Acute and chronic ethanol consumption differentially impact pathways limiting hepatic protein synthesis

Abstract

This review identifies the various pathways responsible for modulating hepatic protein synthesis following acute and chronic alcohol intoxication and describes the mechanism(s) responsible for these changes. Alcohol intoxication induces a defect in global protein synthetic rates that is localized to impaired translation of mRNA at the level of peptide-chain initiation. Translation initiation is regulated at two steps: formation of the 43S preinitiation complex [controlled by eukaryotic initiation factors 2 (eIF2) and 2B (eIF2B)] and the binding of mRNA to the 40S ribosome (controlled by the eIF4F complex). To date, alcohol-induced alterations in eIF2 and eIF2B content and activity are best investigated. Ethanol decreases eIF2B activity when ingested either acutely or chronically. The reduced eIF2B activity most likely is a consequence of twofold increased phosphorylation of the alpha-subunit of eIF2 on Ser(51) following acute intoxication. The increase in eIF2alpha phosphorylation after chronic alcohol consumption is the same as that induced by acute ethanol intoxication, and protein synthesis is not further reduced by long-term alcohol ingestion despite additional reduced expression of initiation factors and elongation factors. eIF2alpha phosphorylation alone appears sufficient to maximally inhibit hepatic protein synthesis. Indeed, pretreatment with Salubrinal, an inhibitor of eIF2alpha(P) phosphatase, before ethanol treatment does not further inhibit protein synthesis or increase eIF2alpha phosphorylation, suggesting that acute ethanol intoxication causes maximal eIF2alpha phosphorylation elevation and hepatic protein synthesis inhibition. Ethanol-induced inhibition of hepatic protein synthesis is not rapidly reversed by cessation of ethanol consumption. In conclusion, sustained eIF2alpha phosphorylation is a hallmark of excessive alcohol intake leading to inhibition of protein synthesis. Enhanced phosphorylation of eIF2alpha represents a unique response of liver to alcohol intoxication, because the ethanol-induced elevation of eIF2alpha(P) is not observed in skeletal muscle or heart.

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

“…29 In light of these findings, we set out to examine the mechanistic underpinnings of ethanol-induced down-regulation of signaling in the mTOR pathway. Chronically exposing lymphoma cell lines at levels readily attainable in human plasma (0-0.092 g/dL, or ϳ3 drinks per day maximally) 6 resulted in decreased phosphorylation of key downstream proteins involved in mTOR pathway signaling, including mTOR, p70 S6 kinase, RPS6, and 4E-BP1 (Figures 1,3B). Importantly, these levels of ethanol do not significantly impinge on cell viability ( Figure S2).…”

“…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.…”

“…Mice receiving water supplemented with ethanol (10% vol/vol) can achieve blood alcohol concentrations that range from 0.05 to 0.15 g/dL, a level sufficient to impair motor skills in humans. 6 De Feo et al have shown that consumption of 3 or 4 glasses of wine over the course of a meal, an amount commonly consumed by social drinkers, is sufficient to significantly inhibit hepatic protein translation. 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.…”

Crepidiastrum denticulatumExtract Protects the Liver Against Chronic Alcohol-Induced Damage and Fat Accumulation in Rats

“…2 Among these tissues, the liver is the major site of alcohol-induced damage because it directly receives blood containing high concentrations of alcohol and is the major organ of ethanol metabolism, producing toxic metabolites from alcohol. 3 Liver injury due to ethanol exposure is mediated by two well-characterized pathways. 4 The first pathway involves alcohol oxidation by alcohol dehydrogenase and aldehyde dehydrogenase.…”