AICAR, an AMPK Activator, Has Protective Effects on Alcohol‐Induced Fatty Liver in Rats

Tomita, Kengo; Tamiya, Gen; Ando, Satoshi; Kitamura, Naoto; Koizumi, Haruna; Kato, Shinichi; Horie, Yoshinori; Kaneko, Takehiko; Azuma, Toshifumi; Nagata, Hiroshi; Ishii, Hiromasa; Hibi, Toshifumi

doi:10.1097/01.alc.0000191126.11479.69

Cited by 100 publications

(67 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, alcohol-associated inhibition of AMP kinase contributes to fat accumulation via stimulation of lipogenesis and inhibition of fat oxidation. Additionally, it has been demonstrated that activation of AMP kinase by the adipocytokine adiponectin and other agents improves both alcohol and obesity-induced fatty liver disease in rodent models [28][29][30] demonstrating the key role of AMP kinase in the development of steatosis. Clearly, the question that still remains to be answered is, what is the mechanism through which ethanol inhibits AMP kinase activity?…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

388

302

View full text Add to dashboard Cite

Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

show abstract

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

388

302

View full text Add to dashboard Cite

show abstract

“…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

415

339

View full text Add to dashboard Cite

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.

show abstract

“…The involvement of SREBP-1c in the development of alcoholic fatty liver in animals has been demonstrated (5,6,14,15,30,32,37,38,39). While both ethanol-mediated AMP-activated kinase (AMPK) inhibition and ethanol-caused ER stress have alternatively been proposed to contribute to the activation of SREBP-1c, the precise molecular mechanisms by which ethanol stimulates SREBP-1 activity remain unclear (5,15,39).…”

mentioning

confidence: 99%

Involvement of mammalian sirtuin 1 in the action of ethanol in the liver

You¹,

Liang²,

Ajmo³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

196

162

View full text Add to dashboard Cite

You M, Liang X, Ajmo JM, Ness GC. Involvement of mammalian sirtuin 1 in the action of ethanol in the liver. Am J Physiol Gastrointest Liver Physiol 294: G892-G898, 2008. First published January 31, 2008 doi:10.1152/ajpgi.00575.2007.-Chronic ethanol feeding causes liver steatosis in animal models by upregulating the sterol regulatory element-binding protein 1 (SREBP-1), which subsequently increases the synthesis of hepatic lipid. SREBP-1 activity is regulated by reversible acetylation at specific lysine residues. The present study tests the hypothesis that activation of SREBP-1 by ethanol may be mediated by mammalian sirtuin 1 (SIRT1), a NAD ϩ -dependent class III protein deacetylase. The effects of ethanol on SIRT1 were determined in cultured rat hepatoma cells and in the livers of ethanol-fed mice. In rat H4IIEC3 cells, we observed that ethanol exposure induced SREBP-1c lysine acetylation and SREBP-1c transcriptional activity. The effect of ethanol was abolished by expression of wild-type SIRT1 or by treatment with resveratrol, a known potent SIRT1 agonist. Conversely, knocking down SIRT1 by the small silencing SIRT1 plasmid SIRT1shRNA or expression of a SIRT1 mutant, SIRT1(H363Y), did not negate the ethanol effect. These findings suggest that the effect of ethanol on SREBP-1 is mediated, at least in part, through SIRT1 inhibition. Consistent with the in vitro findings, chronic ethanol feeding substantially downregulated hepatic SIRT1 in mice. Inhibition of hepatic SIRT1 activity was associated with an increase in the acetylated active nuclear form of SREBP-1c in the livers of ethanol-fed mice. Our results indicate an essential role for SIRT1 in mediating the effects of ethanol on SREBP-1 and hepatic lipid metabolism, as well as the development of alcoholic fatty liver. Hence, SIRT1 may represent a novel therapeutic target for treatment of human alcoholic fatty liver disease. alcoholic liver steatosis; lipid metabolism; acetylation; sterol regulatory element-binding protein-1c; peroxisome proliferator-activated receptor-␥ coactivator-1␣

show abstract

AICAR, an AMPK Activator, Has Protective Effects on Alcohol‐Induced Fatty Liver in Rats

Abstract: In this preclinical rat model, AICAR, an AMPK activator, appears to protect the liver from fatty changes associated with chronic alcohol use. As such, AICAR may have a role in the treatment and prevention of alcohol-induced fatty liver.

Cited by 100 publications

References 14 publications

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Involvement of mammalian sirtuin 1 in the action of ethanol in the liver

Contact Info

Product

Resources

About