Original articles
Jiyu Zhou, Ningning Huang, Yitong Guo, Shuang Cui, Chaoliang Ge, Qingxian He, Xiaojie Pan, Guangji Wang, Hong Wang, Haiping Hao. Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis[J]. Acta Pharmaceutica Sinica B, 2019, 9(3): 526-536

Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis
Jiyu Zhoua, Ningning Huanga, Yitong Guoa, Shuang Cuia, Chaoliang Gea,b, Qingxian Hea, Xiaojie Pana, Guangji Wanga, Hong Wanga, Haiping Haoa
a State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China;
b First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
Abstract:
Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl4-injured mice, D-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNFα (CHX/TNFα)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.
Key words:    Obeticholic acid    Liver fibrosis    Bile acid    Hepatocellular apoptosis    IDN-6556    Farnesoid X receptor    Hepatic stellate cell   
Received: 2018-08-25     Revised:
DOI: 10.1016/j.apsb.2018.11.004
Funds: This research was supported by National Natural Science Foundation of China (grants 81430091, 81720108032, 81421005, 91429308 and 81603194); the Project for Major New Drug Innovation and Development (grant 2015ZX09501010 and 2017ZX09101003-002-003, China); and Overseas Expertise Introduction Project for Discipline Innovation (G20582017001, China); "Double First Class" Initiative Project (CPU2018GF01 and CPU2018GF09, China); State Key Laboratory of Natural Medicines at China Pharmaceutical University (SKLNMZZCX201610 and SKLNMZZCX201801, China) and China Postdoctoral Science Foundation (grants 2016M600455 and 2017T100423).
Corresponding author: Guangji Wang, Hong Wang, Haiping Hao     Email:gjwang@cpu.edu.cn;wanghong@cpu.edu.cn;haipinghao@cpu.edu.cn
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Jiyu Zhou
Ningning Huang
Yitong Guo
Shuang Cui
Chaoliang Ge
Qingxian He
Xiaojie Pan
Guangji Wang
Hong Wang
Haiping Hao

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