ZNF281 drives hepatocyte senescence in alcoholic liver disease by reducing HK2‐stabilized PINK1/Parkin‐mediated mitophagy

Abstract

We investigated the role of zinc‐finger protein 281 (ZNF281), a novel molecule, in ethanol‐induced hepatocyte senescence and uncovered the potential mechanism. Real‐time PCR, Western blot, immunofluorescence staining, and enzyme‐linked immunosorbent assay were performed to explore the role of ZNF281 in hepatocyte senescence. ZNF281 expression was upregulated in both alcohol‐fed mice livers and ethanol‐treated hepatocytes. Silence of ZNF281 in hepatocytes using siRNA mitigated ethanol‐caused decrease in cell viability and increased release of aspartate aminotransferase, alanine transaminase, and lactate dehydrogenase. ZNF281 siRNA reduced senescence‐associated β‐galactosidase‐positive cells under ethanol exposure, abolished cell cycle arrest at G0/G1 phase, and diminished senescence‐associated secretory phenotype and proinflammatory cytokines (IL‐1β and IL‐6) release. At molecular level, ZNF281 deficiency altered the expression profile of senescence‐associated proteins including p53, p21, p16, high mobility group AT‐hook 1, and phospho‐histone H2A.X and telomerase‐associated regulatory factors including telomerase reverse transcriptase, telomeric repeat binding factor 1 (TRF1), and TRF2. ZNF281 knockdown promoted hepatocyte recovery from ethanol‐induced mitochondrial dysfunction and ROS production, which was correlated with rescuing HK2‐PINK1/Parkin signalling‐mediated mitophagy. Mechanistically, ZNF281 directly bound to 5′‐GGCGGCGGGCGG‐3′ motif within HK2 promoter region and transcriptionally repressed HK2 expression. Systematic ZNF281 knockdown by adeno‐associated virus encoding ZNF281 shRNA protected mice from alcohol feeding‐caused hepatocyte injury and senescence. This study provides a novel factor ZNF281 as a driver of hepatocyte senescence during alcoholic liver disease.

Nucleoredoxin Redox Interactions Are Sensitized by Aging and Potentiated by Chronic Alcohol Consumption in the Mouse Liver

“…Our IF analysis revealed that PAR level was significantly increased in untreated aged mice but was exacerbated by chronic alcohol consumption in both young and aged mice ( Figure 4 A). In vitro assays have shown that senescence, a stress response that universally occurs within tissues under pathophysiological conditions, is stimulated in hepatocytes by ethanol, suggesting that it plays a key role in ALD [ 44 ]; moreover, in hepatocyte cultures exposed to ethanol the SA-β-gal activity, a widely used biomarker of cellular senescence, is increased [ 45 ]. Interestingly, our results showed that the activity of SA-β-gal was increased in untreated 18-month-old mice, but this increment was observed from 12 months on and potentiated in 18-month-old mice subjected to the ALD model ( Figure 4 B), indicating that chronic alcohol consumption exacerbated the appearance of senescent cells in the liver of aged mice.…”

What are the common downstream molecular events between alcoholic and nonalcoholic fatty liver?

“…Recent results highlight that plasminogen activator inhibitor-1 and early growth response protein 1 are important regulators of lipopolysaccharide-induced cellular senescence and alcoholic hepatitis [ 53 ]. Another fascinating study showed that a novel factor, zinc‐finger protein 281, is a driver of hepatocyte senescence during ALD by reducing hexokinase II-stabilized PTEN-induced kinase 1/Parkin-mediated mitophagy [ 54 ]. Returning to lysosomes, chronic ethanol consumption disrupts hepatic biogenesis and inhibits the ubiquitin‒proteasome system by impeding hepatic proteasome activity [ 55 ].…”

Regulation of the Nur77-P2X7r Signaling Pathway by Nodakenin: A Potential Protective Function against Alcoholic Liver Disease

“…Alcoholic liver disease (ALD) is a major cause of acute and chronic liver injury and can include simple steatosis, steatohepatitis, advanced fibrosis, cirrhosis, and even hepatocellular carcinoma [ 1 , 2 ]. ALD can be caused by byproducts or metabolites produced during alcohol metabolism and is a major factor that induces chronic liver disease [ 3 ].…”