● The data in this study focus on the functional relationships between autophagy and lipid metabolism. We found that autophagy at least partially augmented LPS-induced foam cell formation owing to its effect on the induction of ADRP.
Foam cell formation is a hallmark of the initial stage of atherosclerosis. The activation of macrophages by LPS has been shown to increase fat accumulation (Figure 1). In fact, studies have demonstrated that LPS influences many aspects of macrophage-derived foam cell formation, such as the promotion of LDL oxidation , lipid uptake , up-regulation of macrophage fatty acid transport and inhibition of cholesterol efflux [25, 26].
Recently, a study has demonstrated that blocking autophagy in cultured preadipocytes decreases the cellular triglyceride content and levels of key adipogenic transcription factors CEBP-α (CCAAT/enhancer-binding protein alpha), CEBP-β (CCAAT/enhancer binding protein beta ) and PPAR-γ . However, little is known about the role of autophagy in atherosclerosis. In this study, we demonstrate that autophagy is activated in LPS-induced macrophage foam cells (Figure 2). Here, we just focus on the autophagy involved in the uptake of lipid and lipid droplet formation in macrophage-derived foam cells. In this work, the activation of autophagy enhanced levels of intracellular cholesterol and triglyceride while inhibition of autophagy could block the accumulation of lipid droplets in macrophages (Figure 3). Consist with these results, an increase rather than a decrease in foam cell formation would be expected in macrophages undergoing autophagy because protein degradation, as well as the decline of protein synthesis, in autophagic cells readily blocks the utilization of lipids for lipid–protein conjugation, which in turn results in the formation of lipid droplets .
ADRP is the major macrophage LD coat protein, and its levels are directly related with cellular neural lipid content . Whole-body as well as macrophage specific ADRP deficiency inhibits foam cell formation and protects against atherosclerosis development . Despite ADRP is an absolute LD coat protein, and was also detected in lysosomes in macrophage foam cell, suggesting that ADRP may play an important role in autophagy . Our results also support a possible role for ADRP in LPS-induced autophagic signaling. Overexpression of ADRP leads to augment of autophagy, which has been shown to increase autophagic signaling. Moreover, inhibition of ADRP can suppress the activation of autophagy (Figures 4, 5). Interestingly, ADRP overexpression prevented cholesterol efflux to apolipoprotein A-I (ApoA-I) . One possible explanation is that ADRP may be localized around cytosolic lipid droplets in the macrophages, protecting them from the activity of cholesterol esterases and thereby reducing the availability of free cholesterol (FC) for efflux. Thus, autophagy is activated in response to a lipid challenge. These results indicated that ADRP could protect LDs against the lipolysis mediated by autophagy and lysosomes in the LPS-induced macrophage foam cell.
In conclusion, these data link autophagy and lipid metabolism, two separate pathways that are both activated by LPS. Although further studies are required to establish a correlation between the regulation of autophagy in macrophages and atherosclerosis, our results suggest that the autophagic activity may be involved in the accumulation of lipid droplets in macrophage foam cells. Furthermore, our data indicate that ADRP facilitates autophagic activity in the LPS-induced macrophage foam cells. Summarily, these results are helpful for us to understand the role of autophagy in the development of atherosclerosis.