeled native low density lipoprotein (NLDL) was 4-fold increased and degradation of 125I-labeled acetylated LDL (AcLDL) was 2-3-fold decreased. Addition of NLDL (50 microg/ml) or AcLDL (25 microg/ml) into the incubation medium of activated macrophages induced 9-14- and 1.25-fold increase of cholesteryl ester synthesis, respectively, compared with control. Addition of NLDL and AcLDL into the incubation medium completely inhibited cholesterol synthesis in control macrophages but had only slightly effect on cholesterol synthesis in activated macrophages. Injection of RXR, PPAR-alpha, or PPAR-gamma agonists--9-cis-retinoic acid (5 mg/kg), bezafibrate (10 mg/kg), or rosiglitazone (10 mg/kg), respectively--30 min before zymosan or LPS injection led to significant decrease of lipid synthesis. Ten hour preincubation of activated in vivo macrophages with the abovementioned agonists (5 microM) decreased cholesteryl ester synthesis induced by NLDL and AcLDL addition into the cell cultivation medium. The data suggest that RXR, PPAR-alpha, or PPAR-gamma agonists inhibited lipid synthesis and induction of cholesteryl ester synthesis in inflammatory macrophages caused by capture of native or modified LDL.

Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

“…LPS-treated cells display a very robust membrane rearrangement (25,26); hence they require a high energy supply to accomplish all the remodeling that activation encompasses, including the upregulation of many genes and proteins. In fact, TAG production is increased in activated macrophages (6,(27)(28)(29), and its hydrolysis is an absolute requirement for efficient ATP supply and macrophage functioning (30). Thus, the possibility exists that in the absence of lipin-1 macrophages may not be able to meet the necessary energy levels to fulfill all their activation requirements, resulting in alteration of the whole cell reprograming.…”

Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia

“…Treatment with LPS resulted in a significant increase in cellular TG levels in microglia. The effect of LPS on lipid synthesis in macrophages has been previously examined [47,48]. It was demonstrated that macrophages (RAW 264.7) treated with LPS accumulate TG, but not cholesterol esters (CE) [48].…”

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

“…A recent study has demonstrated SREBP-1a is abundantly expressed in macrophages (Im et al, 2011). Interestingly, lipopolysaccharide (LPS), which was shown to increase de novo lipogenesis in macrophages in vivo (Posokhova et al, 2008), upregulates SREBP-1a mRNA and nuclear protein levels, and stimulates lipogenesis in wild-type but not SREBP-1a-deficient macrophages (Im et al, 2011).…”

“…Moreover, ADRP augments TNFα, MCP-1, and IL-6 induction in acLDL-induced macrophages, suggesting that enhancing inflammation might be one role of ADRP in atherosclerosis . In addition, LPS and other Toll-like receptor (TLR) ligands, which have been previously shown to increase macrophage TG and CE accumulation (Tobias and Curtiss, 2005;Posokhova et al, 2008), increase the expression of ADRP as part of a coordinated change in macrophage physiology (Feingold et al, 2010).…”