Pathogenesis and Management of Alcoholic Liver Disease

Farooq, Mariya; Bataller, Ramón

doi:10.1159/000444545

Cited by 51 publications

(40 citation statements)

References 59 publications

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“…Alcoholic liver disease is one of the most serious medical consequences of chronic ethanol use[ 1 , 2 ]. Investigations into the mechanisms of ethanol-induced liver injury have revealed that chronic ethanol abuse causes alterations in the methionine metabolism[ 3 - 5 ].…”

Section: Introductionmentioning

confidence: 99%

Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury

Osna

Feng

Ganesan³

et al. 2016

WJG

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AIMTo investigate the hypothesis that exposure to guanidinoacetate (GAA, a potent methyl-group consumer) either alone or combined with ethanol intake for a prolonged period of time would cause more advanced liver pathology thus identifying methylation defects as the initiator and stimulator for progressive liver damage.METHODSAdult male Wistar rats were fed the control or ethanol Lieber DeCarli diet in the absence or presence of GAA supplementation. At the end of 6 wk of the feeding regimen, various biochemical and histological analyses were conducted.RESULTSContrary to our expectations, we observed that GAA treatment alone resulted in a histologically normal liver without evidence of hepatosteatosis despite persistence of some abnormal biochemical parameters. This protection could result from the generation of creatine from the ingested GAA. Ethanol treatment for 6 wk exhibited changes in liver methionine metabolism and persistence of histological and biochemical defects as reported before. Further, when the rats were fed the GAA-supplemented ethanol diet, similar histological and biochemical changes as observed after 2 wk of combined treatment, including inflammation, macro- and micro-vesicular steatosis and a marked decrease in the methylation index were noted. In addition, rats on the combined treatment exhibited increased liver toxicity and even early fibrotic changes in a subset of animals in this group. The worsening liver pathology could be related to the profound reduction in the hepatic methylation index, an increased accumulation of GAA and the inability of creatine generated to exert its hepato-protective effects in the setting of ethanol.CONCLUSIONTo conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage.

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Section: Introductionmentioning

confidence: 99%

Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury

Osna

Feng

Ganesan³

et al. 2016

WJG

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“…Alcoholic liver disease (ALD) is an alcohol-associated pathologic process characterized by a range of liver disorders from steatosis, steatohepatitis, hepatitis, fibrosis/ cirrhosis, to hepatocellular carcinoma and liver failure. 1,2 Studies in rodents and humans have demonstrated that excessive alcohol consumption induces pathophysiological conditions in multiple organs. Ethanol-induced liver dysfunctions are driven by organ crosstalk via intestineeliver, adiposeeliver, or adiposeeintestine-liver axis.…”

mentioning

confidence: 99%

“…1e3 Alcohol intake induces liver dysfunction by breaking barrier integrity and function of small intestine and by promoting growth of intestinal pathogenic bacteria and harmful metabolites (eg, lipopolysaccharides). 1,2 Ethanol exposure damages the liver by impairing fibroblast growth factor (FGF) 15/19, an ileum-derived hormone, and by disrupting FGF 15/19-mediated signaling. 4e6 Altered intestinal microbiota and abnormal bile acid metabolism are also involved in the pathogenesis of ALD.…”

mentioning

confidence: 99%

Intestinal SIRT1 Deficiency Protects Mice from Ethanol-Induced Liver Injury by Mitigating Ferroptosis

Zhou

DeCaro

et al. 2020

The American Journal of Pathology

103

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Aberrant liver sirtuin 1 (SIRT1), a mammalian NAD þ-dependent protein deacetylase, is implicated in the pathogenesis of alcoholic liver disease (ALD). However, the role of intestinal SIRT1 in ALD is presently unknown. This study investigated the involvement of intestine-specific SIRT1 in ethanol-induced liver dysfunction in mice. Ethanol feeding studies were performed on knockout mice with intestinal-specific SIRT1 deletion [SIRT1i knockout (KO)] and flox control [wild-type (WT)] mice with a chroniceplusbinge ethanol feeding protocol. After ethanol administration, hepatic inflammation and liver injury were substantially attenuated in the SIRT1iKO mice compared with the WT mice, suggesting that intestinal SIRT1 played a detrimental role in the ethanol-induced liver injury. Mechanistically, the hepatic protective effect of intestinal SIRT1 deficiency was attributable to ameliorated dysfunctional iron metabolism, increased hepatic glutathione contents, and attenuated lipid peroxidation, along with inhibition of a panel of genes implicated in the ferroptosis process in the livers of ethanol-fed mice. This study demonstrates that ablation of intestinal SIRT1 protected mice from the ethanol-induced inflammation and liver damage. The protective effects of intestinal SIRT1 deficiency are mediated, at least partially, by mitigating hepatic ferroptosis. Targeting intestinal SIRT1 or dampening hepatic ferroptosis signaling may have therapeutic potential for ALD in humans.

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“… 69 Moreover, steatosis is rapidly resolved by abstinence, which remains a mainline therapy for ALD and AH, and, thus, the likelihood that addressing liver steatosis as an effective therapeutic target for AH is minimal, as it is self-resolving in compliant patients. 70 , 71 …”

Section: Alcoholic Liver Disease In the Mouse – Limited Pathologymentioning

confidence: 99%

Alcoholic Hepatitis: Lost in Translation

Woolbright

Jaeschke

2017

Journal of Clinical and Translational Hepatology

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Alcoholic hepatitis is the most severe and acute form of alcoholic liver disease. The mortality rate associated with alcoholic hepatitis is high, largely due to the lack of suitable pharmacological interventions. While there has been substantial research in the area, generating pharmacological interventions has been plagued by the lack of a robust mouse model both for testing and for understanding the underlying pathology. A number of major notable advances have been made in this area recently, with the goal of generating a mouse model of alcoholic hepatitis. The purpose of this article is to review recent advances in modeling alcoholic liver disease both in vitro and in vivo in the mouse, and place them in the context of the greater spectrum of alcoholic liver disease, with a focus on how we can translate current advances into a high-fidelity model of alcoholic hepatitis. In addition, we will review the basic mechanisms of alcoholic hepatitis as it is currently understood, focusing on recent advancements in diagnosis, prognosis and current pathophysiology, especially as it relates to the profound immune dysfunction present during alcoholic hepatitis.

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Pathogenesis and Management of Alcoholic Liver Disease

Cited by 51 publications

References 59 publications

Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury

Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury

Intestinal SIRT1 Deficiency Protects Mice from Ethanol-Induced Liver Injury by Mitigating Ferroptosis

Alcoholic Hepatitis: Lost in Translation

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