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Open AccessArticle

Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease

1
Lipid Research Laboratory, VA Medical Center, Washington, DC 98100, USA
2
Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, Washington, DC 20037, USA
3
Department of Biology, The Catholic University of America, Washington, DC 20064, USA
4
Laboratory of Hepatic Diseases; Catedras-CONACYT and National Institute of Genomic Medicine (INMEGEN), CDMX 64460, Mexico
*
Author to whom correspondence should be addressed.
Cells 2019, 8(11), 1337; https://doi.org/10.3390/cells8111337
Received: 2 September 2019 / Revised: 11 October 2019 / Accepted: 21 October 2019 / Published: 29 October 2019
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. View Full-Text
Keywords: Akt1; Akt2; Akt3; Akt isoforms; alcoholic liver disease; liver fibrosis; inflammation; proliferation; migration Akt1; Akt2; Akt3; Akt isoforms; alcoholic liver disease; liver fibrosis; inflammation; proliferation; migration
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Reyes-Gordillo, K.; Shah, R.; Arellanes-Robledo, J.; Cheng, Y.; Ibrahim, J.; Tuma, P.L. Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease. Cells 2019, 8, 1337.

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