Autophagy involved in lipopolysaccharide-induced foam cell formation is mediated by adipose differentiation-related protein

Xiumin Zhang,Pengfei Zheng,Wen Sui,Jing Ye,Xuyang Feng,Peizhen Hu,Zuyi Yuan,Yuan Yuan,Jun Feng,Chao Wang

doi:10.1186/1476-511x-13-10

Xiumin Zhang, Pengfei Zheng + Show 8 more

Open Access

https://doi.org/10.1186/1476-511x-13-10

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Abstract

BackgroundAutophagy is an essential process for breaking down macromolecules and aged/damaged cellular organelles to maintain cellular energy balance and cellular nutritional status. The idea that autophagy regulates lipid metabolism is an emerging concept with important implications for atherosclerosis. However, the potential role of autophagy and its relationship with lipid metabolism in foam cell formation remains unclear. In this study, we found that autophagy was involved in the lipopolysaccharide (LPS)-induced the formation of foam cells and was at least partially dependent on adipose differentiation-related protein (ADRP).MethodFoam cell formation was evaluated by Oil red O staining. Autophagic activity was determined by immunofluorescence and Western blotting. ADRP gene expression of ADRP was examined by real-time PCR (RT-PCR). The protein expression of ADRP and LC3 was measured using Western blotting analysis. Intracellular cholesterol and triglyceride levels in foam cells were quantitatively measured by enzymatic colorimetric assays.ResultsLPS promoted foam cell formation by inducing lipid accumulation in macrophages. The activation of autophagy with rapamycin (Rap) decreased intracellular cholesterol and triglyceride levels, whereas the inhibition of autophagy with 3-methyladenine (3MA) enhanced the accumulation of lipid droplets. Overexpression of ADRP alone increased the formation of foam cells and consequently autophagic activity. In contrast, the inhibitory effects of ADRP activity with siRNA suppressed the activation of autophagy. Taken together, we propose a novel role for ADRP in the regulation of macrophage autophagy during LPS stimulation.ConclusionWe defined a new molecular pathway in which LPS-induced foam cell formation is regulated through autophagy. These findings facilitate the understanding of the role of autophagy in the development of atherosclerosis.

Highlights

Atherosclerosis is a chronic lipid metabolism disorder characterized by the deposition of excess lipids in large arteries
We propose a novel role for adipose differentiation-related protein (ADRP) in the regulation of macrophage autophagy during LPS stimulation
LPS promotes foam cell formation by inducing lipid accumulation in macrophages To examine the effect of LPS on macrophage lipid accumulation during foam cell formation, human THP-1 macrophage-derived foam cells were incubated with LPS (1 μg/ml) aggregates for a different periods (0, 8, 16, and 24 h), followed by visualization of lipid laden in macrophages with Oil Red O staining

Summary

Introduction

Atherosclerosis is a chronic lipid metabolism disorder characterized by the deposition of excess lipids in large arteries. Macrophages take up excessive modified lipoproteins, leading to the accumulation of intracellular cholesterol and triglycerides in the form of lipid droplets and the formation of foam cells, which appear to be Autophagy is a highly regulated intracellular degradation process that mediates the clearance of cytoplasmic proteins, certain pathogens and organelles [3]. LPS, a potential mediator of inflammatory responses, has been found to induce the macrophage-derived foam cell formation in vitro and promote the development of atherosclerotic plaque in vivo [6,7]. The potential role of autophagy and its relationship with lipid metabolism in foam cell formation remains unclear. We found that autophagy was involved in the lipopolysaccharide (LPS)-induced the formation of foam cells and was at least partially dependent on adipose differentiation-related protein (ADRP)

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