Journal Article

Deoxycholic Acid Promotes Pyroptosis in Free Fatty Acid-Induced Steatotic Hepatocytes by Inhibiting PINK1-Mediated Mitophagy

Zhu, Xuan, Lin Xiaozhuan, Guo Honghui, Yan, Xin, Ruan Yongdui, Gao Xuebin, Li, Xiang, Mai Meiqing

2022

Overview

Abstract—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.

• Publisher: Springer Nature B.V
• Subject: Apoptosis / Autophagy / Bile / Bile acids / Cell death / Cirrhosis / Cyanides / Deoxycholic acid / Fatty acids / Fatty liver / Fibrosis / Hepatocytes / Inflammasomes / Inflammation / Kinases / Liver cirrhosis / Liver diseases / Mitophagy / Palmitic acid / PTEN protein / PTEN-induced putative kinase / Public health / Pyroptosis / Ubiquitin / Ubiquitin-protein ligase