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ARS Home » Southeast Area » Little Rock, Arkansas » Arkansas Children's Nutrition Center » Research » Publications at this Location » Publication #187208
Title: CHRONIC ETHANOL INTAKE IMPAIRS INSULIN SIGNALING IN RATS BY DISRUPTING AKT ASSOCIATION WITH THE CELL MEMBRANE

Author
item HE, LING - ACNC/UAMS
item SIMMEN, FRANK - ACNC/UAMS
item RONIS, MARTIN - ACNC/UAMS
item BADGER, THOMAS - ACNC/UAMS

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/31/2006
Publication Date: 4/21/2006
Citation: He, L., Simmen, F.A., Ronis, M.J., Badger, T.M. 2006. Chronic ethanol intake impairs insulin signaling in rats by disrupting AKT association with the cell membrane. Journal of Biological Chemistry. 281:11126-11134.

Interpretive Summary: Alcohol is a significant percentage of the total caloric intake of many Americans and unfortunately, a surprisingly large number of women continue to drink alcohol during pregnancy. Chronic and excessive alcohol consumption is an important and modifiable risk factor for development of type 2 diabetes. We have been studying the effects of alcohol, dietary factors and nutritional status using animal models. We previously reported elevations in the major alcohol metabolizing enzyme Class 1 Alcohol Dehydrogenase (ADH) in ethanol-fed rats. This finding could explain faster alcohol disappearance from the body in alcoholics and increased ADH may also be involved in development of alcohol-induced liver damage. In the current study we demonstrated that alcohol increases a protein important in the actions of insulin, called TRB3. TRB3 interferes with insulin action by blocking the actions of another important "master regulator protein" called Akt. We suspect that these effects explain how chronic alcohol consumption leads to development of Type 2 diabetes in alcoholics.

Technical Abstract: Chronic and excessive alcohol consumption is an important and modifiable risk factor for type 2 diabetes. We previously reported elevations in Class 1 Alcohol Dehydrogenase (ADH) expression in ethanol-fed rats that were coincident with reduced levels of mature, nuclear SREBP-1, suggesting that this insulin-induced transcription factor is a transcriptional repressor of the ADH gene. In this report, we have studied the effects of insulin and ethanol on ADH expression in a highly differentiated rat hepatoma cell line (FGC-4) and the in vivo effects of chronic intake of ethanol-containing diets on hepatic insulin signaling. Chronic ethanol intake led to decreased phosphorylation of Akt (PKB) at Thr308, increased phosphorylation of Akt at Ser473, and decreased phosphorylation of GSK3b, a downstream effector of Akt. Membrane-associated Akt content was decreased and cytosolic Akt content increased in livers of rats fed an ethanol-containing diet. Thus, disruptive effects of ethanol on insulin signaling occurred via impaired phosphorylation of Akt at Thr308. TRB3, a negative regulator of Akt, was induced in liver of ethanol-fed rats. In ethanol-treated FGC-4 cells, RNA interference knockdown of TRB3 increased membrane-associated Akt and the phosphorylation of Akt at Thr308. Our results suggest that ethanol induces TRB3, which through binding of the PH domain of Akt prevents plasma membrane association with Akt, Akt-Thr308 phosphorylation and subsequent Akt-mediated signaling. Ethanol inhibition of insulin signaling reduces nSREBP accumulation and results in disinhibition of Class 1 ADH transcription.