Ethanol-induced retention of nascent proteins in rat hepatocytes is accompanied by altered distribution of the small GTP-binding protein rab2.

Larkin, Janet M.; Oswald, Barbara; McNiven, Mark A.

doi:10.1172/jci119021

Cited by 25 publications

(25 citation statements)

References 42 publications

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“…Among Rab family members, studies from our laboratory and others have demonstrated only that EtOH exposure modulates the expression or cellular distribution of a subset of Rabs 45, 51, 52, 53. Therefore, the findings presented in this study are perhaps the first to demonstrate that the GTPase activity of a given Rab family member is diminished with EtOH exposure.…”

Section: Discussionsupporting

confidence: 49%

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: Discussionsupporting

confidence: 49%

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

Schulze¹,

Rasineni

Weller³

et al. 2017

Hepatology Communications

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“…Research on the liver has demonstrated that short and long-term ethanol exposure induces retention of nascent proteins (Larkin et al, 1996). The ethanol-induced protein retention in the liver resulted from impaired vesicle transport and protein trafficking (Ghosh et al, 1995;Torok et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Influence of virgin coconut oil (VCNO) on oxidative stress, serum testosterone and gonadotropic hormones (FSH, LH) in chronic ethanol ingestion

Dosumu¹,

Duru²,

Osinubi³

et al. 2010

ABJNA

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The present study explored the effect of virgin coconut oil on oxidative stress, testosterone and gonadotropic hormones in alcohol-induced testicular injury. Twenty-five male rats were randomly assigned to one of five groups (n=5). The oil was processed from the mature endosperm of coconut and administered at 6.7 ml/kg body weight, while alcohol was given orally at 7 ml/kg body weight. After sacrifice, testicular malondialdehyde and serum hormone levels were determined. Testicular malondialdehyde levels increased significantly in animals treated with alcohol alone (p < 0.001), and animals treated with alcohol following virgin coconut oil treatment (p < 0.05) while the other groups showed a significant decrease (p < 0.05) when compared with the control. However, when compared with the group treated with alcohol alone, all the other groups showed a significant decrease (p < 0.05) in testicular malondialdehyde level. Serum testosterone levels increased significantly (p < 0.05) in rats treated with virgin coconut oil when compared with the alcohol-only treated group, while serum FSH and LH levels were not significantly different from the control values in all the treatment groups. Virgin coconut oil effectively lowered alcohol-induced oxidative stress by reducing testicular malondialdehyde levels and ameliorated the deleterious effect of alcohol on serum testosterone level, but showed no effect on serum FSH and LH levels.

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“…An effect of the virus-related chronic immune activation on the trafficking and secretion of ASGP-R has never been shown. In contrast, alcohol and its derivatives lead to a significant impairment of hepatocellular membrane protein trafficking, for instance by disrupting the flow of newly synthesized proteins to the plasma membrane via abnormal lipidation of Rab proteins (small GTP-binding proteins regulating vesicular trafficking) 29,30 but also other pathways. 31,32 As one of the main proteins within the hepatocellular plasma membrane, multiple steps in the trafficking of ASGP-R have been shown to be affected in ALD.…”

Section: Discussionmentioning

confidence: 99%

Asialoglycoprotein receptor facilitates hemolysis in patients with alcoholic liver cirrhosis

et al. 2004

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Hemolysis in patients with advanced alcoholic liver disease is a common clinical problem and indicates an unfavorable prognosis. In many cases, the etiology of the hemolysis remains unknown. We observed three patients with alcoholic liver disease, suffering from severe hemolytic anemia, requiring multiple blood transfusions. Steroid therapy was ineffective and two of the patients died. All patients had a soluble variant of the human asialoglycoprotein receptor (s-ASGP-R) in their serum, as well as high titers of autoantibodies against this receptor (anti-ASGP-R). Consecutively, examination of 60 patients with alcoholic liver disease revealed a high incidence for s-ASGP-R (36%) and anti-ASGP-R (27%) in patients with alcoholic liver cirrhosis (ALC) compared to patients with cirrhosis due to viral hepatitis. The potential etiology of hemolysis was studied in vitro on erythrocytes from patients with ALC and from healthy donors. Isolated ASGP-R but not anti-ASGP-R bound to the surface of erythrocytes preferentially of blood group A1 and caused dose-dependent agglutination and hemolysis, while this phenomenon was much lower using erythrocytes of the blood group B and almost absent with blood group O-erythrocytes. Furthermore, agglutination and hemolysis only occurred in erythrocytes from ALC-patients or after the pretreatment of cells with neuraminidase. ASGP-R induced agglutination and hemolysis was blocked by the competitive ASGP-R inhibitor asialofetuin. In conclusion, our results indicate a new, non-immunological mechanism for hemolysis in patients with alcoholic liver disease, mediated through agglutination by a soluble variant of the human asialoglycoprotein receptor and mechanical shear stress.

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Ethanol-induced retention of nascent proteins in rat hepatocytes is accompanied by altered distribution of the small GTP-binding protein rab2.

Abstract: Chronic ethanol consumption induces hepatocellular retention of nascent proteins leading to hepatomegaly. While the molecular mechanisms behind this impairment are undefined, it has been predicted that protein retention results from a disruption of vesicle-mediated secretory processes.

Cited by 25 publications

References 42 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

Influence of virgin coconut oil (VCNO) on oxidative stress, serum testosterone and gonadotropic hormones (FSH, LH) in chronic ethanol ingestion

Asialoglycoprotein receptor facilitates hemolysis in patients with alcoholic liver cirrhosis

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