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: 3.12). 04/2008; 90(3):460-6. DOI: 10.1016/j.biochi.2007.09.019
Source: PubMed

ABSTRACT 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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    • "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.
    Biochemical pharmacology 05/2013; 86(2). DOI:10.1016/j.bcp.2013.05.007 · 4.65 Impact Factor
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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 pThr172AMPKα and acetyl CoA Carboxylase (ACC). HF plus ethanol decreased pSer108AMPKβ, yet a marked 1.5-fold increase in pThr172AMPKα occurred. No change was evident in pSer79ACC 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.
    The Journal of nutritional biochemistry 03/2013; 24(8). DOI:10.1016/j.jnutbio.2012.12.002 · 4.59 Impact Factor
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    • "RSV also has some direct metabolic effects such as modulation of the activity of F1–F0 mitochondrial ATPase/ATPsynthase [29]. Both EtOH and RSV have opposite effects on AMPkinase (serine threonine kinase) (AMPk) [11] [30] [31]. "
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    ABSTRACT: The effects of trans-resveratrol (RSV) combined with ethanol (EtOH) were evaluated by (31)P NMR on total ATP and sn-glycerol-3-phosphate (sn-G3P) contents measured in real time in isolated and perfused whole liver of the rat. Mitochondrial ATP turnover was assessed by using specific inhibitors of glycolytic and mitochondrial ATP supply (iodacetate and KCN, respectively). In RSV alone, the slight decrease in ATP content (-14±5% of the initial content), sn-G3P content and ATP turnover were similar to those in the Krebs-Henseleit buffer control. Compared to control, EtOH alone (14 or 70 mmol/L) induced a decrease in ATP content (-24.95±2.95% of initial content, p<0.05) and an increase in sn-G3P (+158±22%), whereas ATP turnover tended to be increased. RSV (20 μmol/L) combined with EtOH, (i) maintained ATP content near 100%, (ii) induced a 1.6-fold increase in mitochondrial ATP turnover (p=0.049 and p=0.004 vs EtOH 14 and 70 mmol/L alone, respectively) and (iii) led to an increase in sn-G3P (+49±9% and +81±6% for 14 and 70 mmol/L EtOH, respectively). These improvements were obtained only when glycolysis was efficient at the time of addition of EtOH+RSV. Glycolysis inhibition by iodacetate (IAA) evidenced an almost 21% contribution of this pathway to ATP content. RSV alone or RSV+EtOH prevented the ATP decrease induced by IAA addition (p<0.05 vs control). This is the first demonstration of the combined effects of RSV and EtOH on liver energy metabolism. RSV increased (i) the flux of substrates through ATP producing pathways (glycolysis and phosphorylative oxidation) probably via the activation of AMPkinase, and (ii) maintained the glycolysis deviation to sn-G3P linked to NADH+H⁺ re-oxidation occurring during EtOH detoxication, thus reducing the energy cost due to the latter.
    Pharmacological Research 03/2012; 65(3):387-95. DOI:10.1016/j.phrs.2011.12.003 · 3.98 Impact Factor
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