Fig. 9.

IMB17–15 has two pharmacological effects on NAFLD. First, IMB17–15 inhibits ASBT and subsequently suppresses ileal FXR and FXR-activated FGF15/19 expression, changes that reduce ERK and JNK phosphorylation in the liver and upregulate CYP7A1 activity. CYP7A1 is the key enzyme in BA biosynthesis, and its stimulation accelerates the transformation of cholesterol into BAs and leads to the inhibition of the inflammatory response. Second, IMB17–15 stimulates the phosphorylation of AMPKα and enhances the expression of PPARα and thus promotes TG oxidation and HDL metabolism through an ASBT-independent mechanism. The potent anti-NAFLD activity of IMB17–15 is attributable to these two synergistic effects. AMPKα adenosine monophosphate (AMP)-activated protein kinase, ASBT/SLC10A2 apical Na+-dependent bile salt transporter, BA bile acid, CYP7A1 cholesterol 7α-hydroxylase, ERK extracellular regulated protein kinases, FGF fibroblast growth factor, FXR farnesoid X receptor, HDL-c high density lipoprotein cholesterol, JNK c-Jun N-terminal kinase, NAFLD Nonalcoholic fatty liver disease, PPARα peroxisome proliferator activated receptor α, TG triglyceride