Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice

Tanaka, Satoshi; Hikita, Hayato; Tatsumi, Tomohide; Sakamori, Ryotaro; Nozaki, Yuichi; Sakane, Sadatsugu; Shiode, Yuto; Nakabori, Tasuku; Saito, Yoshinobu; Hiramatsu, Naoki; Tabata, Keisuke; Kawabata, Tsuyoshi; Hamasaki, Maho; Eguchi, Hidetoshi; Nagano, Hiroaki; Yoshimori, Tamotsu; Takehara, Tetsuo

doi:10.1002/hep.28820

Cited by 297 publications

(246 citation statements)

References 45 publications

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“…provided evidence that the decreased expression of a specific enzyme, glycine N-methyltransferase, may result in abnormally high levels of serum methionine and S -adenosylmethionine, resulting in impaired lipophagy within a subset of NAFLD patients [104]. Conversely, an autophagy-inhibiting protein, Rubicon, exhibits slight elevation in liver samples taken from patients with NAFLD [105]. Studies performed using Rubicon-knockout mice confirmed an enhancement in levels of hepatic lipophagy, evidenced by electron micrographs demonstrating the presence of numerous double-membrane structures tightly wrapped along the LD surface.…”

Section: Lipophagy In Disease Statesmentioning

confidence: 99%

Breaking fat: The regulation and mechanisms of lipophagy

Schulze

Sathyanarayan

Mashek

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

189

115

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Lipophagy is defined as the autophagic degradation of intracellular lipid droplets (LDs). While the field of lipophagy research is relatively young, an expansion of research in this area over the past several years has greatly advanced our understanding of lipophagy. Since its original characterization in fasted liver, the contribution of lipophagy is now recognized in various organisms, cell types, metabolic states and disease models. Moreover, recent studies provide exciting new insights into the underlying mechanisms of lipophagy induction as well as the consequences of lipophagy on cell metabolism and signaling. This review summarizes recent work focusing on LDs and lipophagy as well as highlighting challenges and future directions of research as our understanding of lipophagy continues to grow and evolve.

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Section: Lipophagy In Disease Statesmentioning

confidence: 99%

Breaking fat: The regulation and mechanisms of lipophagy

Schulze

Sathyanarayan

Mashek

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

189

115

View full text Add to dashboard Cite

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“…Impairment of autophagic flux induced the accumulation of autophagosomes in palmitic acid-treated but not oleic acid-treated cells. In addition, Tanaka et al investigated the association between NASH and rubicon, a beclin 1-interacting negative regulator of autophagosome–lysosome fusion [77]. Rubicon is post-transcriptionally up-regulated by palmitic acid, suppressing the late stages of autophagy.…”

Section: Autophagy and Endoplasmic Reticulum (Er) Stress In Nashmentioning

confidence: 99%

To die or not to die: death signaling in nonalcoholic fatty liver disease

Akazawa

Nakao

2018

J Gastroenterol

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Non-alcoholic fatty liver disease (NAFLD) is an emerging liver disease worldwide. In subset of patients, NAFLD progresses to its advanced form, nonalcoholic steatohepatitis (NASH), which is accompanied with inflammation and fibrosis. Saturated free fatty acid-induced hepatocyte apoptosis is a feature of NASH. Death signaling in NASH does not always result in apoptosis, but can alternatively lead to the survival of cells presenting signs of pro-inflammatory and pro-fibrotic signals. With the current lack of established treatments for NASH, it is important to understand the molecular mechanisms responsible for disease development and progression. This review focuses on the latest findings in hepatocyte death signaling and discusses possible targets for intervention, including caspases, death receptor and c-Jun N-terminal kinase 1 signaling, oxidative stress, and endoplasmic reticulum stress, as well as epigenomic factors.

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“…Besides, Zhang et al also found that branched chain amino acids directly exacerbated hepatic lipotoxicity by inhibiting autophagy and reducing lipogenesis in the hepatocyte [51]. Tanaka et al further reported that Rubicon inhibited autophagy and accelerated hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice [52]. Taken together, these data reveal that targeting inhibition of autophagy in hepatocytes could induce lipid accumulation, impair β-oxidation, and aggravate liver injury.…”

Section: Discussionmentioning

confidence: 91%

“…Numerousstudies [34], [35], [36] in hepatocytes have shown a crucial role for autophagy in LD metabolism. In this study, we hypothesized that autophagy could play a pivotal role in LD disappearance during HSC activation.…”

Section: Resultsmentioning

confidence: 99%

Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell

et al. 2017

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Activation of hepatic stellate cells (HSCs) is a pivotal event in liver fibrosis, characterized by dramatic disappearance of lipid droplets (LDs). Although LD disappearance has long been considered one of the hallmarks of HSC activation, the underlying molecular mechanisms are largely unknown. In this study, we sought to investigate the role of autophagy in the process of LD disappearance, and to further examine the underlying mechanisms in this molecular context. We found that LD disappearance during HSC activation was associated with a coordinate increase in autophagy. Inhibition or depletion of autophagy by Atg5 siRNA impaired LD disappearance of quiescent HSCs, and also restored lipocyte phenotype of activated HSCs. In contrast, induction of autophagy by Atg5 plasmid accelerated LD loss of quiescent HSCs. Importantly, our study also identified a crucial role for reactive oxygen species (ROS) in the facilitation of autophagy activation. Antioxidants, such as glutathione and N-acetyl cysteine, significantly abrogated ROS production, and in turn, prevented autophagosome generation and autophagic flux during HSC activation. Besides, we found that HSC activation triggered Rab25 overexpression, and promoted the combination of Rab25 and PI3KCIII, which direct autophagy to recognize, wrap and degrade LDs. Down-regulation of Rab25 activity, using Rab25 siRNA, blocked the target recognition of autophagy on LDs, and inhibited LD disappearance of quiescent HSCs. Moreover, the scavenging of excessive ROS could disrupt the interaction between autophagy and Rab25, and increase intracellular lipid content. Overall, these results provide novel implications to reveal the molecular mechanism of LD disappearance during HSC activation, and also identify ROS-Rab25-dependent autophagy as a potential target for the treatment of liver fibrosis.

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Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice

Abstract: Rubicon is overexpressed and plays a pathogenic role in NAFLD by accelerating hepatocellular lipoapoptosis and lipid accumulation, as well as inhibiting autophagy. Rubicon may be a novel therapeutic target for regulating NAFLD development and progression. (Hepatology 2016;64:1994-2014).

Cited by 297 publications

References 45 publications

Breaking fat: The regulation and mechanisms of lipophagy

Breaking fat: The regulation and mechanisms of lipophagy

To die or not to die: death signaling in nonalcoholic fatty liver disease

Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell

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