Downregulation of the small GTPase SAR1A: a key event underlying alcohol-induced Golgi fragmentation in hepatocytes

Petrosyan, Armen; Cheng, Pi Wan; Clemens, Dahn L.; Casey, Carol A.

doi:10.1038/srep17127

Cited by 30 publications

(71 citation statements)

References 73 publications

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“…We hypothesized that these additional targets of miR‐18a and miR‐25 may also play key roles, together with SOCS5, in promoting or maintaining HCC in a combinatorial manner. Interestingly, knockdown of SAR1A in normal hepatocytes was shown to mimic the effect of chronic alcohol consumption on liver damage . The tumor suppressor TSC1 is a key repressor of the mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

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A novel SOCS5/miR‐18/miR‐25 axis promotes tumorigenesis in liver cancer

Sánchez-Mejías

Kwon

Chew

et al. 2018

Intl Journal of Cancer

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The role of miRNAs with tumor suppressive activity in liver cancer has been well studied. However, little is known about potential oncomiRs in HCC. In our study, we conducted a systematic evaluation of candidate oncomiRs and found that upregulation of miR-18a and miR-25 in HCC was associated with poor patient survival and promoted proliferation in HCC cell lines. These two miRNAs belong to the polycistronic paralogous miR-17-92 and miR-25-106b clusters respectively. Although the members of both clusters are often upregulated in HCC, the contribution of individual miRNAs in these clusters to HCC tumorigenesis is not fully understood. We validated SOCS5 as a bona fide target of both miRNAs, and established, for the first time, the tumor suppressive role of SOCS5 in liver cancer. We further investigated the mechanism by which SOCS5 contributes to tumorigenesis, demonstrated that this SOCS5/miR-18a/miR-25 axis regulates the tumor suppressor TSC1 and downstream mTOR signaling, and highlighted the potential therapeutic use of miR-18a and miR-25 inhibition in restoring SOCS5 levels in HCC.

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Section: Discussionmentioning

confidence: 99%

“…Interestingly, knockdown of SAR1A in normal hepatocytes was shown to mimic the effect of chronic alcohol consumption on liver damage. 41 The tumor suppressor TSC1 is a key repressor of the mTOR signaling pathway. Our results demonstrated that SOCS5 regulates the expression of TSC1 as well as downstream mTOR signaling (Fig.…”

Section: Discussionmentioning

confidence: 99%

A novel SOCS5/miR‐18/miR‐25 axis promotes tumorigenesis in liver cancer

Sánchez-Mejías

Kwon

Chew

et al. 2018

Intl Journal of Cancer

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“…Other small GTPases, including RhoA, Rac1, and Sar1a, have been found to be impaired by exposure to EtOH 46, 47, 48, 49. It is possible that EtOH directly acts on these GTPases (e.g., interfering with posttranslational lipid modifications) or perhaps functions indirectly on known guanine nucleotide exchange factors, preventing appropriate GTP cycling and an inability of these enzymes to bind nucleotide.…”

Section: Discussionmentioning

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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“…(26) In man and animal, chronic alcohol feeding with nutritionally adequate diets induced ultrastructural abnormalities of hepatocytes. (27) There is also an adaptive Golgi stress response (GSR) that involves Golgi resident protein 60 (GCP60), heat shock protein 47 (HSP47), and transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) to cope with disrupted homeostasis of the Golgi. (21,22) However, persistent stress on the Golgi disturbs metabolism in the liver, and dysfunction of the Golgi apparatus is associated with various stress-induced liver injuries.…”

Section: Introductionmentioning

confidence: 99%

Disrupted ER‐to‐Golgi trafficking underlies anti‐HIV drugs and alcohol‐induced cellular stress and hepatic injury

Han

et al. 2017

Hepatology Communications

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Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are involved in anti‐human immunodeficiency virus (HIV) drugs and alcohol‐induced liver disease in a significant number of patients infected with HIV. However, the precise mechanism by which the drugs and alcohol cause ER stress remains elusive. We found that ritonavir‐boosted lopinavir (RL) activated two canonical UPR branches without activation of the third canonical activating transcription factor 6 (ATF6) branch in either HepG2 cells or primary mouse hepatocytes. In the RL‐treated cells, ATF6 localization in the Golgi apparatus required for its activation was reduced; this was followed by Golgi fragmentation and dislocation/redistribution of Golgi‐resident enzymes. Severities of Golgi fragmentation induced by other anti‐HIV drugs varied and were correlated with the ER stress response. In the liver of mice fed RL, alcohol feeding deteriorated the Golgi fragmentation, which was correlated with ER stress, elevated alanine aminotransferase, and liver steatosis. The Golgi stress response (GSR) markers GCP60 and HSP47 were increased in RL‐treated liver cells, and knockdown of transcription factor for immunoglobulin heavy‐chain enhancer 3 of the GSR by small interfering RNA worsened RL‐induced cell death. Cotreatment of pharmacological agent H89 with RL inhibited the RL‐induced Golgi enzyme dislocation and ER stress. Moreover, the coat protein complex II (COPII) complexes that mediate ER‐to‐Golgi trafficking accumulated in the RL‐treated liver cells; this was not due to interference of RL with the initial assembly of the COPII complexes. RL also inhibited Golgi fragmentation and reassembly induced by short treatment and removal of brefeldin A. Conclusion: Our study indicates that ER‐to‐Golgi trafficking is disrupted by anti‐HIV drugs and/or alcohol, and this contributes to subsequent ER stress and hepatic injury. (Hepatology Communications 2017;1:122‐139)

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Downregulation of the small GTPase SAR1A: a key event underlying alcohol-induced Golgi fragmentation in hepatocytes

Cited by 30 publications

References 73 publications

A novel SOCS5/miR‐18/miR‐25 axis promotes tumorigenesis in liver cancer

A novel SOCS5/miR‐18/miR‐25 axis promotes tumorigenesis in liver cancer

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

Disrupted ER‐to‐Golgi trafficking underlies anti‐HIV drugs and alcohol‐induced cellular stress and hepatic injury

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