Abstract：
Hyperlipidemic pancreatitis (HP) is an inflammatory injury of the pancreas triggered by elevated serum triglyceride (TG) levels. The mechanistic target of rapamycin (mTOR) signaling pathway plays a crucial role in regulating lipid homeostasis and inflammation. This study aimed to investigate whether the activity of mTOR complex 2 (mTORC2) affects the progression of HP and its underlying mechanisms. In vivo, a high-fat diet and retrograde administration of sodium taurocholate were employed to establish the HP models in rats, with pancreatic tissue pathology evaluated. The expression of Rictor and peroxisome proliferator-activator receptor (PPAR) was examined. The serum levels of TG, fatty acid metabolites, inflammatory and lipid metabolism-related factors were determined. In vitro, pancreatic acinar cells (PACs) were exposed to palmitic acid and cholecystokinin-8. PAC apoptosis, pyroptosis, and ferroptosis were assessed. In the HP models, rats and PACs exhibited upregulated Rictor and downregulated PPARα, and Rictor knockdown promoted PPARα expression. In vivo, Rictor knockdown decreased the serum levels of TG, α-amylase, total cholesterol, low-density lipoprotein cholesterol, lactate dehydrogenase, and inflammatory factors, while increasing high-density lipoprotein cholesterol levels. Rictor knockdown increased ACOX1 and CPT1α and decreased SREBP-1, CD36, SCD1, ACLY, and ACACA. Rictor knockdown reduced damage to pancreatic tissue structure. In vitro, Rictor knockdown inhibited PAC apoptosis, pyroptosis, and ferroptosis. Treatment with the PPARα antagonist GW6471 abolished the beneficial effects of Rictor knockdown. Rictor/mTORC2 deficiency reduces serum TG levels, maintains lipid homeostasis, and suppresses inflammation by inhibiting PPARα expression. Weakening mTORC2 activity holds promise as a novel therapeutic strategy for HP.
摘要：
高脂血症性胰腺炎（HP）是由血清甘油三酯（TG）水平升高引发的胰腺炎症损伤。雷帕霉素（mTOR）信号通路在调节脂质稳态和炎症中起着至关重要的作用。本研究旨在探讨mTOR复合物2（mTORC2）的活性是否影响HP的进展及其潜在机制。在体内,采用高脂饮食和牛磺胆酸钠逆行给药建立大鼠HP模型，与胰腺组织病理评估。检查了Rictor和过氧化物酶体增殖物激活物受体（PPAR）的表达。血清TG、脂肪酸代谢物，确定炎症和脂质代谢相关因子.体外，胰腺腺泡细胞（PACs）暴露于棕榈酸和胆囊收缩素-8。PAC细胞凋亡,焦亡,和铁性凋亡进行了评估。在HP型号中，大鼠和PAC表现出Rictor上调和PPARα下调，Rictor敲除促进PPARα表达。在体内,Rictor敲除降低血清TG水平，α-淀粉酶,总胆固醇,低密度脂蛋白胆固醇，乳酸脱氢酶,和炎症因子，同时增加高密度脂蛋白胆固醇水平。Rictor敲低增加了ACOX1和CPT1α，降低了SREBP-1，CD36，SCD1，ACLY，和ACACA。Rictor敲除减少对胰腺组织结构的损伤。体外，Rictor敲低抑制PAC细胞凋亡，焦亡,和铁中毒。用PPARα拮抗剂GW6471治疗消除了Rictor敲低的有益作用。Rictor/mTORC2缺乏降低血清TG水平，维持脂质稳态，并通过抑制PPARα表达来抑制炎症。减弱mTORC2活性有望成为HP的新型治疗策略。
