Palmitic acid aggravates inflammation of pancreatic acinar cells by enhancing unfolded protein response induced CCAAT-enhancer-binding protein β-CCAAT-enhancer-binding protein α activation.
Hypertriglyceridemia is an independent risk factor for acute pancreatitis, in which the pathological mechanisms are not fully illustrated. Intracellular inflammatory response is a key pathological response in acute pancreatitis and endoplasmic reticulum stress has been suggested to induce inflammation and CCAAT-enhancer-binding protein expression. Therefore, the current study aims to elucidate the possible relationship between endoplasmic reticulum stress and inflammation in hypertriglyceridemia associated pancreatitis and the possible involvement of CCAAT-enhancer-binding protein. In cholecystokinin-8 stimulated rat primary acinar cells, incubation with palmitic acid caused the activation of endoplasmic reticulum stress and inflammatory responses. Pre-incubation with the chemical chaperone 4-phenylbutyric acid inhibited inflammatory responses induced by palmitic acid, whereas stimulation with the endoplasmic reticulum stress inducer thapsigargin alone induced inflammatory responses. Meanwhile we found that the transcription factors CCAAT-enhancer-binding protein α and CCAAT-enhancer-binding protein β were also induced in the palmitic acid-stimulated pancreatic acinar cells, and were similarly inhibited by 4-phenylbutyric acid pre-incubation and induced by thapsigargin stimulation alone, indicating that endoplasmic reticulum stress was responsible for CCAAT-enhancer-binding protein α and CCAAT-enhancer-binding protein β induction in the pancreatic acinar cells. Knockdown of CCAAT-enhancer-binding protein β by siRNA transfection inhibited inflammatory responses and CCAAT-enhancer-binding protein α induction but did not affect endoplasmic reticulum stress. Our study provides strong evidence that in response to palmitic acid stimulation, endoplasmic reticulum stress induces inflammatory responses in pancreatic acinar cells through induction of the CCAAT-enhancer-binding protein family, wherein CCAAT-enhancer-binding protein β activation is responsible for CCAAT-enhancer-binding protein α activation.
Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Jianghong
J
Wu
Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Guoyong
G
Hu
Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yingying
Y
Lu
Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Junyuan
J
Zheng
Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Jing
J
Chen
Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: richardwangxp@163.com.
Xingpeng
X
Wang
Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: zengyue1592@yahoo.com.
Yue
Y
Zeng
D061354:Acinar Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015228:Hypertriglyceridemia / Q000150:complications; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D019308:Palmitic Acid / Q000494:pharmacology*; D010179:Pancreas / Q000473:pathology*; D010195:Pancreatitis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects*
D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D019308:Palmitic Acid
Acute pancreatitis; C/EBPβ; ER stress; Inflammatory responses; NF-κB; Pancreatic acinar cells