AMPK activation by liquiritigenin inhibited oxidative hepatic injury and mitochondrial dysfunction induced by nutrition deprivation as mediated with induction of farnesoid X receptor
- 572 Downloads
Nutrition is indispensable for cell survival and proliferation. Thus, loss of nutrition caused by serum starvation in cells could induce formation of reactive oxygen species (ROS), resulting in cell death. Liquiritigenin (LQ) is an active flavonoid in licorice and plays a role in the liver as a hepatic protectant.
This study investigated the effect of LQ, metformin [an activator of activated AMP-activated protein kinase (AMPK)] and GW4064 [a ligand of farnesoid X receptor (FXR)] on mitochondrial dysfunction and oxidative stress induced by serum deprivation as well as its molecular mechanism, as assessed by immunoblot and flow cytometer assays.
Serum deprivation in HepG2, H4IIE and AML12 cells successfully induced oxidative stress and apoptosis, as indicated by depletion of glutathione, formation of ROS, and altered expression of apoptosis-related proteins such as procaspase-3, poly(ADP-ribose) polymerase, and Bcl-2. However, LQ pretreatment significantly blocked these pathological changes and mitochondrial dysfunction caused by serum deprivation. Moreover, LQ activated AMPK in HepG2 cells and mice liver, as shown by phosphorylation of AMPK and ACC, and this activation was mediated by its upstream kinase (i.e., LKB1). Experiments using a chemical inhibitor of AMPK with LKB1-deficient Hela cells revealed the role of the LKB1–AMPK pathway in cellular protection conferred by LQ. LQ also induced protein and mRNA expression of both FXR as well as small heterodimer partner, which is important since treatment with FXR ligand GW4064 protected hepatocytes against cell death and mitochondrial damage induced by serum deprivation.
AMPK activators such as LQ can protect hepatocytes against oxidative hepatic injury and mitochondrial dysfunction induced by serum deprivation, and the beneficial effect might be mediated through the LKB1 pathway as well as FXR induction.
KeywordsAMPK FXR Liquiritigenin Mitochondria Nutrition deprivation
AMP-activated protein kinase
Fluorescence-activated cell sorter
Farnesoid X receptor
Mitochondrial membrane permeability
Reactive oxygen species
Small heterodimer partner
This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government [MSIP] (No. 2014R1A2A2A01007375) and also supported by NRF Grant (No. 2012R1A5A2A42671316).
Compliance with ethical standards
Conflict of interest
The authors declare that we have no conflict of interests.
- 4.Zhang Q, Yang YJ, Wang H, Dong QT, Wang TJ, Qian HY, Xu H (2012) Autophagy activation: a novel mechanism of atorvastatin to protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway. Stem Cells Dev 21:1321–1332CrossRefGoogle Scholar
- 18.Imamura K, Oqura T, Kishimoto A, Kaminishi M, Esumi H (2001) Cell cycle regulation via p53 phosphorylation by a 5′-AMP activated protein kinase activator, 5-aminomidiazole-4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line. Biochem Biophys Res Commun 287:562–567CrossRefGoogle Scholar
- 37.Zhao J, Ming Y, Wan Q, Ye S, Xie S, Zhu Y, Wang Y, Zhong Z, Li L, Ye Q (2014) Gypenoside attenuates hepatic ischemia/reperfusion injury in mice via anti-oxidative and anti-apoptotic bioactivities. Exp Ther Med 7:1388–1392Google Scholar
- 52.Noh K, Kim YM, Kim YW, Kim SG (2011) Farnesoid X receptor activation by chenodeoxycholic acid induces detoxifying enzymes through AMP-activated protein kinase and extracellular signal-regulated kinase 1/2-mediated phosphorylation of CCAAT/enhancer binding protein β. Drug Metab Dispos 39:1451–1459CrossRefGoogle Scholar