University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Population and Quantitative Health Sciences

Publication Date

2021-02-22

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biological Factors | Cell Biology | Cellular and Molecular Physiology | Digestive System Diseases | Enzymes and Coenzymes | Gastroenterology | Hepatology

Abstract

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.

Keywords

Hepatitis, Hepatology, Inflammation

Rights and Permissions

Copyright: © 2021, Miyata et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

DOI of Published Version

10.1172/jci.insight.140180

Source

Miyata T, Wu X, Fan X, Huang E, Sanz-Garcia C, Ross CKC, Roychowdhury S, Bellar A, McMullen MR, Dasarathy J, Allende DS, Caballeria J, Sancho-Bru P, McClain CJ, Mitchell M, McCullough AJ, Radaeva S, Barton B, Szabo G, Dasarathy S, Nagy LE. Differential role of MLKL in alcohol-associated and non-alcohol-associated fatty liver diseases in mice and humans. JCI Insight. 2021 Feb 22;6(4):e140180. doi: 10.1172/jci.insight.140180. PMID: 33616081; PMCID: PMC7934930. Link to article on publisher's site

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

JCI insight

PubMed ID

33616081

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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