Depending on the stage of hepatosteatosis, p53 causes apoptosis primarily through either DRAM-induced autophagy or BAX.
Depending on the stage of hepatosteatosis, p53 causes apoptosis primarily through either DRAM-induced autophagy or BAX.
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根据肝脂肪变性的阶段，p53 主要通过 DRAM 诱导的自噬或 BAX 引起细胞凋亡
DOI：
10.1111/liv.12238
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发表时间：
2013-11
期刊：
影响因子：
--
通讯作者：
Li N
中科院分区：
文献类型：
--
作者：
Liu K;Lou J;Wen T;Yin J;Xu B;Ding W;Wang A;Liu D;Zhang C;Chen D;Li N
p53介导的细胞凋亡在肝成骨病的发展中起病理作用。值得注意的是，p53可以促进损伤调节的自噬调节因子（DRAM）的表达，这是自噬介导的细胞凋亡的诱导剂。然而，p53介导的细胞凋亡与肝细胞自噬之间的关系尚不清楚。本研究旨在探讨p53如何协调自噬和细胞凋亡影响肝骨附着症。用油酸（OA）处理HepG2细胞24 h，诱导肝纤维化。小鼠分别饲喂高脂饮食20周和40周，诱导肝纤维化。OA诱导脂肪变性严重程度和细胞凋亡的剂量依赖性增加。在400 μM OA诱导的轻度脂肪变性中，自噬是诱导细胞凋亡的关键因子，而在800和1200 μM OA诱导的重度脂肪变性中则无此作用。siRNA对p53的抑制作用主要阻断oa诱导的细胞凋亡和自噬。此外，oa诱导的自噬依赖于DRAM，主要发生在DRAM定位的线粒体（mitophagy）中。在1200 μM OA诱导的严重脂肪变性中，凋亡主要依赖于p53诱导的BAX表达，BAX也定位于线粒体。我们的体内研究表明，p53的表达在轻度和重度肝骨附着症中都有所增加。轻度肝骨化症患者DRAM表达和自噬增加，而重度肝骨化症患者BAX表达增加。P53可能通过不同机制诱导细胞凋亡。dam介导的线粒体自噬是轻度肝骨化症的主要凋亡诱导因子，而p53诱导的BAX表达主要诱导重度肝骨化症的凋亡。
Apoptosis mediated by p53 plays a pathological role in the progression of hepatosteatosis. It is noteworthy that p53 can promote the expression of damage-regulated autophagy modulator (DRAM), an inducer of autophagy-mediated apoptosis. However, the relationship between p53-mediated apoptosis and autophagy in hepatosteatosis remains elusive. This study aimed to examine how p53 orchestrates autophagy and apoptosis to affect hepatosteatosis. HepG2 cells were treated with oleic acid (OA) for 24 h to induce hepatosteatosis. Mice were fed a high-fat diet for 20 or 40 weeks to induce hepatosteatosis. OA induced a dose-dependent increase in steatosis severity and apoptosis. OA also induced autophagy, which was a critical inducer of apoptosis in mild steatosis induced by 400 μM OA, but not in the more severe steatosis induced by 800 and 1200 μM OA. p53 inhibition by siRNA mostly blocked OA-induced apoptosis and autophagy. Moreover, OA-induced autophagy was DRAM-dependent and primarily occurred in the mitochondria (mitophagy), where DRAM was localized. In severe steatosis induced by 1200 μM OA, apoptosis was mainly dependent on p53-induced expression of BAX, which was also localized to the mitochondria. Our in vivo study showed that p53 expression increased in both mild and severe hepatosteatosis. Increased DRAM expression and autophagy were identified in mild hepatosteatosis, whereas greater BAX expression was observed in severe hepatosteatosis. p53 may induce apoptosis via different mechanisms. DRAM-mediated mitophagy is a primary apoptotic inducer in mild hepatosteatosis, whereas p53-induced BAX expression mainly induces apoptosis in severe hepatosteatosis.
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DOI：
10.1126/science.1204265
发表时间：
2011-06-24
期刊：
Science (New York, N.Y.)
影响因子：
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