Abstract:
Ferroptosis is closely associated with inflammatory diseases, including acute pancreatitis (AP); however, the involvement of ferroptosis in hypertriglyceridemic pancreatitis (HTGP) remains unclear. In the present study, we aimed to explore the relationship between lipid metabolism and ferroptosis in HTGP and the alleviating effect of liproxstatin-1 (Lip-1) in vivo. This study represents the first exploration of lipid metabolism and endoplasmic reticulum stress (ERS) in HTGP, targeting ferroptosis as a key factor in HTGP. Hypertriglyceridemia (HTG) was induced under high-fat diet conditions. Cerulein was then injected to establish AP and HTGP models. Lip-1, a specific ferroptosis inhibitor, was administered before the induction of AP and HTGP in rats, respectively. Serum triglyceride, amylase, inflammatory factors, pathological and ultrastructural structures, lipid peroxidation, and iron overload indicators related to ferroptosis were tested. Moreover, the interaction between ferroptosis and ERS was assessed. We found HTG can exacerbate the development of AP, with an increased inflammatory response and intensified ferroptosis process. Lip-1 treatment can attenuate pancreatic injury by inhibiting ferroptosis through lipid metabolism and further resisting activations of ERS-related proteins. Totally, our results proved lipid metabolism can promote ferroptosis in HTGP by regulating ACSL4/LPCAT3 protein levels. Additionally, ERS may participate in ferroptosis via the Bip/p-EIF2α/CHOP pathway, followed by the alleviating effect of Lip-1 in the rat model.
摘要:
铁凋亡与炎症性疾病密切相关,包括急性胰腺炎(AP);然而,在高甘油三酯血症性胰腺炎(HTGP)中,铁细胞凋亡是否参与尚不清楚.在本研究中,我们旨在探讨HTGP中脂质代谢与铁凋亡的关系以及利丙沙星抑制素-1(Lip-1)在体内的缓解作用。本研究首次探索脂质代谢和内质网应激(ERS)在HTGP,靶向铁性凋亡是HTGP的关键因素。在高脂肪饮食条件下诱发高甘油三酯血症(HTG)。然后注射Cerulein以建立AP和HTGP模型。Lip-1,一种特异性的铁凋亡抑制剂,在大鼠诱导AP和HTGP之前给药,分别。血清甘油三酯,淀粉酶,炎症因子,病理和超微结构,脂质过氧化,并对铁凋亡相关的铁过载指标进行检测。此外,评估了铁细胞凋亡和ERS之间的相互作用.我们发现HTG会加剧AP的发展,增加的炎症反应和强化的铁死亡过程。Lip-1治疗可以通过脂质代谢抑制铁凋亡并进一步抵抗ERS相关蛋白的激活来减轻胰腺损伤。完全正确,我们的结果证明脂质代谢可以通过调节ACSL4/LPCAT3蛋白水平促进HTGP中的铁凋亡。此外,ERS可能通过Bip/p-EIF2α/CHOP途径参与铁凋亡,其次是Lip-1对大鼠模型的缓解作用。