Bouchardatine analogue alleviates non‐alcoholic hepatic fatty liver disease/non‐alcoholic steatohepatitis in high‐fat fed mice by inhibiting ATP synthase activity

Rao, Y, Lu, Y, Li, C and Ye, J., et al, 2019, 'Bouchardatine analogue alleviates non‐alcoholic hepatic fatty liver disease/non‐alcoholic steatohepatitis in high‐fat fed mice by inhibiting ATP synthase activity', British Journal of Pharmacology, vol. 176, pp. 2877-2893.


Document type: Journal Article
Collection: Journal Articles

Title Bouchardatine analogue alleviates non‐alcoholic hepatic fatty liver disease/non‐alcoholic steatohepatitis in high‐fat fed mice by inhibiting ATP synthase activity
Author(s) Rao, Y
Lu, Y
Li, C
Ye, J., et al,
Year 2019
Journal name British Journal of Pharmacology
Volume number 176
Start page 2877
End page 2893
Total pages 17
Publisher John Wiley & Sons
Abstract Background and Purpose Non‐alcoholic hepatic fatty liver disease (NAFLD) is a manifestation of the metabolic syndrome in the liver and non‐alcoholic steatohepatitis (NASH) represents its advanced stage. R17 derived from bouchardatine, shows benefits in the metabolic syndrome, but has not been tested in the liver. The present study examined the pharmacological effects of R17 in a model of NAFLD/NASH and its mode of action. Experimental Approach The effects of R17 were examined in mice fed a high‐fat (HF) diet to induce the pathological characteristics of NAFLD/NASH and in cultures of HuH7 cells. We used histological and immunohistochemical techniques along with western blotting and siRNA. Generation of ROS and apoptosis were measured. Key Results Administration of R17 (20 mg·kg−1, i.p. every other day) for 5 weeks reversed HF‐induced hepatic triglyceride content, inflammation (inflammatory cytokines and macrophage numbers), injury (hepatocyte ballooning and apoptosis, plasma levels of alanine aminotransferase and aspartate aminotransferase), and fibrogenesis (collagen deposition and mRNA expression of fibrosis markers). In cultured cells, R17 reduced cell steatosis from both lipogenesis and fatty acid influx. The attenuated inflammation and cell injury were associated with inhibition of both endoplasmic reticulum (ER) stress and oxidative stress. Notably, R17 activated the liver kinase B1‐AMP‐activated protein kinase (AMPK) pathway by inhibiting activity of ATP synthase, rather than direct stimulation of AMPK. Conclusion and Implications R17 has therapeutic potential for NAFLD/NASH. Its mode of action involves the elimination of ER and oxidative stresses, possibly via activating the LKB1‐AMPK axis by inhibiting the activity of ATP synthase.
Subject Pharmacology and Pharmaceutical Sciences not elsewhere classified
Endocrinology
Keyword(s) Endoplasmic-Reticulum Stress
Insulin-Resistance
Oxidative Stress
Concise Guide
AMPK
Pharmacology
Kinase
Pathogenesis
Lipogenesis
Macrophage
DOI - identifier 10.1111/bph.14713
Copyright notice © 2019 The British Pharmacological Society
ISSN 1476-5381
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