Hepatic kinome atlas: An in-depth identification of kinase pathways in liver fibrosis of humans and rodents

Justin F. Creeden, Zachary A. Kipp, Mei Xu, Robert M. Flight, Hunter N.B. Moseley, Genesee J. Martinez, Wang Hsin Lee, Khaled Alganem, Ali S. Imami, Megan R. McMullen, Sanjoy Roychowdhury, Atta M. Nawabi, Jennifer A. Hipp, Samir Softic, Steven A. Weinman, Robert McCullumsmith, Laura E. Nagy, Terry D. Hinds

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background and Aims: Resolution of pathways that converge to induce deleterious effects in hepatic diseases, such as in the later stages, have potential antifibrotic effects that may improve outcomes. We aimed to explore whether humans and rodents display similar fibrotic signaling networks. Approach and Results: We assiduously mapped kinase pathways using 340 substrate targets, upstream bioinformatic analysis of kinase pathways, and over 2000 random sampling iterations using the PamGene PamStation kinome microarray chip technology. Using this technology, we characterized a large number of kinases with altered activity in liver fibrosis of both species. Gene expression and immunostaining analyses validated many of these kinases as bona fide signaling events. Surprisingly, the insulin receptor emerged as a considerable protein tyrosine kinase that is hyperactive in fibrotic liver disease in humans and rodents. Discoidin domain receptor tyrosine kinase, activated by collagen that increases during fibrosis, was another hyperactive protein tyrosine kinase in humans and rodents with fibrosis. The serine/threonine kinases found to be the most active in fibrosis were dystrophy type 1 protein kinase and members of the protein kinase family of kinases. We compared the fibrotic events over four models: humans with cirrhosis and three murine models with differing levels of fibrosis, including two models of fatty liver disease with emerging fibrosis. The data demonstrate a high concordance between human and rodent hepatic kinome signaling that focalizes, as shown by our network analysis of detrimental pathways. Conclusions: Our findings establish a comprehensive kinase atlas for liver fibrosis, which identifies analogous signaling events conserved among humans and rodents.

Original languageEnglish
Pages (from-to)1376-1388
Number of pages13
JournalHepatology
Volume76
Issue number5
DOIs
StatePublished - Nov 2022

Bibliographical note

Funding Information:
Supported by the National Institutes of Health (1R01DK121797, NIMH R01 MH107487, R01 AG057598, R01 MH121102, P50 AA024333); the University of Toledo Foundation; National Science New Network Foundation (2020026); the Biostatistics and Bioinformatics Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558); and by the University of Kentucky Office of the Vice President for Research through the Diabetes and Obesity Research Priority Area

Publisher Copyright:
© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

ASJC Scopus subject areas

  • Hepatology

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