Hepatic autophagy fluctuates during the development of non-alcoholic fatty liver disease
Autor: | Yujen Tseng, Ge Ge, Jie Liu, Jun Zhang, Hao Ding, Yan-Yun Ma |
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Rok vydání: | 2020 |
Předmět: |
Male
Steatosis Time Factors Palmitic Acid Specialties of internal medicine Autophagy-Related Proteins mTORC1 Mechanistic Target of Rapamycin Complex 1 Diet High-Fat Mice 03 medical and health sciences Methionine 0302 clinical medicine Non-alcoholic Fatty Liver Disease In vivo Fatty liver Autophagy medicine Animals Humans Sirolimus Hepatology business.industry Hep G2 Cells General Medicine medicine.disease Hedgehog signaling pathway Choline Deficiency Disease Models Animal RC581-951 Liver 030220 oncology & carcinogenesis Hepatocytes Cancer research 030211 gastroenterology & hepatology business Flux (metabolism) Intracellular Signal Transduction |
Zdroj: | Annals of Hepatology, Vol 19, Iss 5, Pp 516-522 (2020) |
ISSN: | 1665-2681 |
Popis: | Introduction and objectives Autophagy has emerged as a critical regulatory pathway in non-alcoholic fatty liver disease (NAFLD). However, the variability of hepatic autophagy during NAFLD development remains controversial. This study aimed to elucidate the dynamics of hepatic autophagy and its underlying mechanism during NAFLD development both in vivo and in vitro. Materials and methods Autophagy markers were evaluated in the livers of mice fed a high fat diet or a methionine-choline-deficient diet and in HepG2 cells treated with palmitic acid (PA) by western blotting. Intrahepatic and intracellular triacylglycerol levels were assessed using biochemical quantification and lipid staining. Autophagic flux was monitored using an LC3 turnover assay and tandem mRFP-GFP-LC3 fluorescence analysis. Results Hepatic autophagy was enhanced in early stages but blocked at later stages of NAFLD development both in vivo and in vitro. Analysis of autophagic flux revealed that both autophagic synthesis and degradation were initially activated and progressively inhibited afterwards. The activation of mammalian target of rapamycin complex 1 (mTORC1), a central regulator of autophagy, was found to be negatively correlated with autophagic synthesis; moreover, pharmacological inhibition of mTORC1 by rapamycin alleviated hepatic steatosis through recovery of autophagic flux in hepatocytes with prolonged PA treatment. Conclusions Hepatic autophagy fluctuates during the development of NAFLD in which mTORC1 signalling plays a critical regulatory role, suggesting a therapeutic potential of autophagy modulation by targeting the mTORC1 signalling pathway in NAFLD. |
Databáze: | OpenAIRE |
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