Beta-Caryophyllene Modifies Intracellular Lipid Composition in a Cell Model of Hepatic Steatosis by Acting through CB2 and PPAR Receptors

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease; however, no specific pharmacological therapy has yet been approved for this condition. Plant-derived extracts can be an important source for the development of new drugs. The aim of this study was to investigate the effects of (E)-β-caryophyllene (BCP), a phytocannabinoid recently found to be beneficial against metabolic diseases, on HepG2 steatotic hepatocytes. Using a fluorescence-based lipid quantification assay and GC-MS analysis, we show that BCP is able to decrease lipid accumulation in steatotic conditions and to change the typical steatotic lipid profile by primarily reducing saturated fatty acids. By employing specific antagonists, we demonstrate that BCP action is mediated by multiple receptors: CB2 cannabinoid receptor, peroxisome proliferator-activated receptor α (PPARα) and γ (PPARγ). Interestingly, BCP was able to counteract the increase in CB2 and the reduction in PPARα receptor expression observed in steatotic conditions. Moreover, through immunofluorescence and confocal microscopy, we demonstrate that CB2 receptors are mainly intracellularly localized and that BCP is internalized in HepG2 cells with a maximum peak at 2 h, suggesting a direct interaction with intracellular receptors. The results obtained with BCP in normal and steatotic hepatocytes encourage future applications in the treatment of NAFLD.

The Role of Cannabidiol in Liver Disease: A Systemic Review

“…Additionally, it can decrease liver fibrosis by activating hepatic peroxisomes or inhibiting stellate cell activation [110,111]. In a recent study, a newly discovered phytocannabinoid (E)-β-caryophyllene was found to counteract the reduction of PPARα in hepatic steatosis [112].…”

Natural products in atherosclerosis therapy by targeting PPARs: a review focusing on lipid metabolism and inflammation

“…Saikosaponin D and diosgenin serve as PPARα agonists, promoting PPARα-mediated fatty acid oxidation and inhibiting CD36-mediated fatty acid uptake and SREBP-1c-mediated de novo lipogenesis ( 128 , 129 ). Oleanolic acid, a pentacyclic triterpenoid, and (E)-β-caryophyllene, a bicyclic sesquiterpene hydrocarbon, act as dual activator of PPARα and PPARγ, decreasing hyperglycemia and lipid accumulation ( 130 , 131 ). Furthermore, Saikosaponin A and ginsenoside 20(R/S)-Rg3 act as natural PPARγ activators, ameliorating hyperlipidemia and atherosclerosis ( 72 , 132 ).…”