FABP4 alleviates endoplasmic reticulum stress‑mediated ischemia‑reperfusion injury in PC12 cells via regulation of PPARγ

Abstract

Ischemic stroke is a life-threatening complication with a high rate of morbidity. Circulating fatty acid binding protein 4 (FABP4) has been reported to be associated with the outcome of acute ischemic stroke. The present study aimed to illustrate the function of FABP4 in ischemic stroke. PC12 cells exposed to oxygen glucose deprivation/reoxygenation (OGD/R) were used to mimic ischemia-reperfusion (I/R) injury in ischemic stroke. Cell viability was estimated using a Cell Counting Kit-8 assay. The expression of FABP4 in PC12 cells under OGD/R was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). PC12 cells were transfected with FABP4 small interfering RNA (siRNA), inflammatory cytokines and reactive oxygen species (ROS) were determined via RT-qPCR and ROS assay kit. Western blotting was performed to detect endoplasmic reticulum stress (ERS)-related proteins and peroxisome proliferator-activated receptor γ (PPARγ). Flow cytometry was used to evaluate the cell apoptotic rate. The expression of FABP4 increased gradually with the prolongation of reoxygenation within 8 h. FABP4-knockdown inhibited the transcription of inflammatory cytokines, the production of ROS and decreased cell apoptosis. Furthermore, decreased ERS-related proteins and increased PPARγ were estimated in PC12 cells transfected with FABP4 siRNA. PPARγ inhibitor GW9662 weakened the anti-apoptotic effect of FABP4-knockdown. Taken together, these results indicated that FABP4-knockdown suppressed cell apoptosis via relieving ERS; this effect was reversed by treatment of GW9662.

Correlation between the serum FABP4, ANGPTL3, and ANGPTL4 levels and coronary artery disease

“…FABP4 is also involved in oxidative stress and inflammation. FABP4 reduces cyclooxygenase‐2 and inducible nitric oxide synthase expression in macrophages through IKK‐NF‐κB and JNK‐AP‐1 pathways, 15 and thus promotes oxidative stress response. FABP4 also regulates the expression of inflammatory cytokines, such as interleukin (IL)‐1β, IL‐6, and TNF‐α, and thus promotes inflammatory necrosis 15 .…”

“…FABP4 reduces cyclooxygenase‐2 and inducible nitric oxide synthase expression in macrophages through IKK‐NF‐κB and JNK‐AP‐1 pathways, 15 and thus promotes oxidative stress response. FABP4 also regulates the expression of inflammatory cytokines, such as interleukin (IL)‐1β, IL‐6, and TNF‐α, and thus promotes inflammatory necrosis 15 . FABP4 can also upregulate the expression of adhesion molecules, such as integrin β2, α4, P‐selectin ligand protein, intercellular cell adhesion molecule 1 (ICAM‐1), vascular cell adhesion molecule 1 (VCAM‐1), and P‐selectin, and thus promote ox‐LDL‐induced cell adhesions and AS development 11 …”

Application of systemic inflammation indices and lipid metabolism-related factors in coronary artery disease

“…Studies have shown that FABP4 deficiency can inhibit IKK-NF-κB and JNK-AP-1 pathways, reducing the expression of cyclooxygenase-2 and inducible nitric oxide synthase in macrophages [ 28 ], which relieves endoplasmic reticulum stress through the PPARγ pathway. Meanwhile, FABP4 deficiency can also down-regulate the inflammatory cytokines interleukin-1β (IL-1β), IL-6, and TNF-α expression to inhibit the inflammatory response [ 29 ]. In this study, the serum FABP4 level was higher in the CAD group than in the non-CAD group, indicating an increase in serum FABP4 in CAD patients; however, FABP4 was not found to be statistically significant after adjusting for confounding factors in the multivariate study.…”

Fatty Acid-Binding Proteins: Their Roles in Ischemic Stroke and Potential as Drug Targets

“…In addition to the disruption of the BBB, FABP4 is also actively involved in apoptotic signaling activation, endoplasmic reticulum stress, oxidative stress, inflammation, and mitochondrial damage, all of which are important processes in the ischemic cascade. For example, FABP4 has been demonstrated to exacerbate I/R injury in mouse kidney tissue by modulating glucose-regulated protein 78 (GRP78)/C/EBP homologous protein (CHOP)/caspase-12 signaling to induce ER stress [ 92 ], whereas in a cellular I/R model, the involvement of FABP4 in endoplasmic reticulum stress has been found to be mediated via the PPARγ [ 102 ] and PI3K/Akt [ 103 ] pathways. As an important mediator of the inflammatory response, FABP4 is known to promote inflammation via mitochondrial uncoupling protein 2 (UCP2) [ 104 , 105 ], Toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB) signaling [ 106 , 107 ].…”