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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #187206
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 MEHENDALE, HARIHARA - UNIV OF LOUISIANA
item RONIS, MARTIN - ACNC/UAMS
item BADGER, THOMAS - ACNC/UAMS

Submitted to: Endocrine Society Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 4/27/2006
Publication Date: 6/23/2006
Citation: He, L., Simmen, F.A., Mehendale, H.M., Ronis, M.J., Badger, T.M. 2006. Chronic ethanol intake impairs insulin signaling in rats by disrupting Akt association with the cell membrane [abstract]. The Endocrine Society, 88th Annual Meeting, June 23-27, 2006, Boston, Massachusetts. 2006 CDROM. Program No. P2-211.

Interpretive Summary:

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.