Adipocyte Fatty Acid Binding Protein Potentiates Toxic Lipids-Induced Endoplasmic Reticulum Stress in Macrophages via Inhibition of Janus Kinase 2-dependent Autophagy

Ruby L C Hoo,Donghai Wu,Zhiguang Zhou,Kenneth K Y Cheng,Aimin Xu,Lingling Shu,Xiaoping Wu,Boya Liao

doi:10.1038/srep40657

Abstract

Lipotoxicity is implicated in the pathogenesis of obesity-related inflammatory complications by promoting macrophage infiltration and activation. Endoplasmic reticulum (ER) stress and adipocyte fatty acid binding protein (A-FABP) play key roles in obesity and mediate inflammatory activity through similar signaling pathways. However, little is known about their interplay in lipid-induced inflammatory responses. Here, we showed that prolonged treatment of palmitic acid (PA) increased ER stress and expression of A-FABP, which was accompanied by reduced autophagic flux in macrophages. Over-expression of A-FABP impaired PA-induced autophagy associating with enhanced ER stress and pro-inflammatory cytokine production, while genetic ablation or pharmacological inhibition of A-FABP reversed the conditions. PA-induced expression of autophagy-related protein (Atg)7 was attenuated in A-FABP over-expressed macrophages, but was elevated in A-FABP-deficient macrophages. Mechanistically, A-FABP potentiated the effects of PA by inhibition of Janus Kinase (JAK)2 activity, thus diminished PA-induced Atg7 expression contributing to impaired autophagy and further augmentation of ER stress. These findings suggest that A-FABP acts as autophagy inhibitor to instigate toxic lipids-induced ER stress through inhibition of JAK2-dependent autophagy, which in turn triggers inflammatory responses in macrophages. A-FABP-JAK2 axis may represent an important pathological pathway contributing to obesity-related inflammatory diseases.

Highlights

Lipotoxicity is implicated in the pathogenesis of obesity-related inflammatory complications by promoting macrophage infiltration and activation
Elevated Endoplasmic reticulum (ER) stress is shown to activate autophagy[8,19], the palmitic acid (PA)-induced elevation of ER stress was associated with a dynamic change of autophagy as the conversion of LC3I to LC3II was markedly increased upon PA induction in the first 8 hours but gradually decreased at later time points which was accompanied by an enhanced accumulation of p62, an ubiquitin-binding scaffold protein that is degraded through autophagy[31] (Fig. 1A)
Impaired autophagy in macrophages has mild effects on the metabolic function and adipose tissue inflammation of obese mice[40,41], defective autophagy has been shown to underlie the pathogenesis of obesity-related disorders such as steatohepatitis, atherosclerosis and cardiomyopathy associating with increased ER stress and inflammation[13,16,40,42]

Summary

Introduction

Lipotoxicity is implicated in the pathogenesis of obesity-related inflammatory complications by promoting macrophage infiltration and activation. A-FABP potentiated the effects of PA by inhibition of Janus Kinase (JAK)[2] activity, diminished PA-induced Atg[7] expression contributing to impaired autophagy and further augmentation of ER stress These findings suggest that A-FABP acts as autophagy inhibitor to instigate toxic lipids-induced ER stress through inhibition of JAK2-dependent autophagy, which in turn triggers inflammatory responses in macrophages. Elevated endoplasmic reticulum (ER) stress is observed in metabolic organs of obese animals[3] This results in the elicitation of unfolded protein response (UPR) which in turn activates c-Jun N-terminal kinases (JNK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pro-inflammatory signaling pathways[4] implicating in the molecular mechanism of lipotoxicity. Impairment of JAK2-dependent autophagy further instigates ER stress, thereby leading to the exaggeration of inflammatory responses in macrophages

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Conclusion