Differential Contributions of C3, C5, and Decay-Accelerating Factor to Ethanol-Induced Fatty Liver in Mice

Pritchard, Michele T.; McMullen, Megan R.; Stavitsky, Abram B.; Cohen, Jessica I.; Lin, Feng; Medof, M. Edward; Nagy, Laura E.

doi:10.1053/j.gastro.2007.01.053

Cited by 143 publications

(194 citation statements)

References 47 publications

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“…Kupffer cell activation contributes to intrahepatic recruitment and activation of granulocytes [159][160][161] . Acetaldehyde and LPS [162][163][164] stimulate parenchymal and nonparenchymal cells to produce IL-8, chemokine CXC ligand (CXCL)1 (Gro-α) and IL-17 that directly or indirectly contribute to neutrophil infiltration and severity of AH [165][166][167] . An alternative pathway that contributes to expression of inflammatory cytokines is the complement system.…”

Section: Ethanol Oxidation and Activation Of Innate And Adaptive Immumentioning

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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Section: Ethanol Oxidation and Activation Of Innate And Adaptive Immumentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

413

339

View full text Add to dashboard Cite

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Section: Introductionmentioning

confidence: 99%

“…Recent work by the Nagy [36] and Lindros [37] laboratories have revealed that activation of the complement pathway is necessary for the development of chronic alcohol induced steatosis. Indeed, both laboratories have independently shown that, unlike wild-type mice, complement component C3 − /− mice do not develop fatty liver when fed an ethanol-containing diet for 6 weeks [36,37]. More interesting, however, is the observation by Pritchard et al showing that even though the C3 − /− mice were protective against ethanol-mediated steatosis, mice still had elevated serum ALT and hepatic TNFα levels following alcohol exposure indicating hepatic inflammatory injury in the absence of steatosis [36].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, both laboratories have independently shown that, unlike wild-type mice, complement component C3 − /− mice do not develop fatty liver when fed an ethanol-containing diet for 6 weeks [36,37]. More interesting, however, is the observation by Pritchard et al showing that even though the C3 − /− mice were protective against ethanol-mediated steatosis, mice still had elevated serum ALT and hepatic TNFα levels following alcohol exposure indicating hepatic inflammatory injury in the absence of steatosis [36]. In support of this, Diehl and colleagues demonstrated that inhibition of hepatocyte triglyceride synthesis and steatosis increased liver injury and fibrosis in obese mice with NASH [38].…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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“…O resultado obtido está de acordo com essa informação, embora C5 só tenha sido importante no fundo genético B6. Contudo, além desse papel protetor, C5 também é responsável por aumentar o grau de lesão em diferentes modelos experimentais (Pritchard et al, 2007). Devido a capacidade de C5a estimular e atrair diversos tipos celulares para o sítio de inflamação (Liu et al, 2013;Mashruwala et al, 2011;Mollnes et al, 2002;Moulton et al, 2007;Snyderman et al, 1971;Ward, Zvaifler, 1971) …”

Section: Discussionunclassified

Importância do componente C5 do sistema complemento para o controle de leptospirose in vivo em modelos murinos.

Castro¹

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AGRADECIMENTOSAos meus pais e minhas irmãs, por tudo o que representam para mim, pelo apoio em todos os momentos, e sem os quais eu não seria o que sou nem estaria onde estou agora.A Prof. Dr. Lourdes, que me aceitou no laboratório e confiou a mim a execução deste projeto, permitindo que eu crescesse profissionalmente e aprendesse não apenas a "executar tarefas", mas a refletir sobre o que está sendo realizado.A Dr. Angela Barbosa, pela ajuda oferecida durante o projeto.Aos professores do Departamento de Imunologia, pelas aulas, discussões e toda a ajuda fornecida nesses últimos três anos.A todos os funcionários do departamento e do instituto, pelo fornecimento e manutenção dos camundongos utilizados neste projeto, o auxílio fornecido desde a inscrição para a prova de ingresso no programa até a entrega desse texto aos professores que compõem a banca, e pela manutenção de um espaço agradável onde pude passar bons momentos.A Fapesp pelo auxílio financeiro fornecido durante toda a execução do projeto.Ao CNPq pelo auxílio financeiro fornecido no início do mestrado.A BioClin pelo fornecimento dos kits para dosagem de parâmetros bioquímicos no soro dos camundongos.A Lorena Bavia, companheira de bons e maus momentos que me recebeu no laboratório e foi muito importante para a minha formação.A todos os colegas e ex-colegas do laboratório (José Antônio, André, Leandro, Alfredo, Marlene, Tatiana, Adriana, Mónica, Karina, Daniella, Lorena), pela ajuda, as risadas e os bons momentos que passamos no laboratório.

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Differential Contributions of C3, C5, and Decay-Accelerating Factor to Ethanol-Induced Fatty Liver in Mice

Cited by 143 publications

References 47 publications

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

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

Importância do componente C5 do sistema complemento para o controle de leptospirose in vivo em modelos murinos.

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