PMID- 16962100 OWN - NLM STAT- MEDLINE DCOM- 20070223 LR - 20240214 IS - 0014-4886 (Print) IS - 0014-4886 (Linking) VI - 203 IP - 1 DP - 2007 Jan TI - Acetaldehyde promotes rapamycin-dependent activation of p70(S6K) and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells. PG - 196-204 AB - Alcohol intake is one of the important lifestyle factors for the risk of insulin resistance and type 2 diabetes. Acetaldehyde, the major ethanol metabolite which is far more reactive than ethanol, has been postulated to participate in alcohol-induced tissue injury although its direct impact on insulin signaling is unclear. This study was designed to examine the effect of acetaldehyde on glucose uptake and insulin signaling in human dopaminergic SH-SY5Y cells. Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. Glucose uptake and apoptosis were measured using [(3)H]-2-deoxyglucose uptake and caspase-3 assay, respectively. Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. Acetaldehyde inhibited mTOR phosphorylation without affecting total mTOR and insulin-elicited response on mTOR phosphorylation. Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation. FAU - Fang, Cindy X AU - Fang CX AD - Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA. FAU - Yang, Xiaoping AU - Yang X FAU - Sreejayan, Nair AU - Sreejayan N FAU - Ren, Jun AU - Ren J LA - eng GR - 1R15AA/HL13575-01/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20060907 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Cell Cycle Proteins) RN - 0 (EIF4EBP1 protein, human) RN - 0 (IRS2 protein, human) RN - 0 (Insulin) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Phosphoproteins) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - GO1N1ZPR3B (Acetaldehyde) RN - IY9XDZ35W2 (Glucose) RN - VTD58H1Z2X (Dopamine) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Acetaldehyde/*adverse effects MH - Adaptor Proteins, Signal Transducing/drug effects/metabolism MH - Alcohol-Induced Disorders, Nervous System/complications/metabolism/physiopathology MH - Apoptosis/drug effects/physiology MH - Cell Cycle Proteins MH - Cell Line, Tumor MH - Diabetes Mellitus, Type 2/chemically induced/metabolism/physiopathology MH - Dopamine/metabolism MH - Glucose/*metabolism MH - Humans MH - Insulin/metabolism MH - Insulin Receptor Substrate Proteins MH - Insulin Resistance/physiology MH - Intracellular Signaling Peptides and Proteins/drug effects/metabolism MH - Metabolic Syndrome/chemically induced/metabolism/physiopathology MH - Neurons/*drug effects/metabolism MH - Phosphoproteins/drug effects/metabolism MH - Phosphorylation/drug effects MH - Protein Kinases/drug effects/*metabolism MH - Proto-Oncogene Proteins c-akt/*drug effects/metabolism MH - Ribosomal Protein S6 Kinases, 70-kDa/drug effects/*metabolism MH - Signal Transduction/drug effects/physiology MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases EDAT- 2006/09/12 09:00 MHDA- 2007/02/24 09:00 CRDT- 2006/09/12 09:00 PHST- 2006/03/27 00:00 [received] PHST- 2006/07/27 00:00 [revised] PHST- 2006/08/01 00:00 [accepted] PHST- 2006/09/12 09:00 [pubmed] PHST- 2007/02/24 09:00 [medline] PHST- 2006/09/12 09:00 [entrez] AID - S0014-4886(06)00473-0 [pii] AID - 10.1016/j.expneurol.2006.08.002 [doi] PST - ppublish SO - Exp Neurol. 2007 Jan;203(1):196-204. doi: 10.1016/j.expneurol.2006.08.002. Epub 2006 Sep 7.