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

Autor: Creeden JF; Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA., Kipp ZA; Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA., Xu M; Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA., Flight RM; Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.; Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.; Resource Center for Stable Isotope Resolved Metabolomics, University of Kentucky, Lexington, Kentucky, USA., Moseley HNB; Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.; Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.; Resource Center for Stable Isotope Resolved Metabolomics, University of Kentucky, Lexington, Kentucky, USA.; Institute for Biomedical Informatics, University of Kentucky, Lexington, Kentucky, USA.; Center for Clinical and Translational Science, University of Kentucky, Lexington, Kentucky, USA., Martinez GJ; Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA., Lee WH; Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA., Alganem K; Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA., Imami AS; Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA., McMullen MR; Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA., Roychowdhury S; Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA., Nawabi AM; Division of Transplant and Hepatobiliary, Department of Surgery, The University of Kansas Medical Center, Kansas City, Kansas, USA., Hipp JA; Strata Oncology, Ann Arbor, Michigan, USA., Softic S; Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA.; Department of Pediatrics, University of Kentucky, Lexington, Kentucky, USA., Weinman SA; Department of Internal Medicine and Liver Center, University of Kansas Medical Center, Kansas City, Kansas, USA., McCullumsmith R; Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.; Neurosciences Institute, ProMedica, Toledo, Ohio, USA., Nagy LE; Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA.; Department of Gastroenterology and Hepatology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio, USA.; Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA., Hinds TD Jr; Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA.; Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.; Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
Jazyk: angličtina
Zdroj: Hepatology (Baltimore, Md.) [Hepatology] 2022 Nov; Vol. 76 (5), pp. 1376-1388. Date of Electronic Publication: 2022 Apr 08.
DOI: 10.1002/hep.32467
Abstrakt: 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.
(© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
Externí odkaz: