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Akt1 and Akt2 Isoforms Play Distinct Roles in the Development of Inflammation and Fibrosis during Alcoholic Liver Disease
Author(s) -
Gordillo Karina Reyes,
Shah Ruchi,
Tuma Pamela L,
Robledo Jaime Arellanes,
Cheng Ying,
Lakshman Raj M
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.495.8
Subject(s) - akt1 , akt2 , protein kinase b , hepatic stellate cell , microbiology and biotechnology , pi3k/akt/mtor pathway , biology , cancer research , inflammation , gene silencing , phosphorylation , signal transduction , chemistry , immunology , biochemistry , endocrinology , gene
Akt isoforms (Akt1, Akt2, and Akt3), the key phosphorylating kinases, play vital and unique roles in all aspects of alcoholic liver disease (ALD). In vitro , cell specific silencing of Akt isoforms in acetaldehyde+LPS and/or ethanol+LPS treated human hepatic stellate cells (HSC), Kupffer cells and/or VL17A hepatocyte cultures; and in vivo , Akt1 and Akt2 silencing in a chronic ethanol/binge/lipopolysaccharide (EBL) induced mouse liver injury model using pharmacological inhibitors, were used to gain a better understanding of how each Aktisoform differentially regulates cellular functions during ALD. This study involves hepatocyte and Kupffer cells inflammation, and hepatic stellate cells proliferation, migration and fibrogenesis, which cumulatively lead to the pathogenesis of ALD. Herein, our in vitro results showed that siRNA‐directed silencing of Akt2, but not Akt1, significantly suppressed cell inflammatory markers in HSC and Kupffer cells. While Akt1 and Akt2 inhibited cell proliferation in HSC; Akt2 alone inhibited cell migration in HSC; and Akt1 and Akt2, but not Akt3 inhibited the fibrogenic markers in hepatocytes and HSC. Moreover, although Akt isoforms show extensive sequence similarity, they are localized in different subcellular compartments in HSC. On the other hand, our in vivo results showed that EBL treatment in wild‐type C57BL/6 mice stimulated all three isoforms of Akt with concomitant increases in phosphorylated species of phosphoinositide dependent kinase‐1, mammalian target‐o‐rapamycin complex 2, and phosphatidylinositol‐3‐kinase, resulting in increases in inflammatory, proliferative, and fibrogenic genes. In addition, pharmacological blocking of Akt2, but not Akt1, inhibited EBL‐induced inflammation; and of Akt1 and Akt2 inhibited the pro‐fibrogenic markers as well as fibrosis. Our finding suggest that Akt isoforms play unique roles against inflammation, cell proliferation, migration, and fibrogenesis during EBL‐induced liver injury. These in vitro and in vivo results also suggest that close attention must be paid when targeting all Akt isoforms as a therapeutic intervention. Support or Funding Information NIAAA/NIH K01 award ‐ number: K01AA025140‐02 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .