Endocannabinoid Receptors Gene Expression in Morbidly Obese Women with Nonalcoholic Fatty Liver Disease

Abstract

Background. Recent reports suggest a role for the endocannabinoid system in the pathology of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the relationship between liver expression of cannabinoid (CB) receptor subtypes, CB1 and CB2, in morbidly obese (MO) women with different histological stages of NAFLD. Methods. We analysed hepatic CB1 and CB2 mRNA expression, and the expression of genes involved in lipid metabolism in 72 MO women, subclassified by liver histology into MO with normal liver (NL, n = 16), simple steatosis (SS, n = 28), and nonalcoholic steatohepatitis (NASH, n = 28) by enzyme-linked immunosorbent assay and RT-PCR. Results. We found that CB1 mRNA expression was significantly higher in NASH compared with SS and correlated negatively with PPARα. Regarding CB2, CB2 mRNA expression correlated positively with ACC1, PPARγ, IL6, TNFα, resistin, and adiponectin. Conclusions. The increased expression of CB1 in NASH and the negative correlation with PPARα suggest a deleterious role of CB1 in NAFLD. Regarding CB2, its positive correlation with the anti-inflammatory molecule adiponectin and, paradoxically, with inflammatory genes suggests that this receptor has a dual role. Taken together, our results suggest that endocannabinoid receptors might be involved in the pathogenesis of NAFLD, a finding which justifies further study.

The Endocannabinoid System: Pivotal Orchestrator of Obesity and Metabolic Disease

“…Consequently, development of insulin and leptin resistance could lead to ECS overactivity in the WAT, favoring fat accumulation. Increased ECS tone in obese animals and humans (see below) is also observed in the liver, and this is probably due to a feed-forward loop in which CB 1 R upregulation by high-fat diet is CB 1 Rdependent [65][66][67]. Activation of CB 1 Rs in hepatocytes enhances the expression of key lipogenesis markers, such as sterol regulatory element binding transcription factor 1 (SREBPF1), acetyl coenzyme-A carboxylase-1 (ACC1), and fatty acid synthase (FAS), likely through inhibition of the activity of 5 0 -AMP-activated protein kinase (AMPK), causing lipid accumulation and hepatic steatosis [68][69][70].…”

Loss of fatty acid binding protein-1 alters the hepatic endocannabinoid system response to a high-fat diet

“…Concomitant with AEA activation of CB1 inducing SREBP1-mediated transcription of lipogenic enzymes, CB1 activation decreases CPT1 (rate limiting enzyme in mitochondrial FA oxidation) and decreases FA oxidation (31,41). Conversely, the non-ARA-containing NAEs (OEA, PEA), which do not bind CB1, nevertheless enter the nucleus to activate PPAR transcription of FA oxidative genes, such as Cpt1a, Acox1, and Ppara itself (1,19,42,43).…”

Cannabinoid receptor type 2 agonist JWH-133 deteriorates the liver toxicity induced by cypermethrin

“…The effects are usually based on the antifibrogenic or antiinflammatory effect induced by CB2 expressing liver fibrogenic cells and/or hepatic immune cells (32,33,43). Auguet et al (51) reported that hepatic CB2 expression did not have significant differences between morbidly obese with normal liver, simple steatosis, or nonalcoholic steatohepatitis, and they also stated a positive correlation between liver CB2 and gene expression of adiponectin, which is an antiinflammatory factor. Authors have reported that CB2 is a molecule with a dual action.…”