Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2019; 25(45): 6607-6618
Published online Dec 7, 2019. doi: 10.3748/wjg.v25.i45.6607
LB100 ameliorates nonalcoholic fatty liver disease via the AMPK/Sirt1 pathway
Xue-Yang Chen, Chang-Zhou Cai, Meng-Li Yu, Ze-Min Feng, Yu-Wei Zhang, Pei-Hao Liu, Hang Zeng, Chao-Hui Yu
Xue-Yang Chen, Chang-Zhou Cai, Meng-Li Yu, Ze-Min Feng, Yu-Wei Zhang, Pei-Hao Liu, Hang Zeng, Chao-Hui Yu, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.
Chao-Hui Yu, Clinical Research Center for Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
Author contributions: Chen XY and Cai CZ designed and performed the study, conducted the statistical analysis and wrote the paper; Yu ML, Feng ZM, Zhang YW, Liu PH and Zeng H performed the study and provided guidance during revision; Yu CH supervised the study and provided consultation during the entire study.
Institutional animal care and use committee statement: All experiments were conducted with approval of the First Affiliated Hospital of Zhejiang University Institutional Animal Care and Use Committee.
Conflict-of-interest statement: Authors have no conflicts of interest to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: Authors have read the ARRIVE guidelines and prepared and revised the manuscript according to the ARRIVE guidelines.
Open-Access: This is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Chao-Hui Yu, MD, PhD, Chief Doctor, Professor, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China.
Telephone: +86-571-87236739 Fax: +86-571-87236739
Received: October 16, 2019
Peer-review started: October 16, 2019
First decision: November 4, 2019
Revised: November 10, 2019
Accepted: November 23, 2019
Article in press: November 24, 2019
Published online: December 7, 2019
Research background

Nowadays, no pharmacological therapy is approved for nonalcoholic fatty liver disease (NAFLD). Recent studies have shown that serine/threonine protein phosphatase 2A (PP2A) is closely related to obesity and insulin resistance. LB100 is a water-soluble PP2A small molecule inhibitor. Thus, we hypothesize that LB100 can ameliorate hepatic lipid accumulation in fatty liver.

Research motivation

Increasing evidence indicates that PP2A regulates the AMPK, which is a monitor of cellular energy status. AMPK and Sirtuin 1 (Sirt1) are closely related to lipid metabolism and activate each other in a finely tuned network. However, as a first-line PP2A inhibitor, there is little data regarding the influence of LB100 on NAFLD and its underlying mechanism. Thus, studies on the potential effect of LB100 on NAFLD are urgently required.

Research objectives

To elucidate the effect and underlying mechanism of LB100 in NAFLD.

Research methods

This research was performed using C57BL/6 mice fed a high fat diet (HFD) for 16 wk and L02 cells stimulated with free fatty acids (FFAs) for 24 h to establish in vivo and in vitro models of hepatic steatosis. Mice were injected intraperitoneally with vehicle or LB100 (1.5 mg/kg, three times a week) and L02 cells were treated with LB100 (6 μmol/L) to determine the effect of LB100 on NAFLD.

Research results

LB100 significantly ameliorated HFD-induced obesity, hepatic lipid accumulation and hepatic injury in mice accompanied by activation of the AMPK/Sirt1 signaling pathway. Similar results were observed in L02 cells stimulated with FFAs. Further studies showed that the curative effect of LB100 on lipid deposition was abolished by pharmacological inhibition of AMPK in L02 cells.

Research conclusions

PP2A inhibition by LB100 significantly ameliorates hepatic steatosis by regulating hepatic lipogenesis and fatty acid oxidation via the AMPK/Sirt1 pathway.

Research perspectives

LB100 is a promising therapeutic strategy for NAFLD. Further clinical application should be considered.