The role of MLKL in Hepatic Ischemia-Reperfusion Injury of Alcoholic Steatotic Livers

Abstract

Alcohol-related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the primary causes of chronic liver disease in western countries. Liver transplantation is currently one of the most efficient approaches to save patients with liver failure, which is often associated with hepatic ischemia-reperfusion (IR) injury. IR injury is exacerbated by hepatic steatosis, yet the mechanism remains elusive. Necroptosis is a form of regulated cell death mediated by receptor-interacting protein kinase 1 (RIP1), RIP3 and mixed lineage kinase domain-like (MLKL) protein, which has been implicated in the pathogenesis of ALD and NAFLD. Though necroptosis plays an important role in IR injury of high fat diet -induced steatotic livers, the role of necroptosis in IR injury of ethanol -induced steototic livers has not been investigated. In the present study, we used chronic plus binge alcohol (Gao-binge) feeding followed by IR surgery to investigate IR liver injury with ethanol-associated steatosis. We found that the levels of key necroptotic proteins MLKL and RIP3 increased in alcohol-fed mouse livers. Moreover, we observed increased liver injury after IR in control diet-fed mice, which was further exacerbated by alcohol feeding based on serum alanine aminotransferase (ALT) levels and TUNEL staining of necrotic cells. Hepatic neutrophil infiltration also increased in alcohol-fed mice after IR surgery. However, deletion of Mlkl did not protect against IR liver injury in alcohol-fed mice compared with matched wild-type mice. In conclusion, alcoholic steatosis promotes IR injury, which seems to be independent of MLKL-mediated necroptosis.

Necroptosis in Organ Transplantation: Mechanisms and Potential Therapeutic Targets

“…Moreover, Ripk3 −/− or Ripk3 kinase-dead knock-in mice were protected against IR injury 24 h after reperfusion, irrespective of diet [ 31 ]. Alcohol consumption increased the levels of liver MLKL and RIPK3 in mice and corresponded with more severe liver IR injury [ 32 ].…”

Advancements in the Alcohol-Associated Liver Disease Model

“…Necrosis is a novel form of PCD mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL) [ 21 ]. Necrosis has been shown to play a key role in oxidative stress, steatosis, and inflammatory response in ALD [ 24 , 25 , 26 , 27 ]. Following ethanol ingestion, ROS production promotes RIPK1 activation, leading to RIPK3 recruitment and necroptosis, while RIPK1 and RIPK3 can mediate the reactivation of necrosis by ROS production, forming a positive feedback loop [ 28 ].…”

A Small Molecule Chemiluminophore with near 600 nm Emission for In Vivo Imaging of Myeloperoxidase and Inflammatory Diseases

“…Liver diseases, including chronic liver disease, cirrhosis, severe acute liver injury, as well as hepatoma are mainly responsible for the marked associated morbidity and mortality worldwide. Alcoholic liver injury (ALI) as a major form of chronic liver injury can be induced by Binge drinking. − Clinically, simple steatosis followed by fibrosis are the hallmark presentations, but more severe conditions including alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma could be induced. − Acute liver failure (ALF) is a fatal disease with widespread hepatocellular necrosis, acute deterioration of liver function, and multiorgan failure, which can evolve over days or weeks to a lethal consequence. − Consequently, it is critical to early and exact diagnosis or identification of ALI/ALF in living systems to prevent and prediagnose liver-related diseases. More importantly, the features of hepatic neutrophil infiltration make neutrophils potentially targets in liver diseases.…”