Alcoholic Liver Injury in the Rat Is Associated with Reduced Expression of Peroxisome Proliferator-α (PPARα)-Regulated Genes and Is Ameliorated by PPARα Activation

Nanji, Amin A.; Dannenberg, Andrew J.; Jokelainen, Kalle; Bass, Nathan M.

doi:10.1124/jpet.103.064717

Cited by 111 publications

(85 citation statements)

References 73 publications

(80 reference statements)

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“…In PPARa null mice, ethanol-induced liver injuries including steatosis were more extensive than in wildtype mice (43). Treatment of ethanol-fed animals with known PPARa activators (WY14 643, or clofibrate) ameliorated ethanol-induced fatty liver through increasing PGC-1a/PPARa activity and upregulating expression of many PGC-1a/PPAR-a regulated enzymes including long-chain acyl-CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, acyl-CoA oxidase (AOX), and very-long-chain acyl-CoA synthetase (42,44).…”

Section: Effects Of Ethanol On Pgc-1a/ppara Functionmentioning

confidence: 99%

Adiponectin and alcoholic fatty liver disease

2008

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Worldwide, one of the most prevalent forms of chronic disease is alcoholic fatty liver, which may progress to more severe forms of liver injury including steatohepatitis, fibrosis, and cirrhosis. The molecular mechanisms by which ethanol consumption causes accumulation of hepatic lipid are multiple and complex. Chronic ethanol exposure is thought to cause enhanced hepatic lipogenesis and impaired fatty acid oxidation by inhibiting key hepatic transcriptional regulators such as AMP‐activated kinase (AMPK), sirtuin 1 (SIRT1), PPAR‐gamma coactivator alpha (PGC‐1α), peroxisome proliferator‐activated receptor alpha (PPARα), and sterol regulatory element‐binding protein 1 (SREBP‐1). Adiponectin is an adipose‐derived hormone with a variety of beneficial biological functions. Increasing evidence suggests that altered adiponectin production in adipose tissue and impaired expression of hepatic adiponectin receptors (AdipoRs) are associated with the development of alcoholic liver steatosis in several rodent models. More importantly, studies have demonstrated a protective role of adiponectin against alcoholic liver steatosis. The hepato‐protective effect of adiponectin is largely mediated by the coordination of multiple signaling pathways in the liver, leading to enhanced fat oxidation, reduced lipid synthesis and prevention of hepatic steatosis. This review begins with an assessment of the current understanding of the role of adiponectin and its receptors in the regulation of lipid homeostasis in liver, with emphasis on their relationship to the development of alcoholic liver steatosis. Following sections will review hepatic signaling molecules involved in the protective actions of adiponectin against alcoholic fatty liver and summarize the current knowledge of regulatory mechanisms of adiponectin expression and secretion in response to chronic ethanol exposure. We will conclude with a discussion of potential strategies for treating human alcoholic fatty liver disease (AFLD), including nutritional and pharmacological modulation of adiponectin and its receptors. © 2008 IUBMB IUBMB Life, 60(12): 790–797, 2008

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Section: Effects Of Ethanol On Pgc-1a/ppara Functionmentioning

confidence: 99%

Adiponectin and alcoholic fatty liver disease

2008

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“…Acetaldehyde does not induce collagen synthesis in quiescent HSCs [122] and it is not able to modulate PPARγ phosphorylation in these cells. The molecular events involved in the unresponsiveness of quiescent HSCs to fibrogenic stimuli [64] , including acetaldehyde, remain speculative.…”

Section: Mechanism Of Alcohol-induced Fibrogenesismentioning

confidence: 99%

“…This effect is accompanied by a reduction in the ability of this receptor to bind its DNA consensus sequence, reflecting a possible covalent modification by acetaldehyde or changes in its phosphorylation state. Accordingly, chronic ethanol feeding in mice inhibited PPARα DNA binding activity and decreased PPARα target genes [63,64] . In mouse models of ALD, treatment with PPARα ligands such as WY14, 643 and clofibrate, restores receptor activity and significantly ameliorates fat accumulation and necroinflammation [63,64] .…”

Section: Mechanisms Of Alcoholic Fatty Livermentioning

confidence: 99%

“…Accordingly, chronic ethanol feeding in mice inhibited PPARα DNA binding activity and decreased PPARα target genes [63,64] . In mouse models of ALD, treatment with PPARα ligands such as WY14, 643 and clofibrate, restores receptor activity and significantly ameliorates fat accumulation and necroinflammation [63,64] . In addition, ethanol can also inhibit PPARα via upregulation of CYP2E1-derived oxidative stress [65] .…”

Section: Mechanisms Of Alcoholic Fatty Livermentioning

confidence: 99%

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Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

415

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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“…Chronic ethanol administration in mice is associated with inhibition of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR) ␣, two critical signaling molecules controlling the pathways of hepatic fatty acid oxidation. [12][13][14][15] These molecules are the major mediators of the metabolic effect of adiponectin. 16,17 Adiponectin is exclusively expressed and secreted from adipose tissue.…”

mentioning

confidence: 99%

Role of Adiponectin in the Protective Action of Dietary Saturated Fat Against Alcoholic Fatty Liver in Mice * #

et al. 2005

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The protective effect of dietary saturated fatty acids against the development of alcoholic liver disease has long been known, but the underlying mechanism is not completely understood. We examined the involvement of the adipocyte hormone adiponectin. Circulating adiponectin levels were significantly elevated by chronic ethanol administration to mice consuming a diet high in saturated fat. The increase in circulating adiponectin was associated with the activation a set of hepatic signaling pathways mediated through AMP-activated protein kinase, PPAR-␣, and PPAR-␥ coactivator ␣, which in turn led to markedly increased rates of fatty acid oxidation, prevention of hepatic steatosis, and alleviation of liver enzyme changes. Furthermore, treatment of rat 3T3-L1 adipocytes with saturated fatty acids (palmitic or stearic acids) in the presence of ethanol increased secretion of adiponectin and enhanced activity of a mouse adiponectin promoter. In conclusion, the protective action of saturated fat against the development of alcoholic fatty liver in mice is partially mediated through induction of adiponectin. The present findings suggest a novel paradigm for dietary fatty acids in the pathogenesis of alcoholic liver disease and provide a promising therapeutic strategy-nutritional modulation of adiponectin-in treating human alcoholic fatty liver disease. (HEPATOLOGY 2005;42:568 -577.)

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Alcoholic Liver Injury in the Rat Is Associated with Reduced Expression of Peroxisome Proliferator-α (PPARα)-Regulated Genes and Is Ameliorated by PPARα Activation

Cited by 111 publications

References 73 publications

Adiponectin and alcoholic fatty liver disease

Adiponectin and alcoholic fatty liver disease

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Role of Adiponectin in the Protective Action of Dietary Saturated Fat Against Alcoholic Fatty Liver in Mice * #

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