Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate Nonalcoholic Steatohepatitis

Farnesoid
X receptor (FXR) has emerged as a promising therapeutic
target for nonalcoholic steatohepatitis (NASH) because of its tightly
interwoven relationship with bile acid homeostasis, inflammation,
fibrosis, and glucose and lipid metabolism. Evidence showed that intestinal
FXR antagonism exhibited remarkable metabolic improvements in mice.
Herein, we developed a series of betulinic acid derivatives as potent
intestinal FXR antagonists, and F6 was identified as
the most potent one with an IC50 at 2.1 μM. F6 selectively inhibited intestinal FXR signaling and ameliorated
the hepatic steatosis, inflammation, and fibrosis in Gubra-amylin
NASH (GAN) and high-fat with methionine and choline deficiency (HFMCD)
diet-induced NASH models. The beneficial effects were achieved by
direct antagonism of intestinal FXR and feedback activation of hepatic
FXR, thereby decreasing ceramides and repressing inflammasome activation
in the liver. Collectively, our work substantially supports F6 as a promising drug candidate against NASH and demonstrates
that antagonism of intestinal FXR signaling is a practical strategy
for treating metabolic diseases.