TY - JOUR
T1 - Differential role of MLKL in alcohol-associated and non-alcohol-associated fatty liver diseases in mice and humans
AU - Miyata, Tatsunori
AU - Wu, Xiaoqin
AU - Fan, Xiude
AU - Huang, Emily
AU - Sanz-Garcia, Carlos
AU - Cajigas-Du Ross, Christina K.
AU - Roychowdhury, Sanjoy
AU - Bellar, Annette
AU - McMullen, Megan R.
AU - Dasarathy, Jaividhya
AU - Allende, Daniela S.
AU - Caballeria, Joan
AU - Sancho-Bru, Pau
AU - McClain, Craig J.
AU - Mitchell, Mack
AU - McCullough, Arthur J.
AU - Radaeva, Svetlana
AU - Barton, Bruce
AU - Szabo, Gyongyi
AU - Dasarathy, Srinivasan
AU - Nagy, Laura E.
N1 - Publisher Copyright:
© 2021, Miyata et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2021/2/22
Y1 - 2021/2/22
N2 - Hepatocellular death contributes to progression of alcohol-associated (ALD-associated) and non-alcohol-associated (NAFL/NASH) liver diseases. However, receptor-interaction protein kinase 3 (RIP3), an intermediate in necroptotic cell death, contributes to injury in murine models of ALD but not NAFL/NASH. We show here that a differential role for mixed-lineage kinase domain-like protein (MLKL), the downstream effector of RIP3, in murine models of ALD versus NAFL/NASH and that RIP1-RIP3-MLKL can be used as biomarkers to distinguish alcohol-associated hepatitis (AH) from NASH. Phospho-MLKL was higher in livers of patients with NASH compared with AH or healthy controls (HCs). MLKL expression, phosphorylation, oligomerization, and translocation to plasma membrane were induced in WT mice fed diets high in fat, fructose, and cholesterol but not in response to Gao-binge (acute on chronic) ethanol exposure. Mlkl-/- mice were not protected from ethanol-induced hepatocellular injury, which was associated with increased expression of chemokines and neutrophil recruitment. Circulating concentrations of RIP1 and RIP3, but not MLKL, distinguished patients with AH from HCs or patients with NASH. Taken together, these data indicate that MLKL is differentially activated in ALD/AH compared with NAFL/NASH in both murine models and patients. Furthermore, plasma RIP1 and RIP3 may be promising biomarkers for distinguishing AH and NASH.
AB - Hepatocellular death contributes to progression of alcohol-associated (ALD-associated) and non-alcohol-associated (NAFL/NASH) liver diseases. However, receptor-interaction protein kinase 3 (RIP3), an intermediate in necroptotic cell death, contributes to injury in murine models of ALD but not NAFL/NASH. We show here that a differential role for mixed-lineage kinase domain-like protein (MLKL), the downstream effector of RIP3, in murine models of ALD versus NAFL/NASH and that RIP1-RIP3-MLKL can be used as biomarkers to distinguish alcohol-associated hepatitis (AH) from NASH. Phospho-MLKL was higher in livers of patients with NASH compared with AH or healthy controls (HCs). MLKL expression, phosphorylation, oligomerization, and translocation to plasma membrane were induced in WT mice fed diets high in fat, fructose, and cholesterol but not in response to Gao-binge (acute on chronic) ethanol exposure. Mlkl-/- mice were not protected from ethanol-induced hepatocellular injury, which was associated with increased expression of chemokines and neutrophil recruitment. Circulating concentrations of RIP1 and RIP3, but not MLKL, distinguished patients with AH from HCs or patients with NASH. Taken together, these data indicate that MLKL is differentially activated in ALD/AH compared with NAFL/NASH in both murine models and patients. Furthermore, plasma RIP1 and RIP3 may be promising biomarkers for distinguishing AH and NASH.
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U2 - 10.1172/jci.insight.140180
DO - 10.1172/jci.insight.140180
M3 - Article
C2 - 33616081
AN - SCOPUS:85101918333
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 4
M1 - e140180
ER -