Hypertriglyceridemia (HTG) can aggravate acute pancreatitis (AP), but its pathogenesis remains unclear. As autophagic activity is closely related to lipid metabolism and AP, we investigated the autophagic response in models of AP aggravated by HTG and explored whether rapamycin has a protective effect against HTG-related pancreatitis. HTG-associated AP models were established in vivo in rats and in vitro. The degree of inflammation, pancreatic injury, the expression of endoplasmic reticulum (ER) stress, and autophagy markers (P62, LC3) were compared. Autophagic flux were assessed using immunostaining, electron microscopy, and immunoblotting. Compared with the normal diet group, the high-fat diet (HFD) AP group exhibited more severe pancreatic injury, apoptosis, and blocked autophagic flux. In addition, the three branches (PERK–eIF2α, ATF-6–GRP78, and IRE1–sXBP1) of the unfolded protein response and mTORC1/S6K1 pathway were activated in HFD AP models. Moreover, the same phenomena were confirmed in vitro in palmitic acid–stimulated pancreatic acinar cells. Preincubation with the mTOR inhibitor rapamycin restored the autophagic flux and markedly reduced the adverse effects of HTG. In conclusion, the autophagic flux is impaired in HFD-induced AP models and is strongly associated with ER stress. Rapamycin could prevent the aggravation of HTG-associated AP via inhibiting mTORC1/S6K1 pathway.

高甘油三酯血症（HTG）可加重急性胰腺炎（AP），但其发病机制尚不清楚。由于自噬活性与脂质代谢和 AP 密切相关，我们研究了 HTG 加重的 AP 模型中的自噬反应，并探讨了雷帕霉素是否对 HTG 相关性胰腺炎具有保护作用。在大鼠体内和体外建立HTG相关AP模型. 比较炎症程度、胰腺损伤、内质网（ER）应激表达、自噬标志物（P62、LC3）。使用免疫染色、电子显微镜和免疫印迹评估自噬通量。与正常饮食组相比，高脂饮食（HFD）AP组表现出更严重的胰腺损伤、细胞凋亡和自噬流受阻。此外，未折叠蛋白反应和 mTORC1/S6K1 通路的三个分支（PERK-eIF2α、ATF-6-GRP78 和 IRE1-sXBP1）在 HFD AP 模型中被激活。此外，在体外也证实了同样的现象在棕榈酸刺激的胰腺腺泡细胞中。与 mTOR 抑制剂雷帕霉素预孵育可恢复自噬通量并显着降低 HTG 的副作用。总之，自噬通量在 HFD 诱导的 AP 模型中受损，并且与 ER 应激密切相关。雷帕霉素可通过抑制 mTORC1/S6K1 通路防止 HTG 相关 AP 的加重。