Ethanol consumption impairs regulation of fatty acid metabolism by decreasing the activity of AMP-activated protein kinase in rat liver

Garcı́a-Villafranca, Javier; Guillén, Alberto; Castro, José María Albertos

doi:10.1016/j.biochi.2007.09.019

Cited by 119 publications

(77 citation statements)

References 39 publications

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“…Ample molecular and physiological evidence connects AMPK activation with fat utilization in the liver. AICAR reduces hepatic TGs under various conditions in rodents (18 -20) and increases fatty acid oxidation in hepatocytes (21,30,59). Knock-out of the AMPK␣2 subunit in the liver (45) results in increased circulating fatty acids, TGs, and a decrease in ␤-hydroxybutyrate, whereas the short term overexpression of a constitutively active form of AMPK␣2 reduces plasma TGs and increases ␤-hydroxybutyrate (17).…”

Section: Discussionmentioning

confidence: 99%

5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) Effect on Glucose Production, but Not Energy Metabolism, Is Independent of Hepatic AMPK in Vivo

Hasenour

Ridley

Hughey

et al. 2014

Journal of Biological Chemistry

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Background: AMPK is implicated as the mediator of AICAR action on liver metabolism. Results: AICAR suppresses glucose production independent of AMPK. Regulation of mitochondrial function is AMPK-dependent. Conclusion: Nucleotide monophosphates rely on AMPK to regulate energy metabolism but not to suppress glucose production. Significance: Targeted AMPK activation will not lower glucose production in metabolic diseases but could improve hepatic energetics.

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Section: Discussionmentioning

confidence: 99%

5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) Effect on Glucose Production, but Not Energy Metabolism, Is Independent of Hepatic AMPK in Vivo

Hasenour

Ridley

Hughey

et al. 2014

Journal of Biological Chemistry

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“…Recently, AMP-activated protein kinase (AMPK) has been suggested to be a new target for ethanol, but the effect of ethanol on AMPK activation is now controversial. Several groups have reported that AMPK activity could be inhibited by ethanol in both hepatic cells [11,12] and brain cells of mice at postnatal day 7 [13,14] . However, HongBrown reported that incubation of C2C12 myocytes with 100 mmol/L ethanol markedly increases AMPK phosphorylation and activity [15] .…”

Section: Introductionmentioning

confidence: 99%

Long-term ethanol exposure inhibits glucose transporter 4 expression via an AMPK-dependent pathway in adipocytes

Song

Guan

et al. 2010

Acta Pharmacol Sin

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Aim:The roles of AMP-activated protein kinase (AMPK) and myocyte enhancer factor 2 isoforms (MEF2A, D) as mediators of the effects of ethanol on glucose transporter 4 (GLUT4) expression are unclear. We studied the effects of ethanol in adipocytes in vivo and in vitro. Methods: Thirty-six male Wistar rats were divided into three groups and given ethanol in a single daily dose of 0, 0.5, or 5 g/kg for 22 weeks. The expression of AMPK, MEF2 isoforms A and D, and GLUT4 was measured and compared in the three groups. The existence of the AMPK/MEF2/GLUT4 pathway in adipocytes and the effects of ethanol on this pathway were studied in (a) epididymal adipose tissue from six male Wistar rats subcutaneously injected with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR, an AMPK activator) or with 0.9% NaCl (control); and (b) isolated rat and human adipocytes treated with or without ethanol, AICAR, and compound C (a selective AMPK inhibitor). Expression of AMPK, MEF2, and GLUT4 was measured by RT-PCR and Western blotting. Results: (1) Long-term ethanol exposure decreased activated AMPK, MEF2A, MEF2D, and GLUT4 expression in rat adipose tissue. (2) In rat and human adipocytes, AICAR-induced AMPK activation, with subsequent elevation of MEF2 and GLUT4 expression, was inhibited by compound C. (3) In vitro ethanol-treatment suppressed the AMPK/MEF2/GLUT4 pathway. Conclusion: The AMPK/MEF2/GLUT4 pathway exists in both rat and human adipocytes, and activated AMPK may positively regulate MEF2 and GLUT4 expression. Ethanol inhibition of this pathway leads to decreased GLUT4 expression, thus reducing insulin sensitivity and glucose tolerance.

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“…AMPK is a metabolic sensor by phosphorylation of enzymes involved in lipid metabolism. Chronic ethanol exposure inhibits AMPK activity in cultured rat hepatocytes through the inhibition of protein kinase (PK)Cζ and liver kinase (LK)B1 phosphorylation [75] , and impaired AMPK activity was shown in hepatocytes isolated from rats fed with ethanol [76] . This inhibition plays a key role in the development of steatosis by the activation of hepatic lipogenesis, cholesterol synthesis, and glucose production in parallel with the decrease in fatty acid oxidation [74] .…”

mentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

413

339

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Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility. Key words: Alcohol metabolism; Acetaldehyde; Reactive oxygen species; Alcoholic liver disease; Protein adducts; Hepatic stellate cells; Liver fibrosis; CYP2E1Core tip: The goal of this article is to review the mechanisms of alcohol-mediated toxicity in parenchymal and non-parenchymal cells of the liver. Specifically, we highlight the effect of oxidative ethanol metabolites such as acetaldehyde and reactive oxygen species in the development of fat accumulation, fibrosis and deranged immune response.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism.

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Ethanol consumption impairs regulation of fatty acid metabolism by decreasing the activity of AMP-activated protein kinase in rat liver

Cited by 119 publications

References 39 publications

5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) Effect on Glucose Production, but Not Energy Metabolism, Is Independent of Hepatic AMPK in Vivo

5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) Effect on Glucose Production, but Not Energy Metabolism, Is Independent of Hepatic AMPK in Vivo

Long-term ethanol exposure inhibits glucose transporter 4 expression via an AMPK-dependent pathway in adipocytes

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

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