Abstract
BackgroundEvidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile.MethodsPost hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD).ResultsTreatment with rimonabant for 12 weeks reduced both ALT and weight (p < 0.01), and there was a negative correlation between Δ ALT and Δ HOMA-IR (p < 0.001), but not between Δ ALT and Δ weight. There was a significant reduction of weight with orlistat (p < 0.01); however, orlistat, metformin and pioglitazone had no effect on ALT. The free androgen index fell in all groups (p < 0.05). The inflammatory marker hs-CRP was reduced by pioglitazone (p < 0.001) alone and did not correlate with changes in ALT. The inflammatory cytokine profile for IL-1β, IL-6, IL-7, IL-10, IL12, TNF-α, MCP-1 and INF-γ did not differ between groups. None of the interventions had an effect on biological variability of ALT.ConclusionRimonabant through CB1 receptor blockade decreased serum ALT that was independent of weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD.Trial registrationISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).
Highlights
Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial
The patients were weight matched in each group (Table 1) and no patient had a fatty liver on ultrasound or a positive HAIR score
No patient suffered any neuropsychatric symptoms during rimonabant therapy. These data show that rimonabant reduced the Alanine aminotransferase (ALT) of obese Polycystic ovary syndrome (PCOS) women while orlistat led to a significant weight reduction, there was no corresponding fall in ALT suggesting that the effect of rimonabant on ALT was independent of the weight loss effect, and this change in ALT correlated with a reduction in insulin resistance
Summary
Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile. It has been recently shown through in vitro and animal studies that the cannabinoid receptor 1 (CB-1) contributes to liver injury, inflammation and may be involved in the initiation of hepatocellular carcinoma through endocannabinoid system activation [1, 2]. Metformin reduces insulin resistance in PCOS [8] and has been shown to have some benefit in NAFLD [9]. Medications causing weight loss (orlistat and rimonabant) have been effective treatments in PCOS [10, 12] and orlistat has shown to improve features of NAFLD [13]
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