Author(s): He J, de la Monte S, Wands JR
Chronic ethanol consumption may produce hepatic injury and impair the ability of the liver to regenerate principally through its action on insulin signaling. These effects are mediated by insulin receptor substrate-1 (IRS-1) via the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/Erk) pathway and by survival signals through phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt). Because a protein phosphatase, phosphatase tensin homolog deleted on chromosome 10 (PTEN), has been reported to block insulin signaling through PI3K, we explored acute ethanol effects on signaling in the context of PTEN function. We measured upstream components of the insulin signal transduction pathway and Akt phosphorylation as an indicator of signaling through PI3K, including the generation of survival signals via glycogen synthase kinase 3beta (GSK3beta) and Bcl-2-associated death promoter (BAD). In addition, the physical association between PTEN and PI3K regulatory (p85alpha) and catalytic (p110alpha) subunits was evaluated both in vitro and in vivo. In Huh-7 cells, there was no effect of acute ethanol exposure on tyrosyl phosphorylation of the insulin receptor, IRS-1, and the association of IRS-1 with PI3K. However, Akt phosphorylation was impaired. The association of PTEN with the PI3K p85alpha subunit was substantially increased and led to the inhibition of downstream insulin-mediated survival signals through Akt, GSK3beta, and BAD; the ethanol effect was reversed by PTEN knockdown with small interfering RNA. These results were confirmed in the liver.
Conclusion: Short-term ethanol exposure rapidly attenuates insulin signaling. The major cellular mechanism involves the increased association of PTEN with the PI3K p85alpha subunit, which results in reduced phospho-Akt formation and impaired downstream survival signaling. These findings may have relevance to acute toxic effects of ethanol on the liver.
Referred From: https://www.ncbi.nlm.nih.gov/pubmed/18027876
Author(s): Miller AM, Horiguchi N, Jeong WI, Radaeva S, Gao B
Author(s): Paula H, Asrani SK, Boetticher NC, Pedersen R, Shah VH, et al.
Author(s): Purohit V, Gao B, Song BJ
Author(s): de la Monte SM, Yeon JE, Tong M, Longato L, Chaudhry R, et al.
Author(s): Denucci SM, Tong M, Longato L, Lawton M, Setshedi M, et al.
Author(s): Onishi Y, Honda M, Ogihara T, Sakoda H, Anai M, et al.
Author(s): Pang M, de la Monte SM, Longato L, Tong M, He J, et al.
Author(s): Ronis MJ, Wands JR, Badger TM, de la Monte SM, Lang CH, et al.
Author(s): Sasaki Y, Wands JR
Author(s): Setshedi M, Longato L, Petersen DR, Ronis M, Chen WC, et al.
Author(s): Gao B, Bataller R
Author(s): Lieber CS
Author(s): Seth D, Haber PS, Syn WK, Diehl AM, Day CP
Author(s): Setshedi M, Wands JR, Monte SM
Author(s): de la Monte SM, Longato L, Tong M, DeNucci S, Wands JR
Author(s): Mohr L, Tanaka S, Wands JR
Author(s): Friedman SL, Nieto N
Author(s): Gyamfi MA, Wan YJ
Author(s): Yessoufou A, Wahli W
Author(s): Viana Abranches M, Esteves de Oliveira FC, Bressan J
Author(s): Heald M, Cawthorne MA
Author(s): Shah P, Mudaliar S
Author(s): Phielix E, Szendroedi J, Roden M
Author(s): Tailleux A, Wouters K, Staels B
Author(s): Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, et al.
Author(s): Enomoto N, Takei Y, Hirose M, Konno A, Shibuya T, et al.
Author(s): de la Monte SM, Pang M, Chaudhry R, Duan K, Longato L, et al.
Author(s): Tomita K, Azuma T, Kitamura N, Nishida J, Tamiya G, et al.
Author(s): Pandol SJ, Gorelick FS, Gerloff A, Lugea A
Author(s): Sozio MS, Liangpunsakul S, Crabb D
Author(s): Ronis MJ, Butura A, Korourian S, Shankar K, Simpson P, et al.
Author(s): Baumgardner JN, Shankar K, Hennings L, Badger TM, Ronis MJ
Author(s): Miller AM, Wang H, Bertola A, Park O, Horiguchi N, et al.
Author(s): Carmiel-Haggai M, Cederbaum AI, Nieto N
Author(s): Bailey SM, Mantena SK, Millender-Swain T, Cakir Y, Jhala NC, et al.
Author(s): Devi SL, Anuradha CV
Author(s): Tang Y, Forsyth CB, Banan A, Fields JZ, Keshavarzian A
Author(s): Uchida T, Kao H, Quispe-Sjogren M, Peters RL
Author(s): Junge J, Horn T, Christoffersen P
Author(s): Wakabayashi T, Horiuchi M, Sakaguchi M, Onda H, Iijima M
Author(s): RÃ¸mert P, Matthiessen ME
Author(s): RÃ¸mert P, Matthiessen ME
Author(s): Ronis MJ, Butura A, Sampey BP, Shankar K, Prior RL, et al.