Increased dietary fat contributes to dysregulation of the LKB1/AMPK pathway and increased damage in a mouse model of early-stage ethanol-mediated steatosis

Colin T Shearn, Rebecca L Smathers, Hua Jiang, David J Orlicky, Kenneth N Maclean, Dennis R Petersen
Journal of Nutritional Biochemistry 2013, 24 (8): 1436-45

OBJECTIVE: The objective of the study was to examine the interaction of moderate and high dietary fat and ethanol with respect to formation of steatosis and regulation of the AMP-activated protein kinase (AMPK) pathway in a mouse model of chronic ethanol consumption.

METHODS: Male C57BL/6J mice were pair-fed a modified Lieber-DeCarli diet composed of either moderate fat [30% fat-derived calories (MF)] or high fat [45% fat-derived calories (HF)] combined with increasing concentrations of ethanol (2%-6%) for 6 weeks.

RESULTS: Chronic ethanol consumption resulted in significant increases in plasma alanine aminotransferase in MF (1.84-fold) and HF mice (2.33-fold), yet liver triglycerides only increased significantly in the HF model (1.62-fold). Ethanol addition significantly increased plasma adiponectin under conditions of MF but not HF. In combination with MF, the addition of ethanol significantly decreased total and hepatic pThr(172)AMPKα and acetyl CoA Carboxylase (ACC). HF plus ethanol decreased pSer(108)AMPKβ, yet a marked 1.5-fold increase in pThr(172)AMPKα occurred. No change was evident in pSer(79)ACC under conditions of ethanol and HF ingestion. In both models, nuclear levels of sterol response element binding protein 1c and carbohydrate response element binding protein were decreased. Surprisingly, MF plus ethanol significantly elevated protein expression of medium-chain acyl-CoA dehydrogenase (MCAD), long-chain acyl-CoA dehydrogenase (LCAD) and very long chain acyl-CoA dehydrogenase but did not significantly affect mRNA expression of other proteins involved in β-oxidation and fatty acid synthesis. HF plus ethanol significantly reduced mRNA expression of both stearoyl CoA desaturase 1 and fatty acid elongase 5, but did not have an effect on MCAD or LCAD.

CONCLUSION: These data suggest that, when co-ingested with ethanol, dietary fat differentially contributes to dysregulation of adiponectin-dependent activation of the AMPK pathway in the liver of mice.

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