过氧化物酶体增殖物激活受体α调控自噬对急性肝衰竭的保护作用与机制

Acute liver failure(ALF), an inflammation-mediated hepatocellular injury process, the immune mechanisms by which the organ damage occurs are not completely understood. Peroxisome proliferator-activated receptor α(PPARα) belongs to the nuclear hormone receptor superfamily of ligand-activated transcription factors having been reported to be involved in a number of cellular processes including lipid metabolism, apoptosis, inflammatory response, and so on. Although studies have demonstrated that PPARα exhibits potent anti-inflammatory activity. However, the functional role of PPARα in the mechanism of ALF is still relatively lacking. Our previous study has demonstrated that PPARα was suppressed in the procession of ALF induced by D-GalN/LPS, the gene and protein level of PPARα were gradually reduced. Serum levels of alanine aminotransferase(ALT) and aspartate aminotransferase(AST),as markers of hepatic damage, were increased throughout the procession of ALF. In addition, good correlation has been shown between the gene level of PPARα and the serum levels of ALT and AST. In the present study, we will first determine the protective role of PPARα in acute liver failure and Whether PPARα could protect liver from injury by mediating autophagy to attenuate inflammatory. In order to further explore the protective cellular mechanism of PPARα, we will then test the role of autophagy in the effect provided by PPARα activation in LPS-induced bone marrow-derived macrophages(BMM) by using 3-MA or knockdown of ATG7 with ATG7-specific siRNA to inhibit autophagy.

急性肝衰竭是一种由炎症介导的肝细胞损伤过程，其器官损伤的免疫学机制尚未完全阐明。过氧化物酶体增殖物激活受体α(PPARα)是由配体激活的核转录因子，已被证实参与了细胞脂质代谢、凋亡及炎症反应等，但在炎症作为其主要病生理机制的急性肝衰竭中，PPARα的作用如何目前尚无研究。在前期研究发现小鼠急性肝衰竭疾病进展过程中PPARα表达进行性减少并与肝损伤的严重程度具有很好相关性的基础上，本研究将在小鼠急性肝衰竭模型上用PPARα的选择性激动剂WY14643干预以探讨PPARα活化能否通过促进细胞自噬减轻炎症反应而对急性肝衰竭产生保护作用；进一步在小鼠骨髓来源的原代巨噬细胞炎症模型上分别用药物3-MA、siAtg7抑制细胞自噬，观察自噬受抑后能否逆转PPARα对炎症反应的原有调节作用，以深入探讨PPARα对急性肝衰竭发挥保护作用的细胞学机制。