Mitochondrial DNA–enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity

Cai, Yan; Xu, Mingjiang; Koritzinsky, Erik H.; Zhou, Zhou; Wang, Wei; Cao, Hongyan; Yuen, Peter S.T.; Ross, Ruth Ann; Star, Robert A.; Liangpunsakul, Suthat; Gao, Bin

doi:10.1172/jci.insight.92634

Cited by 83 publications

(81 citation statements)

References 45 publications

(74 reference statements)

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“…Recent studies identified an ethanol-mediated increase in acrolein adduct formation and a resultant ER stress as a critical contributor to ALD. (4,25) Consistent with the observed increase in 4-HNE and acrolein adduct formation, ethanol feeding led to a significant induction of hepatic ER stress as indicated by increased levels of key proteins of activating transcription factor 3 (Atf3) and Atf4 (Fig. 5E).…”

Section: Pde4 Inhibitor Attenuates Alcohol-mediated Accumulation Of Lsupporting

confidence: 71%

“…Our group and others have shown that ER stress plays a significant pathogenic role in ethanol‐induced hepatocyte injury . Importantly, we showed that formation of acrolein in the liver is a critical contributor to ER stress and ER stress–mediated liver injury .…”

Section: Discussionsupporting

confidence: 48%

“…Our group and others have shown that ER stress plays a significant pathogenic role in ethanol-induced hepatocyte injury. (4,25) Importantly, we showed that formation of acrolein in the liver is a critical contributor to ER stress and ER stress-mediated liver injury. (4) Consistent with previous studies, we found significant formation of acrolein as well as 4-HNE adducts in AF mice, which was attenuated by PDE4 inhibition.…”

Section: Discussionmentioning

confidence: 88%

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Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench

et al. 2019

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Alcoholic liver disease (ALD) is a major cause of liver‐related mortality. There is still no US Food and Drug Administration–approved therapy for ALD, and therefore, identifying therapeutic targets is needed. Our previous work demonstrated that ethanol exposure leads to up‐regulation of cAMP‐degrading phosphodiesterase 4 (PDE4) expression, which compromises normal cAMP signaling in monocytes/macrophages and hepatocytes. This effect of ethanol on cAMP signaling contributes to dysregulated inflammatory response and altered lipid metabolism. It is unknown whether chronic alcohol consumption in humans alters hepatic PDE4 expression and cAMP signaling and whether inadequate cAMP signaling plays a pathogenic role in alcohol‐induced liver injury. Our present work shows that expression of the PDE4 subfamily of enzymes is significantly up‐regulated and cAMP levels are markedly decreased in hepatic tissues of patients with severe ALD. We also demonstrate the anti‐inflammatory efficacy of roflumilast, a clinically available PDE4 inhibitor, on endotoxin‐inducible proinflammatory cytokine production ex vivo in whole blood of patients with alcoholic hepatitis. Moreover, we demonstrate that ethanol‐mediated changes in hepatic PDE4 and cAMP levels play a causal role in liver injury in in vivo and in vitro models of ALD. This study employs a drug delivery system that specifically delivers the PDE4 inhibitor rolipram to the liver to avoid central nervous system side effects associated with this drug. Our results show that PDE4 inhibition significantly attenuates ethanol‐induced hepatic steatosis and injury through multiple mechanisms, including reduced oxidative and endoplasmic reticulum stress both in vivo and in vitro. Conclusion: Increased PDE4 plays a pathogenic role in the development of ALD; hence, directed interventions aimed at inhibiting PDE4 might be an effective treatment for ALD.

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Section: Pde4 Inhibitor Attenuates Alcohol-mediated Accumulation Of Lsupporting

confidence: 71%

Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 88%

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Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench

et al. 2019

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“…Thus, it is tempting to speculate that the miR‐30a concentration in EVs may be the result of changes in autophagy and/or exosome production in ALD. Another study also found increased EV levels in a mouse model of AH . This study identified mitochondrial DNA in the cargo of MVs that showed a biological effect in mediating neutrophil activation in AH.…”

Section: Alcoholic Liver Disease and Alcoholic Hepatitissupporting

confidence: 52%

Extracellular Vesicles in Liver Diseases: Meeting Report from the International Liver Congress 2018

et al. 2019

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Extracellular vesicles (EVs) are small and heterogeneous membrane‐bound structures released by cells and found in all biological fluids. They are effective intercellular communicators, acting on a number of close and/or distant target cells. EV cargo may reflect the cell of origin as well as the specific stress that induces their formation and release. They transport a variety of bioactive molecules, including messenger RNA, noncoding RNAs, proteins, lipids, and metabolites, that can be transferred among cells, regulating various cell responses. Alteration in the concentration and composition of EVs in biological fluids is a typical hallmark of pathologies in different liver diseases. Circulating EVs can serve as biomarkers or as messengers following uptake by other cells. This review is a meeting report from the International Liver Congress 2018 (European Association for the Study of the Liver) celebrated in Paris (Symposium: Extracellular vesicles and signal transmission) that discusses the role of EVs in several liver diseases, highlighting their potential value as disease biomarkers and therapeutic opportunities.

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“…Additional aberrant processes, such as circadian rhythms, 80 autophagy, 81 and ER stress 82 are associated with pathogenesis of ALD. Both adiponectin and FGF15/19 are involved in regulating circadian rhythms, 83,84 autophagy 85,86 and ER stress 87,88 .…”

Section: Discussionmentioning

confidence: 99%

Endocrine Adiponectin‐FGF15/19 Axis in Ethanol-Induced Inflammation and Alcoholic Liver Injury

et al. 2018

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Alcoholic liver disease (ALD) is the most prevalent form of liver diseases, encompassing a spectrum of progressive pathological changes from steatosis to steatohepatitis to fibrosis/cirrhosis and hepatocellular carcinoma. Alcoholic steatosis/steatohepatitis is the initial stage of ALD and a major risk factor for advanced liver injuries. Adiponectin is a hormone secreted from adipocytes. Fibroblast growth factor (FGF) 15 (human homolog, FGF19) is an ileum-derived hormone. Adipocyte-derived adiponectin and gut-derived FGF15/19 regulate each other, share common signaling cascades and exert similar beneficial functions. Emerging evidence has revealed that dysregulated adiponecitn-FGF15/19 axis and impaired hepatic adiponectin-FGF15/19 signaling are associated with alcoholic liver damage in rodents and humans. More importantly, endocrine adiponectin-FGF15/19 signaling confers protection against ethanol-induced liver damage via fine-tuning the adipose-intestine-liver crosstalk, leading to limited hepatic inflammatory responses, and ameliorated alcoholic liver injury. This review is focused on the recently discovered endocrine adiponectin-FGF15/19 axis that is emerging as an essential adipose-gut-liver coordinator involved in the development and progression of alcoholic steatohepatitis.

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Mitochondrial DNA–enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity

Cited by 83 publications

References 45 publications

Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench

Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench

Extracellular Vesicles in Liver Diseases: Meeting Report from the International Liver Congress 2018

Endocrine Adiponectin‐FGF15/19 Axis in Ethanol-Induced Inflammation and Alcoholic Liver Injury

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