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Issue 6, 2019
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Ellagic acid ameliorates AKT-driven hepatic steatosis in mice by suppressing de novo lipogenesis via the AKT/SREBP-1/FASN pathway

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Abstract

Previous studies in humans have indicated that de novo lipogenesis contributes considerably to redundant lipid storage and steatosis in the liver of patients with nonalcoholic fatty liver disease (NAFLD), and then more severe complications occur. Recently, ellagic acid (EA) has drawn attention mainly due to its biological functionalities and a series of molecular targets. However, the molecular mechanism by which EA attenuates hepatic steatosis in individuals with undesirable hepatic genetic alterations remains rarely studied. Here, we evaluate the therapeutic efficacy of EA in a hepatic steatosis mouse model featuring elevated expression of sterol regulatory element-binding protein-1 (SREBP-1) and its downstream modulators of lipogenesis by hydrodynamic injection of v-akt murine thymoma viral oncogene homolog (AKT). Hematoxylin and eosin staining, oil red O staining, immunohistochemistry, immunoblotting, and quantitative polymerase chain reaction (qPCR) were performed for mechanistic investigations. Human hepatoma cell lines were used for mechanical validation in vitro. The results suggest that EA lightens the accumulation of lipids in hepatocytes of AKT-injected mice and an oleic acid-induced in vitro hepatic steatosis model. Mechanistically, EA administration decreases the expression of phospho-AKT (Thr308) and suppresses two effectors lying downstream of the AKT/mTORC1 pathway, ribosomal protein S6 (RPS6) and SREBP-1, in the AKT-injected mice. The consequence of the EA-mediated decrease of SREBP-1 is found to be a transcriptional and translational inhibition of fatty acid synthase (FASN), accompanied by the downregulation of acetyl-CoA carboxylase (ACC). Consistent with in vivo findings, EA efficiently represses the SREBP-1/FASN axis in vitro. Collectively, our study provides a novel mechanism whereby EA alleviates AKT-triggered hepatic de novo lipogenesis, indicating that EA might serve as a potential agent in the therapy of hepatic steatosis in patients with NAFLD and/or steatosis-associated complications, especially in that characterized by activation of AKT/mTORC1 signaling in the liver.

Graphical abstract: Ellagic acid ameliorates AKT-driven hepatic steatosis in mice by suppressing de novo lipogenesis via the AKT/SREBP-1/FASN pathway

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Article information


Submitted
12 Feb 2019
Accepted
29 Apr 2019
First published
30 Apr 2019

Food Funct., 2019,10, 3410-3420
Article type
Paper

Ellagic acid ameliorates AKT-driven hepatic steatosis in mice by suppressing de novo lipogenesis via the AKT/SREBP-1/FASN pathway

C. Zhang, J. Hu, L. Sheng, M. Yuan, Y. Wu, L. Chen, G. Wang and Z. Qiu, Food Funct., 2019, 10, 3410
DOI: 10.1039/C9FO00284G

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