Autophagy regulates lipid metabolism through selective turnover of NCoR1

Saito, Tetsuya; Kuma, Akiko; Sugiura, Yuki; Ichimura, Yoshinobu; Obata, Miki; Kitamura, Hiroshi; Okuda, Shujiro; Lee, Hyeon-Cheol; Ikeda, Kazutaka; Kanegae, Yumi; Saito, Izumu; Auwerx, Johan; Motohashi, Hozumi; Suematsu, Makoto; Soga, Tomoyoshi; Yokomizo, Takehiko; Waguri, Satoshi; Mizushima, Noboru; Komatsu, Masaaki

doi:10.1038/s41467-019-08829-3

Cited by 148 publications

(103 citation statements)

References 69 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is controversy over the causality between autophagy and lipid storage. While some studies have shown an increase in lipid storage and triglyceride content in lipid droplets due to a lack of autophagy, 19,37,38 others have shown the opposite 22,39,40 . Impaired lipid droplet formation is considered to be a causative mechanism responsible for poor hepatic regeneration and hepatocyte hypoproliferation after liver injury.…”

Section: Discussionmentioning

confidence: 99%

Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury

Römermann

Ansari

Schultz‐Moreira

et al. 2020

Liver International

View full text Add to dashboard Cite

Background and aims Autophagy is a critical process in cell survival and the maintenance of homeostasis. However, the implementation of therapeutic approaches based on autophagy mechanisms after liver damage is still challenging. Methods We used a hepatospecific Atg7‐deficient murine model to address this question. Results We showed that the proliferation and regeneration capacity of Atg7‐deficient hepatocytes was impaired. On the one hand, Atg7‐deficient hepatocytes showed steady‐state hyperproliferation. On the other hand, external triggers such as partial hepatectomy (PHx) or cell transplantation did not induce hepatocellular proliferation or liver repopulation. After PHx, hepatocyte proliferation was strongly decreased, accompanied by high mortality. This increase in mortality could be overcome by pharmacological mTOR inhibition. In accordance with hepatocyte hypoproliferation after damage, Atg7‐deficient hepatocytes failed to repopulate the liver in a hepatic injury model. Atg7‐deficient mice showed hepatic hypertrophy, transient cellular hypertrophy, and high transaminase levels followed by strong perisinusoidal/pericellular fibrosis with age. Their elevated modified hepatic activity index (mHAI) was almost exclusively due to apoptosis without any inflammation. These parameters were associated with variations in the triglyceride content and compromised lipid droplet formation after PHx. Mechanistically, we also observed a modulation of HGF, PAK4, NOTCH3 and YES1, which are proteins involved in cell cycle regulation. Conclusion We demonstrated the important role of autophagy in the regeneration capacity of hepatocytes. We showed the causative relationship between autophagy and triglycerides that is essential for promoting liver recovery. Finally, pharmacological mTOR inhibition overcame the impact of autophagy deficiency after liver damage and prevented mortality.

show abstract

Section: Discussionmentioning

confidence: 99%

Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury

Römermann

Ansari

Schultz‐Moreira

et al. 2020

Liver International

View full text Add to dashboard Cite

show abstract

“…This study retrospectively analysed confirmed COVID-19 from Jan 12 2020, to Feb 13 2020 at Tongji Hospital of Huazhong University of Science and Technology in Wuhan, China. All patients enrolled in this study were diagnosed as COVID-19 according to WHO interim guidance [11]. Patients with missing data on clinical characteristics were excluded.…”

Section: Study Populationmentioning

confidence: 99%

Association of the insulin resistance marker TyG index with the severity and mortality of COVID-19

Ren

Yang

Wang

et al. 2020

Cardiovasc Diabetol

133

103

View full text Add to dashboard Cite

Background: The triglyceride and glucose index (TyG) has been proposed as a marker of insulin resistance. This study aims to evaluate the association of the TyG index with the severity and mortality of coronavirus disease 2019 . Methods:The study included a cohort of 151 patients with COVID-19 admitted in a tertiary teaching hospital in Wuhan. Regression models were used to investigate the association between TyG with severity and mortality of COVID-19.Results: In this cohort, 39 (25.8%) patients had diabetes, 62 (41.1%) patients were severe cases, while 33 (22.0%) patients died in hospital. The TyG index levels were significantly higher in the severe cases and death group (mild vs. severe 8.7 ± 0.6 vs. 9.2 ± 0.6, P < 0.001; survivor vs. deceased 8.8 ± 0.6 vs. 9.3 ± 0.7, P < 0.001), respectively. The TyG index was significantly associated with an increased risk of severe case and mortality, after controlling for potential confounders (OR for severe case, 2.9, 95% CI 1.2-6.3, P = 0.007; OR for mortality, 2.9, 95% CI 1.2-6.7, P = 0.016). The associations were not statistically significant for further adjustment of inflammatory factors. Conclusion:TyG index was closely associated with the severity and morbidity in COVID-19 patients, thus it may be a valuable marker for identifying poor outcome of COVID-19.

show abstract

“…By making available different sources of energy and by directly controlling mitochondria homeostasis through selective removal of mitochondria (see below), autophagy is unquestionably a central player in tumor metabolism (36). Indeed, recent evidence demonstrated a tight interplay between autophagy and lipid metabolism, proposing autophagy as a mechanism regulating both β-oxidation and production of ketone bodies (63).…”

Section: Autophagy As Metabolic Pathway: Cell-autonomous Autophagymentioning

confidence: 99%

The Complex Role of Autophagy in Melanoma Evolution: New Perspectives From Mouse Models

2020

View full text Add to dashboard Cite

Despite tremendous efforts in the last decade to improve treatments, melanoma still represents a major therapeutic challenge and overall survival of patients remains poor. Therefore, identifying new targets to counteract melanoma is needed. In this scenario, autophagy, the "self-eating" process of the cell, has recently arisen as new potential candidate in melanoma. Alongside its role as a recycling mechanism for dysfunctional and damaged cell components, autophagy also clearly sits at a crossroad with metabolism, thereby orchestrating cell proliferation, bioenergetics and metabolic rewiring, all hallmarks of cancer cells. In this regard, autophagy, both in tumor and host, has been flagged as an essential player in melanomagenesis and progression. To pave the way to a better understanding of such a complex interplay, the use of genetically engineered mouse models (GEMMs), as well as syngeneic mouse models, has been undoubtedly crucial. Herein, we will explore the latest discoveries in the field, with particular focus on the potential of these models in unraveling the contribution of autophagy in melanoma, along with the therapeutic advantages that may arise.

show abstract

Autophagy regulates lipid metabolism through selective turnover of NCoR1

Cited by 148 publications

References 69 publications

Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury

Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury

Association of the insulin resistance marker TyG index with the severity and mortality of COVID-19

The Complex Role of Autophagy in Melanoma Evolution: New Perspectives From Mouse Models

Contact Info

Product

Resources

About