Adipocyte Fatty Acid-Binding Protein Promotes Palmitate-Induced Mitochondrial Dysfunction and Apoptosis in Macrophages.

Hui Li,Lin Tang,Gan Huang,Feng Zhong,Ai-Min Xu,Jun-Mei Xu,Yang Xiao,Ru-Ping Dai,Zhi-Guang Zhou

doi:10.3389/fimmu.2018.00081

Abstract

A high level of circulating free fatty acids (FFAs) is known to be an important trigger for macrophage apoptosis during the development of atherosclerosis. However, the underlying mechanism by which FFAs result in macrophage apoptosis is not well understood. In cultured human macrophage Thp-1 cells, we showed that palmitate (PA), the most abundant FFA in circulation, induced excessive reactive oxidative substance production, increased malondialdehyde concentration, and decreased adenosine triphosphate levels. Furthermore, PA treatment also led to mitochondrial dysfunction, including the decrease of mitochondrial number, the impairment of respiratory complex IV and succinate dehydrogenase activity, and the reduction of mitochondrial membrane potential. Mitochondrial apoptosis was also detected after PA treatment, indicated by a decrease in cytochrome c release, downregulation of Bcl-2, upregulation of Bax, and increased caspase-3 activity. PA treatment upregulated the expression of adipocyte fatty acid-binding protein (A-FABP), a critical regulator of fatty acid trafficking and lipid metabolism. Inhibition of A-FABP with BMS309403, a small-molecule A-FABP inhibitor, almost reversed all of these indexes. Thus, this study suggested that PA-mediated macrophage apoptosis through A-FABP upregulation, which subsequently resulted in mitochondrial dysfunction and reactive oxidative stress. Inhibition of A-FABP may be a potential therapeutic target for macrophage apoptosis and to delay the progress of atherosclerosis.

Highlights

Macrophage apoptosis is an important characteristic of atherosclerosis development [1, 2]
Our results demonstrated a robust time- and dosedependent increase in apoptosis in the Thp-1 cells treated with PA, as evidenced by DNA fragmentation assayed by cell death enzymelinked immunosorbent assay (ELISA) (Figures 2A,B)
To further confirm whether blocking adipocyte fatty acid-binding protein (A-FABP) could inhibit the apoptotic effect of PA on macrophages, we examined caspase 3 activity, the downstream signaling of apoptosis (Figure 2E)

Summary

Introduction

Macrophage apoptosis is an important characteristic of atherosclerosis development [1, 2]. Macrophage apoptosis can be induced by long-term exposure to high levels of free fatty acids (FFAs), a well-known risk factor predictive of cardiovascular death [3,4,5]. The exact mechanisms remain unclear, accumulating evidence suggests that PA can trigger oxidative stress and mitochondrial dysfunction, and eventually lead to apoptosis in various cell culture models [7,8,9,10,11]. This effect may be partly due to the uncoupling of mitochondrial respiration induced by PA [11]. Knowledge of whether oxidative stress and mitochondrial damage mediates PA-induced macrophage apoptosis, and how they regulate it, is lacking

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