Influence of Fat on Differential Receptor Interacting Serine/Threonine Protein Kinase 1 Activity Leading to Apoptotic Cell Death in Murine Liver Ischemia Reperfusion Injury Through Caspase 8

Abstract

Current understanding is that receptor interacting serine/threonine protein kinase 1 (RIPK1) can lead to two distinct forms of cell death: RIPK3‐mediated necroptosis or caspase 8 (Casp8)‐mediated apoptosis. Here, we report that RIPK1 signaling is indispensable for protection from hepatocellular injury in a steatotic liver undergoing ischemia reperfusion injury (IRI) but not in the lean liver. In lean liver IRI, RIPK1‐mediated cell death is operational, leading to protection in RIP1 kinase‐dead knock‐in (RIPK1 K45A ) mice and necrostatin‐1s (Nec1s)‐treated lean wild‐type (WT) mice. However, when fed a high‐fat diet (HFD), RIPK1 K45A ‐treated and Nec1s‐treated WT mice undergoing IRI demonstrate exacerbated hepatocellular injury along with decreased RIPK1 ubiquitylation. Furthermore, we demonstrate that HFD‐fed RIPK3 –/– /Casp8 –/– mice show protection from IRI, but HFD‐fed RIPK3 –/– /Casp8 –/+ mice do not. We also show that blockade of RIPK1 leads to increased Casp8 activity and decreases mitochondrial viability. Conclusion: Although more studies are required, we provide important proof of concept for RIPK1 inhibition leading to distinctive outcomes in lean and steatotic liver undergoing IRI. Considering the rising incidence of nonalcoholic fatty liver disease (NAFLD) in the general population, it will be imperative to address this critical difference when treating patients with RIPK1 inhibitors. This study also presents a new target for drug therapy to prevent hepatocellular injury in NAFLD.

Apoptotic cell death in disease—Current understanding of the NCCD 2023

“…Similarly, FAS inhibition, FASL neutralization, as well as administration of low-dose TNF (as a pre-conditioning maneuver) have been shown to protect the liver against ischemia/ reperfusion injury by reducing hepatic cell apoptosis and/or inflammation [743][744][745]. Protection of the liver from ischemia/ reperfusion has also been observed in mice deficient for TRAIL [746], as well as upon the conditional knockdown of CASP8 or CASP3, the combined deletion of Casp8 and Ripk3, and the transgenic expression of a BID mutant that cannot be cleaved by CASP8 [283,747,748].…”

Normalization of the α1-Na/K-ATPase/Src Signalosome Restored Microbiota Communities and Rescinded NASH Progression in the Mouse

“…[48][49][50] Liver apoptotic activity was determined through grading five images at 40x magnification of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) stained liver slides (Figure A3C, Click-iT Plus TUNEL assay kit, Invitrogen by Thermo Fisher Scientific, MA). [51][52][53][54][55][56] Lastly, liver cellular senescence was determined by grading five images at 40x magnification of liver slides stained for β-Galactosidase activity (Figure A3D, Cell signaling Technology #9860, MA). Digitally recorded images at 40x magnification on the label (but blinded liver slides), were saved using ImageJ1.51u software.…”

Treatment of nonalcoholic fatty liver disease: from adult trials to perspectives in the management of children and adolescents

“…Interestingly, recent experimental data indicate that blockade of receptor-interacting serine/threonine protein kinase 1 (RIPK1) signaling (crucial for protection from hepatocellular damage in a steatotic liver undergoing ischemia reperfusion injury but not in the lean liver) results in augmented caspase 8 activity and reduces mitochondrial viability, thereby recommending as a new target for drug therapy to inhibit hepatocellular injury in NAFLD [35].…”