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

Abstract

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.

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). During the APR, proteins involved in the uptake and metabolism of FA, such as FABP, FATP, and LPL, are coordinately downregulated in the heart, muscle, and adipose tissue.…”

Myelopoietic Efficacy of Orlistat in Murine Hosts Bearing T Cell Lymphoma: Implication in Macrophage Differentiation and Activation

“…These features indicate that these BMDM displayed a typical M 1 Mϕ phenotype which is required for antitumor activity. Although orlistat is an inhibitor of FASN which is reported to be required by Mϕ for phagocytic ability and other activation associated functions [4–9], orlistat-administration to tumor-bearing mice did not inhibit the expression of FASN in BMC or BMDM (data not shown). The reason for this could be that orlistat poorly diffuses through systematic route to distant tissues [10,14,21,46].…”

“…Fatty acid synthase (FASN)-dependent de novo fatty acid synthesis is identified as an indispensable necessity of hematopoiesis, differentiation and activation of macrophages (Mϕ), which play a central role in host’s antitumor defense [4–9]. Further, the involvement of FASN in M 1 /M 2 macrophage polarization, expression of TLRs, IL-1, TNF-α and phagocytosis has been reported [4–9]. Moreover, inhibition of FASN alters endotoxin responsiveness of macrophages [9].…”

“…Further, the involvement of FASN in M 1 /M 2 macrophage polarization, expression of TLRs, IL-1, TNF-α and phagocytosis has been reported [4–9]. Moreover, inhibition of FASN alters endotoxin responsiveness of macrophages [9]. Interestingly, FASN requirement has been demonstrated to vary depending on stages of macrophage differentiation [7].…”

Plasma Lipoproteins as Crucial Components of Host Defence Against Infections

“…Cholesterol is required for new membrane synthesis in areas of cellular injury that accompany infections. Cholesterol may also be used for activation and proliferation of lymphocytes [97][98][99][100][101].…”