European Journal of Nutrition

, Volume 56, Issue 2, pp 635–647 | Cite as

AMPK activation by liquiritigenin inhibited oxidative hepatic injury and mitochondrial dysfunction induced by nutrition deprivation as mediated with induction of farnesoid X receptor

  • Eun Hye Jung
  • Ju-Hee Lee
  • Sang Chan Kim
  • Young Woo Kim
Original Contribution

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

AMPK FXR Liquiritigenin Mitochondria Nutrition deprivation 

Abbreviations

ACC

Acetyl-CoA carboxylase

AMPK

AMP-activated protein kinase

FACS

Fluorescence-activated cell sorter

FXR

Farnesoid X receptor

GSH

Glutathione

H2DCFH-DA

2′,7′-Dihydrodichlorofluorescein diacetate

LQ

Liquiritigenin

MMP

Mitochondrial membrane permeability

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide

PARP

Poly(ADP-ribose) polymerase

Rh123

Rhodamine 123

ROS

Reactive oxygen species

SD

Serum deprivation

SHP

Small heterodimer partner

Notes

Acknowledgments

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.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Eun Hye Jung
    • 1
  • Ju-Hee Lee
    • 1
    • 2
  • Sang Chan Kim
    • 1
  • Young Woo Kim
    • 1
  1. 1.Department of Herbal Formula, Medical Research Center (MRC-GHF), College of Oriental MedicineDaegu Haany UniversityGyeongsanKorea
  2. 2.College of Oriental MedicineDongguk UniversityGyeongjuKorea

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