O-1602 Promotes Hepatic Steatosis through GPR55 and PI3 Kinase/Akt/SREBP-1c Signaling in Mice

Abstract

Non-alcoholic fatty liver disease is recognized as the leading cause of chronic liver disease. Overnutrition and obesity are associated with hepatic steatosis. G protein-coupled receptor 55 (GPR55) has not been extensively studied in hepatic steatosis, although its endogenous ligands have been implicated in liver disease progression. Therefore, the functions of GPR55 were investigated in Hep3B human hepatoma cells and mice fed high-fat diets. O-1602, the most potent agonist of GPR55, induced lipid accumulation in hepatocytes, which was reversed by treatment with CID16020046, an antagonist of GPR55. O-1602 also induced intracellular calcium rise in Hep3B cells in a GPR55-independent manner. O-1602-induced lipid accumulation was dependent on the PI3 kinase/Akt/SREBP-1c signaling cascade. Furthermore, we found increased levels of lysophosphatidylinositol species of 16:0, 18:0, 18:1, 18:2, 20:1, and 20:2 in the livers of mice fed a high-fat diet for 4 weeks. One-week treatment with CID16020046 suppressed high-fat diet-induced lipid accumulation and O-1602-induced increase of serum triglyceride levels in vivo. Therefore, the present data suggest the pro-steatotic function of GPR55 signaling in hepatocytes and provide a potential therapeutic target for non-alcoholic fatty liver disease.

GPR55 antagonist CID16020046 protects against atherosclerosis development in mice by inhibiting monocyte adhesion and Mac-1 expression

“…We used a two-fold higher dose than the study of Montecucco et al (1 mg/kg vs 0.5 mg/kg) and used HFD instead of high-cholesterol diets (Montecucco et al, 2016). Therefore, a dose of 1 mg/kg seems to be optimal to achieve efficacy in vivo , which has recently been supported in an HFD-induced fatty liver model (Kang, Lee, Park, Liu & Im, 2021). In addition, highcholesterol diets were inadequate to activate GPR55, because lysophosphoinositols, the endogenous ligands of GPR55, are provided in HFD but not in high-cholesterol diets (Im, 2021;Kang, Lee, Park, Liu & Im, 2021).…”

“…This may be due to the blockage of GPR55 in hepatocytes and adipocytes. Indeed, CID16020046 suppressed HFD-induced hepatic steatosis in mice, suggesting that increased lysophosphatidylinositols may be a cause of hepatic steatosis in overnutrition conditions (Kang, Lee, Park, Liu & Im, 2021). In fact, serum levels of lysophosphatidylinositol species of 16:0, 18:1, and 18:1 isomers were found to be high in patients with non-alcoholic steatohepatitis (Fondevila et al, 2021).…”

GPR55 Antagonist CID16020046 Protects against Atherosclerosis Development in Mice by Inhibiting Monocyte Adhesion and Mac-1 Expression

“…We used a two-fold higher dose than the study of Montecucco et al (1 mg/kg vs. 0.5 mg/kg) and used an HFD instead of high-cholesterol diets [ 24 ]. Therefore, a dose of 1 mg/kg seems to be optimal to achieve efficacy in vivo, which has recently been supported in an HFD-induced fatty liver model [ 25 ]. In addition, high-cholesterol diets were inadequate to activate GPR55, because lysophosphoinositols, the endogenous ligands of GPR55, are provided in an HFD but not in high-cholesterol diets [ 25 , 26 ].…”

“…Therefore, a dose of 1 mg/kg seems to be optimal to achieve efficacy in vivo, which has recently been supported in an HFD-induced fatty liver model [ 25 ]. In addition, high-cholesterol diets were inadequate to activate GPR55, because lysophosphoinositols, the endogenous ligands of GPR55, are provided in an HFD but not in high-cholesterol diets [ 25 , 26 ]. Especially, levels of lysophosphatidylinositols of 18:0, 18:1, 18:2, and 18:3 were significantly increased in the liver after HFD feeding [ 25 ].…”

“…In addition, high-cholesterol diets were inadequate to activate GPR55, because lysophosphoinositols, the endogenous ligands of GPR55, are provided in an HFD but not in high-cholesterol diets [ 25 , 26 ]. Especially, levels of lysophosphatidylinositols of 18:0, 18:1, 18:2, and 18:3 were significantly increased in the liver after HFD feeding [ 25 ]. Additionally, an HFD may provide other lipid agonists of GPR55, such as oleoylethanolamide and lysophosphatidylcholines [ 26 , 27 , 28 , 29 ].…”