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Role of the mTOR-autophagy-ER stress pathway in high fructose-induced metabolic-associated fatty liver disease

Abstract

Metabolic-associated fatty liver disease (MAFLD) is the most common metabolic disease with a global prevalence of 25%. While MAFLD is serious and incurable at the later stage, it can be controlled or reversed at the early stage of hepatosteatosis originating from unhealthy diets. Recent laboratory evidence implicates a critical role of the mammalian target of rapamycin (mTOR)-autophagy signaling pathway in the pathogenesis of MAFLD induced by a high-fructose diet mimicking the overconsumption of sugar in humans. This review discusses the possible molecular mechanisms of mTOR-autophagy-endoplasmic reticulum (ER) stress in MAFLD. Based on careful analysis of recent studies, we suggest possible new therapeutic concepts or targets that can be explored for the discovery of new anti-MAFLD drugs.

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Fig. 1: Upstream regulation of mTORC1 activity and resultant downstream changes in autophagy and lipid synthesis.
Fig. 2: Regulation of autophagy on ER stress and lipid metabolism.
Fig. 3: Role of ER stress in MAFLD.
Fig. 4: Mechanism of high fructose (HFru)-induced MetS and MAFLD via the mTOR-autophagy-ER stress pathway.

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Acknowledgements

The authors would like to acknowledge Prof Li-hong Hu and Prof Hua-liang Jiang (Shanghai Institute of Materia Medica, China) for collaborative research on matrine. We would also like to thank Dr. Hao Wang (RMIT University, Australia), who significantly contributed to our initial study on the relationship among mTOR, autophagy and ER stress in high fructose-induced hepatosteatosis. This review was supported in part by the National Natural Science Foundation of China (81870608) and Jiangmen Innovation Research Team Project Fund (2018630100180019806).

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Correspondence to Ji-ming Ye.

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Wang, Yl., Zhou, X., Li, Dl. et al. Role of the mTOR-autophagy-ER stress pathway in high fructose-induced metabolic-associated fatty liver disease. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00629-0

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Keywords

  • mTOR
  • autophagy
  • ER stress
  • MAFLD
  • metabolic syndrome
  • high-fructose diet

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