Adipophilin increases triglyceride storage in human macrophages by stimulation of biosynthesis and inhibition of β‐oxidation

Abstract

Lipid accumulation alters macrophage biology and contributes to lipid retention within the vessel wall. In this study, we investigated the role of adipophilin on triglyceride accumulation and lipid-droplet formation in THP-1-derived macrophages (THP-1 macrophages). In the presence of acetylated low-density lipoprotein, macrophages infected with an adenovirus expressing human adipophilin showed a 31% increase in triglyceride content and a greater number of lipid droplets compared with control cells. Incubation of macrophages with very low-density lipoprotein (VLDL) dramatically increased cellular triglyceride content similarly in control and adipophilin-overexpressing cells. By itself, VLDL increased adipophilin expression, which explains the lack of effect of adipophilin overexpression on cellular triglyceride content in macrophages loaded with VLDL. The lipid-droplet content of macrophages was increased by overexpression of adipophilin and ⁄ or loading with VLDL. In contrast, inhibition of adipophilin expression using siRNA prevented lipid-droplet formation and significantly reduced intracellular triglyceride content. Using inhibitors of b-oxidation and acyl-coenzyme A synthetase, results were obtained which suggest that adipophilin elevates cellular lipids by inhibition of b-oxidation and stimulation of long-chain fatty acid incorporation into triglycerides. Adipophilin expression in THP-1 macrophages altered the cellular content of different lipids and enhanced the size of lipid droplets, consistent with a role for adipophilin in human foam cell formation.

A novel model of cholesterol efflux from lipid-loaded cells

“…Adipophilin elevates cellular lipid levels via inhibition of β-oxidation and stimulation of long-chain fatty acid incorporation into triglycerides. Adipophilin expression in THP-1 macrophages alters the cellular content of different lipids and increases the size of lipid droplets, consistent with the role of adipophilin in human foam cell formation [99] . It has been recently reported that adipophilin blocks lipid efflux and increases lipid accumulation in THP-1 macrophages independently of the expression of lipid efflux-related genes [100] .…”

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

“…In HEK293 cells, overexpression of ADRP has been shown to correlate with decreased association of the major TG lipase named ATGL with LDs and increased TG accumulation as a result of inhibition of TG hydrolysis (Listenberger et al, 2007). ADRP overexpression also increased TG content in THP-1-derived macrophages by promoting the incorporation of fatty acyl-CoAs into TGs and inhibiting fatty acid oxidation (Larigauderie et al, 2006). 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 .…”

PLIN2 inhibits insulin-induced glucose uptake in myoblasts through the activation of the NLRP3 inflammasome

“…Studies have reported increased TAG accumulation and lipid droplet formation when PLIN2 is overexpressed in vitro (8)(9)(10). Conversely, the knockdown of PLIN2 in macrophages has been shown to decrease the size and number of cellular lipids and LDs (8). A previous study using a rat model of diabetes demonstrated that increased levels of Plin2 in skeletal muscle correlated with insulin resistance when the rats were fed a high-fat diet (11).…”

“…One of the 5 perilipins (PLINs), PLIN2, is a marker for LDs in human skeletal muscle, and the levels of intramuscular PLIN2 and triglycerides are closely correlated. Studies have reported increased TAG accumulation and lipid droplet formation when PLIN2 is overexpressed in vitro (8)(9)(10). Conversely, the knockdown of PLIN2 in macrophages has been shown to decrease the size and number of cellular lipids and LDs (8).…”