Metabolic dysfunction-associated
fatty liver disease (MAFLD) is a major health concern with no approved pharmacological
therapies. Molecules developed to activate the
bile acid-receptor TGR5 regulate pathways involved in MALFD pathogenesis, but the therapeutic value of TGR5 activation on the active form of MAFLD, non-
alcoholic steatohepatitis (NASH), still needs to be evaluated. As TGR5 agonism is low in MAFLD, we used strategies to promote the production of endogenous TGR5
ligands or administered pharmacological TGR5 agonists,
INT-777 and
RO5527239, to study the effect of TGR5 activation on liver and
metabolic diseases in high-fat diet-fed foz/foz mice. Although described in the literature, treatment with
fexaramine, an intestine-restricted FXR agonist, did not raise the concentrations of TGR5
ligands nor modulate TGR5 signaling and, accordingly, did not improve dysmetabolic status.
INT-777 and
RO5527239 directly activated TGR5.
INT-777 only increased the TGR5 activation capacity of the portal blood;
RO5527239 also amplified the TGR5 activation capacity of systemic blood. Both molecules improved
glucose tolerance. In spite of the TGR5 activation capacity,
INT-777, but not
RO5527239, reduced
liver disease severity. In conclusion, TGR5 activation in enterohepatic, rather than in peripheral, tissues has beneficial effects on
glucose tolerance and MAFLD.