Cannabinoids Receptors in Liver: Diet and Physiopathology

Cannabis Sativa has been used for its psychoactive and medicinal properties for millennia. However, knowledge into its mechanism of action has only emerged the last decades. It was first demonstrated that brain had specific binding sites for ∆9-tetrahidrocannabinol (∆9-THC; the psychoactive compound of cannabis) named type 1-cannabinoid receptors (CB1R) and then cloned [1,2]. Discovery of CB1R, stimulated research to find its endogenous ligand (s). Arachidonoylethanolamide (Anandamide, AEA) a compound discovered and isolated from porcine brain was able to specifically bind CB1R and had a ∆9-THC-like behavior in selected bioassays [3]. This important finding led to the endocannabinoids (ECs) research era, with extensive research activity during the last 25 years. Subsequently, type 2 cannabinoid receptors (CB2R) were then cloned [4,5], and other lipid molecule, 2-arachidonoylglycerol (2-AG), was proposed to be its physiological agonist [6]. At present, some others molecules are considered ECs such as Homo-γ-linoleylethanolamide and docosatetraenoylethanolamide, but most of research in this area has been carried out with AEA or its synthetic agonists, and 2-AG. At present, AEA is considered the ligand for CB1R and less selective for CB2R, while 2-AG binds with almost same affinity to CB1R and CB2R [7]. Anandamide and 2-AG derive from membrane phospholipids and are biosynthesized through different pathways [8,9]. Enzymes able to hydrolyze AEA (fatty acid amido hydrolase, FAAH) and 2-AG (monoacylglicerol lipase, MAGL) are becoming very important by their ability to modulate availability of endocannabinoids to exert their endocrine/paracrine actions [10]. Type 1 and 2 cannabinoid/endocannabinoid receptors are G-protein coupled receptors sensitive to pertussis toxin (Gi/o). Classical signaling mechanisms involve modulation of cAMP levels, intracellular free calcium concentration by internal ion Abstract