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 famesoid 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.
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