Alcoholic liver disease

O’Shea, Robert; Dasarathy, Srinivasan; McCullough, Arthur J.

doi:10.1002/hep.23258

Cited by 991 publications

(681 citation statements)

References 256 publications

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“…With continued chronic consumption of alcohol (>40 g/day), ALD can eventually progress from relatively benign liver steatosis to more severe sequelae, including alcoholic steatohepatitis, fibrosis, or cirrhosis 1, 2. The initial accumulation of large amounts of triglyceride during ALD may prime the liver to become hypersensitive to damaging conditions, such as alcohol‐induced oxidative stress 3.…”

Section: Introductionmentioning

confidence: 99%

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Schulze¹,

Rasineni

Weller³

et al. 2017

Hepatology Communications

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Alcohol consumption is a well‐established risk factor for the onset and progression of fatty liver disease. An estimated 90% of heavy drinkers are thought to develop significant liver steatosis. For these reasons, an increased understanding of the molecular basis for alcohol‐induced hepatic steatosis is important. It has become clear that autophagy, a catabolic process of intracellular degradation and recycling, plays a key role in hepatic lipid metabolism. We have shown that Rab7, a small guanosine triphosphatase known to regulate membrane trafficking, acts as a key orchestrator of hepatocellular lipophagy, a selective form of autophagy in which lipid droplets (LDs) are specifically targeted for turnover by the autophagic machinery. Nutrient starvation results in Rab7 activation on the surface of the LD and lysosomal compartments, resulting in the mobilization of triglycerides stored within the LDs for energy production. Here, we examine whether the steatotic effects of alcohol exposure are a result of perturbations to the Rab7‐mediated lipophagic pathway. Rats chronically fed an ethanol‐containing diet accumulated significantly higher levels of fat in their hepatocytes. Interestingly, hepatocytes isolated from these ethanol‐fed rats contained juxtanuclear lysosomes that exhibited impaired motility. These changes are similar to those we observed in Rab7‐depleted hepatocytes. Consistent with these defects in the lysosomal compartment, we observed a marked 80% reduction in Rab7 activity in cultured hepatocytes as well as a complete block in starvation‐induced Rab7 activation in primary hepatocytes isolated from chronic ethanol‐fed animals. Conclusion: A mechanism is supported whereby ethanol exposure inhibits Rab7 activity, resulting in the impaired transport, targeting, and fusion of the autophagic machinery with LDs, leading to an accumulation of hepatocellular lipids and hepatic steatosis. (Hepatology Communications 2017;1:140‐152)

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Section: Introductionmentioning

confidence: 99%

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Schulze¹,

Rasineni

Weller³

et al. 2017

Hepatology Communications

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“…Excessive alcohol drinking is a leading cause of chronic liver disease, resulting in liver diseases that range from simple fatty liver to more severe forms of liver injury, such as alcoholic hepatitis, cirrhosis and hepatocellular carcinoma [1]. Oxidative stress has been suggested to play a central role in the mechanism of alcohol-induced damage [2].…”

Section: Introductionmentioning

confidence: 99%

Emodin Ameliorates Ethanol-Induced Fatty Liver Injury in Mice

et al. 2014

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The liver plays a central role in ethanol (EtOH) metabolism, and oxidative stress is implicated in alcohol-mediated liver injury. The present study aimed to investigate the role of emodin in EtOH-induced fatty liver injury. Liver histology, biochemistry and gene-expression studies were performed. Mice fed with an EtOH-containing diet exhibited severe macrovesicular steatosis and higher serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. However, emodin ameliorated liver steatosis and lowered ALT and AST. Emodin also decreased hepatic triglyceride in mice fed with EtOH. In addition, emodin attenuates Oil Red O staining in alcoholic fatty liver in mice. Hepatic cytochrome P450 2E1 protein levels were upregulated in EtOH-fed mice, but downregulated in emodin-treated mice. In addition, emodin decreased hepatic oxidative stress. Furthermore, emodin significantly reduced liver α-smooth muscle actin and collagen type I, whereas it increased the mRNA levels of PPAR-γ. Taken together, emodin plays protective roles in alcohol-mediated liver steatosis.

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“…They had already stopped the practice of glucocorticoids in severe alcoholic hepatitis despite the most current guidelines which still recommend 40mg prednisolone/d for 28 day course with two week taper. 1,6,7 Given the evidence in the article prednisolone therapy may not be wanted by a patient. A physician would have to describe steroid therapy as only possibly providing benefit with an increased risk of infection.…”

Section: Clinical Applicationmentioning

confidence: 99%

Glucocorticoids do not decrease mortality in severe alcoholic hepatitis

Bolig¹

2016

Clin. Res. Pract.

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Alcoholic liver disease

Cited by 991 publications

References 256 publications

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Emodin Ameliorates Ethanol-Induced Fatty Liver Injury in Mice

Glucocorticoids do not decrease mortality in severe alcoholic hepatitis

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