title: Adipocyte Fatty Acid Binding Protein Potentiates Toxic Lipids-Induced Endoplasmic Reticulum Stress in Macrophages via Inhibition of Janus Kinase 2-dependent Autophagy.
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.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Ruby L C
authors.initials: RL
authors.lastname: Hoo
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Shu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Kenneth K Y
authors.initials: KK
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Boya
authors.initials: B
authors.lastname: Liao
authors.affiliation: Key laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Donghai
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Geriatrics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7 / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism*; D050356:Lipid Metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D019308:Palmitic Acid / Q000494:pharmacology; D010587:Phagocytosis; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D019308:Palmitic Acid; D053614:Janus Kinase 2; D000071193:Autophagy-Related Protein 7