Alcoholic Liver Disease on the Rise: Interorgan Cross Talk Driving Liver Injury

Dasarathy, Srinivasan; Brown, J. Mark

doi:10.1111/acer.13370

Cited by 13 publications

(9 citation statements)

References 12 publications

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“…Alcohol is a leading cause of preventable morbidity and mortality worldwide (11,30). Chronic alcohol abuse underlies the pathogenesis of alcoholic liver disease (ALD), encompassed by a spectrum of pathologies, ranging from steatosis to more severe forms of liver injury, including alcoholic hepatitis (AH), fibrosis, and cirrhosis.…”

Section: Introductionmentioning

confidence: 99%

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Complement Factor D protects mice from ethanol-induced inflammation and liver injury

McCullough

McMullen

Sheehan

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown. Activation of complement via the classical and alternative pathways was detected in alcoholic hepatitis patients. Female C57BL/6J [wild type (WT)], C1q-deficient ( C1qa, lacking classical pathway activation), complement protein 4-deficient ( C4, lacking classical and lectin pathway activation), complement factor D-deficient ( FD, lacking alternative pathway activation), and C1qa/FD (lacking classical and alternative pathway activation) mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 or 25 days. Following chronic ethanol exposure, liver injury, steatosis, and proinflammatory cytokine expression were increased in WT but not C1qa, C4, or C1qa/FD mice. In contrast, liver injury, steatosis, and proinflammatory mediators were robustly increased in ethanol-fed FD mice compared with WT mice. Complement activation, assessed by hepatic accumulation of C1q and complement protein 3 (C3) cleavage products (C3b/iC3b/C3c), was evident in livers of WT mice in response to both short-term and chronic ethanol. While C1q accumulated in ethanol-fed FD mice (short term and chronic), C3 cleavage products were detected after short-term but not chronic ethanol. Consistent with impaired complement activation, chronic ethanol induced the accumulation of apoptotic cells and fibrogenic responses in the liver of FD mice. These data highlight the protective role of complement factor D (FD) and suggest that FD-dependent amplification of complement is an adaptive response that promotes hepatic healing and recovery in response to chronic ethanol. NEW & NOTEWORTHY Complement, a component of the innate immune system, is an important pathophysiological contributor to ethanol-induced liver injury. We have identified a novel role for factor D, a component of the alternative pathway, in protecting the liver from ethanol-induced inflammation, accumulation of apoptotic hepatocytes, and profibrotic responses. These data indicate a dual role of complement with regard to inflammatory and protective responses and suggest that accumulation of apoptotic cells impairs hepatic healing/recovery during alcoholic liver disease.

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Section: Introductionmentioning

confidence: 99%

“…Moreover,~70% of individuals who develop AH will progress to cirrhosis (44). While current therapies focus on suppressing inflammation, they are relatively ineffective in patients with severe AH, and outcomes remain poor (11,19,57).…”

Section: Introductionmentioning

confidence: 99%

Complement Factor D protects mice from ethanol-induced inflammation and liver injury

McCullough

McMullen

Sheehan

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…One key aspect of gut-liver communication in ALD is alcohol-related gut dysbiosis. This topic has been recently reviewed extensively [ 71 , 72 ]. Using next generation sequencing, recent studies have described in detail the qualitative and quantitative changes in the gut microbiome in mice [ 73 ] and humans [ 74 ].…”

Section: Known Organ–organ Interactions In Alcoholic Liver Diseasementioning

confidence: 99%

Organ–Organ Crosstalk and Alcoholic Liver Disease

2017

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Alcohol consumption is a common custom worldwide, and the toxic effects of alcohol on several target organs are well-understood. Given the poor prognosis of treating clinically-relevant alcoholic liver disease (ALD) (i.e., alcoholic hepatitis (AH) and cirrhosis), additional research is required to develop more effective therapies. While the stages of ALD have been well-characterized, targeted therapies to prevent or reverse this process in humans are still needed. Better understanding of risk factors and mechanisms underlying disease progression can lead to the development of rational therapies to prevent or reverse ALD in the clinic. A potential area of targeted therapy for ALD may be organ–organ communication in the early stages of the disease. In contrast to AH and end-stage liver diseases, the involvement of multiple organs in the development of ALD is less understood. The impact of these changes on pathology to the liver and other organs may not only influence disease progression during the development of the disease, but also outcomes of end stages diseases. The purpose of this review is to summarize the established and proposed communication between the liver and other organ systems that may contribute to the development and progression of liver disease, as well as to other organs. Potential mechanisms of this organ–organ communication are also discussed.

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“…Alcoholic beverages have been widely used in many countries. Alcohol has direct harmful effects on the liver and excessive alcohol consumption damages nearly every organ . Its progressive liver pathology ranges from benign steatosis to more advanced stages such as steatohepatitis, cirrhosis, and hepatocellular carcinoma .…”

Section: Introductionmentioning

confidence: 99%

Myricetin Ameliorates Ethanol‐Induced Lipid Accumulation in Liver Cells by Reducing Fatty Acid Biosynthesis

Guo

Xue

Pan

et al. 2019

Molecular Nutrition Food Res

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Scope: Alcoholic liver disease is a serious threat to human health. The development of drug candidates from complementary and alternative medicines is an attractive approach. Myricetin can be found in fruit, vegetables, and herbs. This study investigates the protective effect of myricetin on ethanol-induced injury in mouse liver cells. Methods and results: Oil-red O staining, assays of oxidative stress and measurements of inflammatory markers in mouse AML12 liver cells collectively demonstrate that myricetin elicits a curative effect on ethanol-induced injury. Next, the role of myricetin in the metabolic regulation of ethanol pathology in liver cells is assessed by gas chromatography coupled with mass spectrometry. Myricetin inhibits ethanol-stimulated fatty acid biosynthesis. Additionally, dodecanoic acid may be proposed as a potential biomarker related to ethanol pathology or myricetin therapy. It is also observed that myricetin enhances ethanol-induced inhibition of the mitochondrial electron transport chain. Moreover, fumaric acid is found to be a candidate biomarker related to ethanol toxicity or myricetin therapy.

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Alcoholic Liver Disease on the Rise: Interorgan Cross Talk Driving Liver Injury

Cited by 13 publications

References 12 publications

Complement Factor D protects mice from ethanol-induced inflammation and liver injury

Complement Factor D protects mice from ethanol-induced inflammation and liver injury

Organ–Organ Crosstalk and Alcoholic Liver Disease

Myricetin Ameliorates Ethanol‐Induced Lipid Accumulation in Liver Cells by Reducing Fatty Acid Biosynthesis

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