Article

A novel ASBT inhibitor, IMB17-15, repressed nonalcoholic fatty liver disease development in high-fat diet-fed Syrian golden hamsters

Authors: Mao-xu Ge1, Wei-xiao Niu1, Jin-feng Ren1, Shi-ying Cai2, Dong-ke Yu2,3, Hong-tao Liu1,4, Na Zhang1, Yi-xuan Zhang1, Yu-cheng Wang1, Rong-guang Shao1, Ju-xian Wang1, Hong-wei He1
1 NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
2 Department of Internal Medicine and Liver Center, School of Medicine, Yale University, New Haven, CT 06520, USA
3 Personalized Drug Therapy Key Laboratory of Sichuan Province, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu 610072, China
4 Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, China
Correspondence to: Ju-xian Wang: imbjxwang@163.com, Hong-wei He: hehwei@imb.pumc.edu.cn,
DOI: 10.1038/s41401-018-0195-3
Received: 31 August 2018
Accepted: 11 November 2018
Advance online: 20 December 2018

Abstract

The manipulation of bile acid (BA) homeostasis by blocking the ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) may have therapeutic effects in nonalcoholic fatty liver disease. We developed a novel ASBT inhibitor, an N-(3,4-o-dichlorophenyl) −2-(3-trifluoromethoxy) benzamide derivative referred to as IMB17–15, and investigated its therapeutic effects and the molecular mechanisms underlying the effects. Syrian golden hamsters were challenged with high-fat diet (HFD) to induce NAFLD and were subsequently administered 400 mg/kg IMB17–15 by gavage daily for 21 days. Serum, liver, and fecal samples were collected for further analysis. Plasma concentration-time profiles of IMB17–15 were also constructed. The human hepatocyte cell line HL-7702 was treated with Oleic acid (OA) with or without IMB17–15. Western blotting and real-time PCR were used to study the molecular mechanisms of IMB17–15. We found that IMB17–15 inhibited ASBT and subsequently suppressed ileal farnesoid X receptor (FXR) and FXR-activated fibroblast growth factor15/19 (FGF15/19) expression, which reduced the hepatic phosphorylated extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) levels and upregulated the cholesterol 7α-hydroxylase (CYP7A1) activity. Additionally, IMB17–15 stimulated adenosine monophosphate (AMP)-activated protein kinase (AMPKα) phosphorylation and enhanced peroxisome proliferator activated receptor α (PPARα) expression and thus promoted triglyceride (TG) oxidation and high-density lipoprotein cholesterol (HDL-c) metabolism through an ASBT-independent mechanism. In conclusion, a novel ASBT inhibitor known as IMB17–15 protected hamsters against HFD-induced NFALD by manipulating BA and lipid homeostasis. IMB17–15 also reduced lipid deposition in human hepatic cell lines, indicating that it may be useful as a therapy for NAFLD patients.
Keywords: ASBT inhibitor; NAFLD; CYP7A1; AMPKα; PPARα

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