Fig 7. Schematic representation of the effect of BAR501 on LSEC in models of LSEC dysfunction.
CCl4 and methionine feeding alter liver sinusoidal cell function. In these settings LSEC express high levels of endothelin 1 (ET-1) along with reduces eNOS activity due to enhanced binding of eNOS with caveolin-1, and reduced expression of CSE, a H2S-generating enzyme. Activation of GPBAR1 by BAR501, increases CSE expression by CRE-mediated activity, and causes both eNOS and CSE phosphorylation by AKT-mediated mechanism. In addition, AKT-driven phosphorylation of FOXOA1, attenuates ET-1 production. However since eNOS is bound to caveolin 1 the generation of nitrite/nitrate do not increase. Thus, activation of GPBAR1 in CCl4-treated mice, leads to eNOS-independent reduction of intravascular resistance, that is mostly mediated by inhibition of ET-1 and increased release of H2S.