García-Villafranca, J., Guillén, A. & Castro, J. Ethanol consumption impairs regulation of fatty acid metabolism by decreasing the activity of AMP activated protein kinase in rat liver. Biochimie 90, 460-466

Departamento de Bioquímica y Biología Molecular I, Facultad de Biología, Universidad Complutense, Ciudad Universitaria, s/n, Madrid, Spain.
Biochimie (Impact Factor: 2.96). 04/2008; 90(3):460-6. DOI: 10.1016/j.biochi.2007.09.019
Source: PubMed


The mechanisms by which ethanol consumption causes accumulation of hepatic triacylglycerols are complex. AMP-activated protein kinase (AMPK) plays a central role in the regulation of lipid metabolism. Therefore, in the present study we investigated whether AMPK may have a role in the development of ethanol-induced fatty liver. Hepatocytes isolated from rats fed with an ethanol-containing liquid diet showed higher rates of fatty acid and triacylglycerol syntheses, but a decreased rate of fatty acid oxidation, concomitant to a lower activity of carnitine palmitoyltransferase I. Hepatocytes from both ethanol-fed and pair-fed control rats were incubated with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an AMPK activator in intact cells. In both hepatocyte preparations AICAR strongly inhibited the activity of acetyl-CoA carboxylase in parallel to fatty acid synthesis, but cells from ethanol-fed rats showed significantly lower sensitivity to inhibition by AICAR. Moreover, AICAR strongly decreased triacylglycerol synthesis and increased fatty acid oxidation in control hepatocytes, but these effects were markedly attenuated in hepatocytes from ethanol-fed rats. In parallel, AMPK in liver of ethanol-fed rats showed a decreased specific activity and a lower sensitivity to changes in the AMP/ATP ratio, compared to the enzyme of control rats. These effects are consistent with the impairment of AMPK-mediated regulation of fatty acid metabolism after ethanol consumption, that will facilitate triacylglycerol accumulation. Taken together, these findings suggest that a decreased AMPK activity may have an important role in the development of alcoholic fatty liver.

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    • "AMPK is also known to phosphorylate and inactivate ACC, a rate limiting enzyme for fatty acid biosynthesis [57]. From both in vitro and in vivo studies, ethanol treatment inhibits AMPK activity followed by increased levels of mature SREBP-1 and ACC activity [58], [59]. Similar to these reports, we observed elevated levels of TG and hepatic lipid accumulation accompanied by decrease in active p-AMPK and increased amounts of mature SREBP-1c and ACC proteins in the AZT-exposed group (Fig. 6). "
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    ABSTRACT: The clinical effectiveness of Zidovudine (AZT) is constrained due to its side-effects including hepatic steatosis and toxicity. However, the mechanism(s) of hepatic lipid accumulation in AZT-treated individuals is unknown. We hypothesized that AZT-mediated oxidative and endoplasmic reticulum (ER) stress may play a role in the AZT-induced hepatic lipid accumulation. AZT treatment of C57BL/6J female mice (400 mg/day/kg body weight, i.p.) for 10 consecutive days significantly increased hepatic triglyceride levels and inflammation. Markers of oxidative stress such as protein oxidation, nitration, glycation and lipid peroxidation were significantly higher in the AZT-treated mice compared to vehicle controls. Further, the levels of ER stress marker proteins like GRP78, p-PERK, and p-eIF2α were significantly elevated in AZT-treated mice. The level of nuclear SREBP-1c, a transcription factor involved in fat synthesis, was increased while significantly decreased protein levels of phospho-acetyl-CoA carboxylase, phospho-AMP kinase and PPARα as well as inactivation of 3-keto-acyl-CoA thiolase in the mitochondrial fatty acid β-oxidation pathway were observed in AZT-exposed mice compared to those in control animals. Collectively, these data suggest that elevated oxidative and ER stress plays a key role, at least partially, in lipid accumulation, inflammation and hepatotoxicity in AZT-treated mice.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "However, chronic ethanol exposure has been shown to inhibit AMPK activity in cultured rat hepatocytes through the inhibition of PK-z and LKB1 phosphorylation [11] and impaired AMPK activity was shown in hepatocytes isolated from rats fed with ethanol [12]. Moreover, pharmacological AMPK activation abrogated ethanol-induced induction of lipogenesis and reduction of fatty acid oxidation [12] [13]. Thus, alcohol-associated inhibition of AMPK contributes to fat accumulation via stimulation of lipogenesis and inhibition of fat oxidation. "
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    ABSTRACT: Chronic alcohol consumption is a well-known risk factor for liver disease. Progression of alcohol-induced liver disease (ALD) is a multifactorial process that involves a number of genetic, nutritional and environmental factors. Experimental and clinical studies increasingly show that oxidative damage induced by ethanol contribute in many ways to the pathogenesis of alcohol hepatoxicity. Oxidative stress appears to activate AMP-activated protein kinase (AMPK) signaling system, which has emerged in recent years as a kinase that controls the redox-state and mitochondrial function. This review focuses on the most recent insights concerning the activation of AMPK by reactive oxygen species (ROS), and describes recent evidences supporting the hypothesis that AMPK signaling pathways play an important role in promoting cell viability under conditions of oxidative stress, such as during alcohol exposure. We suggest that AMPK activation by ROS can promote cell survival by inducing autophagy, mitochondrial biogenesis and expression of genes involved in antioxidant defense. Hence, increased intracellular concentrations of ROS may represent a general mechanism for enhancement of AMPK-mediated cellular adaptation, including maintenance of redox homeostasis. On the other hand, AMPK inhibition in the liver by ethanol appears to play a key role in the development of steatosis induced by chronic alcohol consumption. Although more studies are needed to assess the functions of AMPK during oxidative stress, AMPK may be a possible therapeutic target in the particular case of alcohol-induced liver disease.
    Full-text · Article · May 2013 · Biochemical pharmacology
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    • "In the literature, reports concerning the effects of ethanol on activation of the AMPK pathway in mice vary depending on the amount of ethanol and the duration of feeding. In some studies, AMPK phosphorylation is increased, whereas, in others, AMPK phosphorylation is decreased [12] [14] [15] [35]. In one report, 40% saturated fat plus ethanol resulted in a twofold increase in AMPKα phosphorylation. "
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    ABSTRACT: 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.
    Full-text · Article · Mar 2013 · The Journal of nutritional biochemistry
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