Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent

The elucidated molecular signaling pathway by which hepatic CB1R regulates hepatic lipid homeostasis. Activation of hepatic CB1R increases p53 expression, acetylation, nuclear localization,and transcriptional activity that together promote the expression of miR-22, which in turn reduces the expression and activity of PPARα and SIRT1. These events lead to reduced fatty acid oxidation and fat accumulation in the liver (left). Treatment with AM6545, a peripherally restricted CB1R antagonist, disrupts this signaling pathway and ameliorates hepatic steatosis by also increasing hepatic OEA and PEA, which may activate PPARα directly, resulting in the enhanced efficacy of AM6545 in ameliorating hepatic steatosis (right).Image 1