Published online Dec 7, 2019. doi: 10.3748/wjg.v25.i45.6607
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
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.
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.
To elucidate the effect and underlying mechanism of LB100 in NAFLD.
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.
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.
PP2A inhibition by LB100 significantly ameliorates hepatic steatosis by regulating hepatic lipogenesis and fatty acid oxidation via the AMPK/Sirt1 pathway.
LB100 is a promising therapeutic strategy for NAFLD. Further clinical application should be considered.