Impaired TFEB-Mediated Lysosome Biogenesis and Autophagy Promote Chronic Ethanol-Induced Liver Injury and Steatosis in Mice

Chao, Xiaojuan; Wang, Shaogui; Zhao, Katrina; Li, Yuan; Williams, Jessica A.; Li, Tiangang; Chavan, Hemantkumar; Krishnamurthy, Partha; He, Xi; Li, Linheng; Ballabio, Andrea; Ni, Hong‐Min; Ding, Wen–Xing

doi:10.1053/j.gastro.2018.05.027

Cited by 242 publications

(221 citation statements)

References 42 publications

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“…Recent evidence suggests that alcohol has differential effects on autophagy that is a critical pathway for maintaining homeostasis by eliminating cellular waste. Acute alcohol treatment activates autophagy, whereas impaired autophagic flux has been reported in chronic mouse models of ALD . However, the molecular mechanisms underlying the effect of chronic alcohol on autophagic flux and lysosome integrity are still unclear.…”

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confidence: 99%

Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

et al. 2019

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Cellular homeostais, that is normally maintained through autophagy, is disrupted in alcoholic liver disease (ALD). Because autophagy and exosome biogenesis share common elements, we hypothesized that increased exosome production in ALD may be linked to disruption of autophagic function. We found impaired autophagy both in ALD and alcoholic hepatitis (AH) mouse models and human livers with ALD as indicated by increased hepatic p62 and LC3‐II levels. Alcohol reduced autophagy flux in vivo in chloroquine‐treated mice as well as in vitro in hepatocytes and macrophages treated with bafilomycin A. Our results revealed that alcohol targets multiple steps in the autophagy pathway. Alcohol‐related decrease in mechanistic target of rapamycin (mTOR) and Ras homolog enriched in brain (Rheb), that initiate autophagy, correlated with increased Beclin1 and autophagy‐related protein 7 (Atg7), proteins involved in phagophore‐autophagosome formation, in ALD. We found that alcohol disrupted autophagy function at the lysosomal level through decreased lysosomal‐associated membrane protein 1 (LAMP1) and lysosomal‐associated membrane protein 2 (LAMP2) in livers with ALD. We identified that micro‐RNA 155 (miR‐155), that is increased by alcohol, targets mTOR, Rheb, LAMP1, and LAMP2 in the authophagy pathway. Consistent with this, miR‐155‐deficient mice were protected from alcohol‐induced disruption of autophagy and showed attenuated exosome production. Mechanistically, down‐regulation of LAMP1 or LAMP2 increased exosome release in hepatocytes and macrophages in the presence and absence of alcohol. These results suggested that the alcohol‐induced increase in exosome production was linked to disruption of autophagy and impaired autophagosome and lysosome function. Conclusion: Alcohol affects multiple genes in the autophagy pathway and impairs autophagic flux at the lysosome level in ALD. Inhibition of LAMP1 and LAMP2 promotes exosome release in ALD. We identified miR‐155 as a mediator of alcohol‐related regulation of autophagy and exosome production in hepatocytes and macrophages.

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Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

et al. 2019

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“…The clinical spectrum of alcoholic liver disease includes alcoholic fatty liver, alcoholic steatohepatitis, cirrhosis, and hepatocellular cancer. Alcoholic fatty liver, also known as steatosis, is the earliest stage of alcoholic liver disease defined by the accumulation of lipid droplets in hepatocytes resulting from increased lipid synthesis and decreased lipid degradation (reviewed in Osna et al) More recently, defects in selective autophagy have also been shown to contribute to alcoholic fatty liver disease …”

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Protective Effect of SMAD‐Specific E3 Ubiquitin Protein Ligase 1 in Alcoholic Steatohepatitis in Mice

Petrášek

Erhartová

2019

Hepatol Commun

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Excessive accumulation of lipids in the liver is crucial in the pathogenesis of alcoholic steatohepatitis and may be partly mediated by impaired degradation of lipid droplets by autophagy. The E3 ubiquitin ligase SMAD‐specific E3 ubiquitin protein ligase 1 (SMURF1) regulates selective autophagy by ubiquitinating proteins on cargo destined for autophagic delivery to the lysosome for degradation. Here, we evaluated the role of SMURF1 in the regulation of hepatic lipid degradation in alcoholic steatohepatitis. In patients with severe alcoholic hepatitis, SMURF1 colocalized with lipid droplet membranes in liver explants. In a mouse model of alcoholic steatohepatitis, Smurf1−/− mice fed an alcohol diet displayed increased hepatocyte accumulation of lipid droplets and triglycerides as well as more severe liver injury compared to wild‐type mice. The increased severity of liver steatosis in alcohol‐fed Smurf1−/− mice was rescued by adeno‐associated virus (AAV) serotype 8‐mediated hepatic expression of wild‐type Smurf1 protein but not by mutant Smurf1 proteins either lacking the catalytically active cysteine 699 required for ubiquitin transfer or the N‐terminal C2 phospholipid membrane‐binding domain. Conclusion: Smurf1 plays a protective role in the pathogenesis of alcoholic steatohepatitis through a mechanism that requires both its ubiquitin‐ligase activity and C2 phospholipid‐binding domains. These findings have implications for understanding the roles of ubiquitin ligases in fatty liver disease.

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“…demonstrated the role of TFEB in lysosome biogenesis and autophagy in a chronic ethanol plus single acute binge mouse model of alcoholic liver disease (11). Liver tissues from mice on Lieber DeCarli ethanol diet for 10 days plus a single acute binge (termed as NIAAA model) showed reduced levels of total and nuclear TFEB compared to controls.…”

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“…Liver tissues from mice on Lieber DeCarli ethanol diet for 10 days plus a single acute binge (termed as NIAAA model) showed reduced levels of total and nuclear TFEB compared to controls. Further, hepatocytes of ethanol fed mice exhibited reduced autophagy and lysosome biogenesis and increased mTOR activation (11). Autophagy flux was studied using GFP-LC3 transgenic mice in the NIAAA binge model in the presence or absence of leupeptin, a lysosomal inhibitor.…”

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confidence: 99%

“…found that ethanol alone did not change the hepatic protein levels of p62, which were increased in leupeptin alone or leupeptin plus ethanol group. Authors postulated that enhanced p62 accumulation in leupeptin plus ethanol treated mice could be due to either impairment in the lysosomal/autolysosomal functions or reduced lysosome numbers (11). Consistent with the hypothesis, ethanol treatment caused a decrease in the lysosome numbers in hepatocytes as quantified by LAMP1 positive vesicles/puncta.…”

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TFEB, a master regulator of lysosome biogenesis and autophagy, is a new player in alcoholic liver disease

Bala¹,

Szabó²

2018

Dig Med Res

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Impaired TFEB-Mediated Lysosome Biogenesis and Autophagy Promote Chronic Ethanol-Induced Liver Injury and Steatosis in Mice

Abstract: We found that ethanol feeding plus an acute binge decreased hepatic expression of TFEB, which is required for lysosomal biogenesis and autophagy. Strategies to block mTOR activity or increase levels of TFEB might be developed to protect the liver from ethanol-induced damage.

Cited by 242 publications

References 42 publications

Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

Protective Effect of SMAD‐Specific E3 Ubiquitin Protein Ligase 1 in Alcoholic Steatohepatitis in Mice

TFEB, a master regulator of lysosome biogenesis and autophagy, is a new player in alcoholic liver disease

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