Chronic alcohol consumption alters mammalian target of rapamycin (mTOR), reduces ribosomal p70s6 kinase and p4E-BP1 levels in mouse cerebral cortex

Abstract

Reduced insulin sensitivity following chronic alcohol consumption may contribute to alcoholinduced brain damage although the underlying mechanism(s) has not been elucidated. This study was designed to examine the effect of chronic alcohol intake on insulin signaling in mouse cerebral cortex. FVB mice were fed with a 4% alcohol diet for 16 weeks. Insulin receptor substrates (IRS-1, IRS-2) and post-receptor signaling molecules Akt, mammalian target of rapamycin (mTOR), ribosomal p70s6 kinase (p70s6k) and the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) as well as the apoptotic marker caspase-3 were evaluated using Western blot analysis. Chronic alcohol intake significantly dampened whole body glucose tolerance, enhanced expression of caspase-3 and mTOR, reduced p70s6k and 4E-BP1 with little effect on Akt signaling in alcohol consuming mice. These data suggest that chronic alcohol intake may contribute to cerebral cortex dysfunction through mechanisms related, at least in part, to dampened post insulin receptor signaling at the levels of mTOR, p70s6k and 4E-BP1.

Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction

“…3 Chronic alcohol intake is associated with disruption of the mTOR-signaling pathway in nonlymphoid tissue, such as the mouse cerebral cortex. 7 However, there are limited published data describing the impact of ethanol exposure on this critical signaling pathway in human neoplasia. Importantly, many of the commonly characterized abnormalities present in cancer include loss of phosphatase with tensin homology, and constitutive activation of The average tumor volume of each group (n ϭ 7) with SD is shown as a function of time (*P Յ 2.17 ϫ 10 Ϫ5 ).…”

“…50 It has been previously shown that chronic ethanol consumption in mice alters the phosphorylation levels of mTOR, p70 S6 kinase, and 4E-BP1 in mouse cerebral cortex. 7 Chronic ethanol exposure in rats has also been shown to sequester eIF4E from the cap-complex, resulting from an increase in For personal use only. on June 19, 2019.…”

“…mTOR is a critical pathway regulating translation by controlling the cellular availability of eIF4E. Given that ethanol exposure has been reported to modulate the mTOR signaling pathway 7 and alcohol consumption is associated with a decreased incidence of NHL, 3 we set out to examine the effect of ethanol on mTOR and its downstream targets in lymphoid cells. As demonstrated by Western blot analysis, ethanol exposure caused a strong dose-dependent decrease in the phosphorylation state of mTOR on Ser 2448 and of key downstream effectors of mTOR: p70 S6 kinase, and RPS6 in both Raji and SUDHL-4 cells ( Figure 1A).…”

“…Previous reports have shown that mice can consume water containing up to 20% ethanol without showing an aversion to the ethanol. 6,7 All control mice were pair-fed with the ethanol consuming groups to ensure nutritional intake was similar among groups. SUDHL-4 cells (10 6 ) were resuspended in 100 L phosphate-buffered saline and then mixed with an equal volume of Matrigel.…”

“…5,6 Chronic alcohol intake is associated with disruption of the mammalian target of rapamycin (mTOR) signaling pathway; however, few mechanistic details are known about how ethanol interrupts this critical signaling pathway involved in translation. 7 mTOR forms 2 functionally distinct multiprotein serine/threonine kinase complexes, mTORC1 and mTORC2. The mTORC1 complex controls protein synthesis by phosphorylating key downstream effector molecules, the translational inhibitor protein 4E-BP1 and, p70 S6 kinase in response to sensory inputs, such as nutritional, growth factor, and cellular energy status.…”