Cargando…
Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease
Akt kinase isoforms (Akt1, Akt2, and Akt3) have generally been thought to play overlapping roles in phosphoinositide 3-kinase (PI3K)-mediated-signaling. However, recent studies have suggested that they display isoform-specific roles in muscle and fat. To determine whether such isoform-specificity is...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912497/ https://www.ncbi.nlm.nih.gov/pubmed/31671832 http://dx.doi.org/10.3390/cells8111337 |
_version_ | 1783479469871202304 |
---|---|
author | Reyes-Gordillo, Karina Shah, Ruchi Arellanes-Robledo, Jaime Cheng, Ying Ibrahim, Joseph Tuma, Pamela L. |
author_facet | Reyes-Gordillo, Karina Shah, Ruchi Arellanes-Robledo, Jaime Cheng, Ying Ibrahim, Joseph Tuma, Pamela L. |
author_sort | Reyes-Gordillo, Karina |
collection | PubMed |
description | Akt kinase isoforms (Akt1, Akt2, and Akt3) have generally been thought to play overlapping roles in phosphoinositide 3-kinase (PI3K)-mediated-signaling. However, recent studies have suggested that they display isoform-specific roles in muscle and fat. To determine whether such isoform-specificity is observed with respect to alcoholic liver disease (ALD) progression, we examined the role of Akt1, Akt2, and Akt3 in hepatic inflammation, and pro-fibrogenic proliferation and migration using Kupffer cells, hepatic stellate cells (HSC), and hepatocytes in an ethanol and lipopolysaccharide (LPS)-induced two-hit model in vitro and in vivo. We determined that siRNA-directed silencing of Akt2, but not Akt1, significantly suppressed cell inflammatory markers in HSC and Kupffer cells. Although both Akt1 and Akt2 inhibited cell proliferation in HSC, only Akt2 inhibited cell migration. Both Akt1 and Akt2, but not Akt3, inhibited fibrogenesis in hepatocytes and HSC. In addition, our in vivo results show that administration of chronic ethanol, binge ethanol and LPS (EBL) in wild-type C57BL/6 mice activated all three Akt isoforms with concomitant increases in activated forms of phosphoinositide dependent kinase-1 (PDK1), mammalian target-of-rapamycin complex 2 (mTORC2), and PI3K, resulting in upregulation in expression of inflammatory, proliferative, and fibrogenic genes. Moreover, pharmacological blocking of Akt2, but not Akt1, inhibited EBL-induced inflammation while blocking of both Akt1 and Akt2 inhibited pro-fibrogenic marker expression and progression of fibrosis. Our findings indicate that Akt isoforms play unique roles in inflammation, cell proliferation, migration, and fibrogenesis during EBL-induced liver injury. Thus, close attention must be paid when targeting all Akt isoforms as a therapeutic intervention. |
format | Online Article Text |
id | pubmed-6912497 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69124972020-01-02 Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease Reyes-Gordillo, Karina Shah, Ruchi Arellanes-Robledo, Jaime Cheng, Ying Ibrahim, Joseph Tuma, Pamela L. Cells Article Akt kinase isoforms (Akt1, Akt2, and Akt3) have generally been thought to play overlapping roles in phosphoinositide 3-kinase (PI3K)-mediated-signaling. However, recent studies have suggested that they display isoform-specific roles in muscle and fat. To determine whether such isoform-specificity is observed with respect to alcoholic liver disease (ALD) progression, we examined the role of Akt1, Akt2, and Akt3 in hepatic inflammation, and pro-fibrogenic proliferation and migration using Kupffer cells, hepatic stellate cells (HSC), and hepatocytes in an ethanol and lipopolysaccharide (LPS)-induced two-hit model in vitro and in vivo. We determined that siRNA-directed silencing of Akt2, but not Akt1, significantly suppressed cell inflammatory markers in HSC and Kupffer cells. Although both Akt1 and Akt2 inhibited cell proliferation in HSC, only Akt2 inhibited cell migration. Both Akt1 and Akt2, but not Akt3, inhibited fibrogenesis in hepatocytes and HSC. In addition, our in vivo results show that administration of chronic ethanol, binge ethanol and LPS (EBL) in wild-type C57BL/6 mice activated all three Akt isoforms with concomitant increases in activated forms of phosphoinositide dependent kinase-1 (PDK1), mammalian target-of-rapamycin complex 2 (mTORC2), and PI3K, resulting in upregulation in expression of inflammatory, proliferative, and fibrogenic genes. Moreover, pharmacological blocking of Akt2, but not Akt1, inhibited EBL-induced inflammation while blocking of both Akt1 and Akt2 inhibited pro-fibrogenic marker expression and progression of fibrosis. Our findings indicate that Akt isoforms play unique roles in inflammation, cell proliferation, migration, and fibrogenesis during EBL-induced liver injury. Thus, close attention must be paid when targeting all Akt isoforms as a therapeutic intervention. MDPI 2019-10-29 /pmc/articles/PMC6912497/ /pubmed/31671832 http://dx.doi.org/10.3390/cells8111337 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Reyes-Gordillo, Karina Shah, Ruchi Arellanes-Robledo, Jaime Cheng, Ying Ibrahim, Joseph Tuma, Pamela L. Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease |
title | Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease |
title_full | Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease |
title_fullStr | Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease |
title_full_unstemmed | Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease |
title_short | Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease |
title_sort | akt1 and akt2 isoforms play distinct roles in regulating the development of inflammation and fibrosis associated with alcoholic liver disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912497/ https://www.ncbi.nlm.nih.gov/pubmed/31671832 http://dx.doi.org/10.3390/cells8111337 |
work_keys_str_mv | AT reyesgordillokarina akt1andakt2isoformsplaydistinctrolesinregulatingthedevelopmentofinflammationandfibrosisassociatedwithalcoholicliverdisease AT shahruchi akt1andakt2isoformsplaydistinctrolesinregulatingthedevelopmentofinflammationandfibrosisassociatedwithalcoholicliverdisease AT arellanesrobledojaime akt1andakt2isoformsplaydistinctrolesinregulatingthedevelopmentofinflammationandfibrosisassociatedwithalcoholicliverdisease AT chengying akt1andakt2isoformsplaydistinctrolesinregulatingthedevelopmentofinflammationandfibrosisassociatedwithalcoholicliverdisease AT ibrahimjoseph akt1andakt2isoformsplaydistinctrolesinregulatingthedevelopmentofinflammationandfibrosisassociatedwithalcoholicliverdisease AT tumapamelal akt1andakt2isoformsplaydistinctrolesinregulatingthedevelopmentofinflammationandfibrosisassociatedwithalcoholicliverdisease |