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

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A novel ASBT inhibitor, IMB17-15, repressed nonalcoholic fatty liver disease development in high-fat diet-fed Syrian golden hamsters.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-12-20 , DOI: 10.1038/s41401-018-0195-3
Mao-Xu Ge ₁ , Wei-Xiao Niu ₁ , Jin-Feng Ren ₁ , Shi-Ying Cai ₂ , Dong-Ke Yu _{2,

3} , Hong-Tao Liu _{1,

4} , Na Zhang ₁ , Yi-Xuan Zhang ₁ , Yu-Cheng Wang ₁ , Rong-Guang Shao ₁ , Ju-Xian Wang ₁ , Hong-Wei He ₁

Affiliation

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.

中文翻译：

一种新型 ASBT 抑制剂 IMB17-15 抑制了高脂饮食喂养的叙利亚金仓鼠的非酒精性脂肪肝疾病的发展。

通过阻断回肠顶端 Na+ 依赖性胆汁盐转运蛋白 (ASBT/SLC10A2) 来操纵胆汁酸 (BA) 稳态可能对非酒精性脂肪肝有治疗作用。我们开发了一种新型 ASBT 抑制剂，一种 N-(3,4-o-二氯苯基)-2-(3-三氟甲氧基) 苯甲酰胺衍生物，称为 IMB17-15，并研究了其治疗效果和作用背后的分子机制。叙利亚金仓鼠受到高脂肪饮食 (HFD) 的挑战以诱导 NAFLD，随后每天通过管饲法给予 400 mg/kg IMB17-15，持续 21 天。收集血清、肝脏和粪便样本用于进一步分析。还构建了 IMB17-15 的血浆浓度-时间曲线。人肝细胞系 HL-7702 用油酸 (OA) 处理，有或没有 IMB17-15。使用蛋白质印迹和实时 PCR 来研究 IMB17-15 的分子机制。我们发现 IMB17-15 抑制 ASBT，随后抑制回肠法尼醇 X 受体 (FXR) 和 FXR 激活的成纤维细胞生长因子 15/19 (FGF15/19) 表达，从而降低肝磷酸化细胞外调节蛋白激酶 (ERK) 和 c-Jun N-末端激酶 (JNK) 水平并上调胆固醇 7α-羟化酶 (CYP7A1) 活性。此外，IMB17-15 刺激一磷酸腺苷 (AMP) 激活的蛋白激酶 (AMPKα) 磷酸化并增强过氧化物酶体增殖物激活受体α (PPARα) 的表达，从而促进甘油三酯 (TG) 氧化和高密度脂蛋白胆固醇 (HDL-c) 代谢通过独立于 ASBT 的机制。综上所述，一种称为 IMB17-15 的新型 ASBT 抑制剂通过操纵 BA 和脂质稳态保护仓鼠免受 HFD 诱导的 NFALD。IMB17-15 还减少了人肝细胞系中的脂质沉积，表明它可用于治疗 NAFLD 患者。

更新日期：2019-05-16

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