Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China.
Department of Traditional Chinese Medicine, the First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China.
Inflammation. 2022 Apr;45(2):639-650. doi: 10.1007/s10753-021-01573-1. Epub 2021 Oct 21.
Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), which can lead to liver fibrosis and cirrhosis. Bile acid levels are correlated with markers of hepatic injury in NASH, suggesting a possible role for bile acids in the progression of NAFLD. Here, we examined the role of deoxycholic acid (DCA) in driving steatotic hepatocytes to pyroptosis, a pro-inflammatory form of programmed cell death. HepG2 cells were stimulated with odium oleate and sodium palmitate for modeling steatotic hepatocytes and then treated with DCA alone or in combination with a specific mitophagy agonist, carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Our results showed that DCA dose-dependently induced a pro-inflammatory response in steatotic hepatocytes but had no significant effect on lipid accumulation. Moreover, activation of the NLRP3 inflammasome and pyroptosis were triggered by DCA. Expression levels of the mitophagy markers PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin were significantly diminished by DCA, whereas induction of mitophagy by CCCP prevented DCA-induced inflammatory response and restored the pyroptosis. Collectively, our data showed that DCA-induced pyroptosis involves the inhibition of PINK1-mediated mitophagy and the activation of the NLRP3 inflammasome. These findings provide insight into the association of DCA with mitophagy, pyroptosis, and inflammation in NASH.
非酒精性脂肪性肝炎（NASH）是一种非酒精性脂肪性肝病（NAFLD）的炎症亚型，可导致肝纤维化和肝硬化。胆汁酸水平与 NASH 中的肝损伤标志物相关，提示胆汁酸在 NAFLD 的进展中可能发挥作用。在这里，我们研究了脱氧胆酸（DCA）在促使脂肪变性肝细胞发生细胞焦亡（一种促炎形式的程序性细胞死亡）中的作用。HepG2 细胞用油酸和棕榈酸钠刺激以模拟脂肪变性肝细胞，然后单独用 DCA 或与特定的线粒体自噬激动剂羰基氰化物 3-氯苯腙（CCCP）联合处理。我们的结果表明，DCA 呈剂量依赖性诱导脂肪变性肝细胞发生促炎反应，但对脂质积累没有显著影响。此外，DCA 激活了 NLRP3 炎性小体并引发了细胞焦亡。DCA 显著降低了线粒体自噬标志物 PTEN 诱导的激酶 1（PINK1）和 E3 泛素连接酶 Parkin 的表达水平，而 CCCP 诱导的线粒体自噬则阻止了 DCA 诱导的炎症反应并恢复了细胞焦亡。总之，我们的数据表明，DCA 诱导的细胞焦亡涉及 PINK1 介导的线粒体自噬的抑制和 NLRP3 炎性小体的激活。这些发现为 DCA 与 NASH 中的线粒体自噬、细胞焦亡和炎症的关联提供了新的认识。
