Rimonabant, a Cannabinoid Receptor Type 1 Inverse Agonist, Inhibits Hepatocyte Lipogenesis by Activating Liver Kinase B1 and AMP-Activated Protein Kinase Axis Downstream of Gαi/o Inhibition

Liver X receptor-alpha (LXR alpha) and its target sterol regulatory element-binding protein-1c (SREBP-1c) play key roles in hepatic lipogenesis. Rimonabant, an inverse agonist of cannabinoid receptor type 1 (CB1), has been studied as an antiobesity drug. In view of the link between CB1 and energy metabolism, this study investigated the effect of rimonabant on LXR alpha-mediated lipogenesis in hepatocytes and the underlying basis. Rimonabant treatment inhibited CYP7A1-LXR alpha response element gene transactivation and an increase in LXR alpha mRNA level by the LXR alpha agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl) ethyl] phenyl]-benzenesulfonamide (T0901317) in HepG2 cells. Rimonabant consistently attenuated the activation of SREBP-1c and its target gene induction. The reversal by CB1 agonists on rimonabant's repression of SREBP-1c supported the role of CB1 in this effect. Rimonabant inhibited the activation of SREBP-1c presumably via G alpha(i/o) inhibition, as did pertussis toxin. Adenylyl cyclase activator forskolin or 8-bromo-cAMP treatment mimicked the action of rimonabant, suggesting that G alpha(i/o) inhibition causes repression of SREBP-1c by increasing the cAMP level. Knockdown or chemical inhibition of protein kinase A (PKA) prevented the inhibition of LXR alpha by rimonabant, supporting the fact that an increase in cAMP content and PKA activation, which catalyzes LXR alpha inhibitory phosphorylation, might be responsible for the antilipogenic effect. In addition, rimonabant activated liver kinase B1 (LKB1), resulting in the activation of AMP-activated protein kinase responsible for LXR alpha repression. Moreover, PKA inhibition prevented the activation of LKB1, supporting the fact that PKA regulates LKB1. In conclusion, rimonabant has an antilipogenic effect in hepatocytes by inhibiting LXR alpha-dependent SREBP-1c induction, as mediated by an increase in PKA activity and PKA-mediated LKB1 activation downstream of CB1-coupled G alpha(i/o) inhibition.