AMP-activated protein kinase activator, HL156A reduces thioacetamide-induced liver fibrosis in mice and inhibits the activation of cultured hepatic stellate cells and macrophages

Lee,Hye  Shin; Shin,Hyun-Sang; Choi,Jinhyeok; Bae,Sung-Jin; Wee,Hee-Jun; Son,Taekwon; Seo,Ji  Hae; Park,Ji-Hyeon; Kim,Sung-Wuk; Kim,Kyu-Won

doi:10.3892/ijo.2016.3627

AMP-activated protein kinase activator, HL156A reduces thioacetamide-induced liver fibrosis in mice and inhibits the activation of cultured hepatic stellate cells and macrophages

Authors:
- Hye Shin Lee
- Hyun-Sang Shin
- Jinhyeok Choi
- Sung-Jin Bae
- Hee-Jun Wee
- Taekwon Son
- Ji Hae Seo
- Ji-Hyeon Park
- Sung-Wuk Kim
- Kyu-Won Kim
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Affiliations: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea, Hanall Biopharma Co. Ltd., Seoul 16170, Republic of Korea
Published online on: July 21, 2016 https://doi.org/10.3892/ijo.2016.3627
Pages: 1407-1414

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Abstract

Cirrhosis, the end-stage of hepatic fibrosis, is not only life-threatening by itself, but also a causative factor of liver cancer. Despite efforts to develop treatment for liver fibrosis, there are no approved agents as anti-fibrotic drugs to date. In the present study, we aimed to investigate the anti-fibrotic effect of the AMP-activated protein kinase (AMPK) activator, HL156A. A mouse model of thioacetamide (TAA)-induced liver fibrosis was used to examine the effect of HL156A in vivo. Mice received either TAA alone or a combination of TAA and HL156A intraperitoneally for a total duration of 6 weeks. Including HL156A during exposure to TAA significantly reduced extracellular matrix (ECM) deposition and production of the hepatic transforming growth factor-β1 (TGF-β1). Immunohistochemical analysis revealed that the activation of hepatic stellate cells and the capillarization of liver sinusoids were also diminished significantly by HL156A co-treatment. The anti-fibrotic effect of HL156A was further studied in vitro by using a rat hepatic stellate cell line, HSC-T6 cells. The induction of α-smooth muscle actin (α-SMA) by TGF-β1 treatment was reversed by HL156A, which was likely via the activation of AMPK. Moreover, HL156A showed anti-inflammatory effects on macrophages. Treatment with HL156A diminished LPS-induced activation of both Raw264.7 macrophage cells and primary cultured mouse macrophages. Taken together, these results imply that the AMPK activator HL156A inhibits hepatic fibrosis via multiple mechanisms and could be a potentially effective agent for fibrosis treatment.

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