1249 NAFLD AND CVD: MAY A SUFFERING LIVER BE USEFUL TO PREDICT CARDIOVASCULAR RISK?

Abstract

Background and Aim: Evidence from clinical and laboratory studies have accumulated indicating that the activation of the cannabinoid system is crucial for non-alcoholic fatty liver disease. However, the association between hepatic cannabinoid receptor with mitochondria function has not been well investigated in obesity-induced fatty liver. In this study, we examined the role of a cannabinoid receptor (CBR) and the lipid accumulation in primary hepatocytes and for it’s ability to modulate pathways implicated in obese mice that develop hyperglycemia and fatty livers. Methods and Results: We challenged hepatocytes with high concentrations of a mixture of oleate and palmitate (HFFA) as a model of hepatic lipogenesis and impairment of mitochondria function. Both cannabinoid receptor-1 antagonist AM251 and silencing of the CB1R gene prevented HFFA-stimulated change in intracellular triglyceride levels, the generation of ROS, and mitochondria membrane potential (MMP). On the other hand, AM251 suppression of steatosis was reflected by a lowering in liver triglyceride contents as compared with obese (ob/ob) controls. In addition, AM251 simultaneously decreased hepatic fatty acid synthesis (SREBP-1c, FAS) and increased b-oxidation (CPT-1, CPT-2) genes expression of ob/ob mice. Reduction of SREBP-1 protein level in livers of ob/ob mice by AM251 treatment modestly improves fat drop deposition. This was accompanied by a marked reversal in the expression of mitochondria biogenesis-related factors (PGC1a and NRF1 and 2) as reflected by the elevated expression of mitochondrial complex I and ATP levels. Conclusions: These data suggest that up-regulated CB1-mediated signaling by increasing SREBP-1 proteins, leading to up-regulation of fatty acid synthesis expression and increased oxidative stress in liver. Thus, AM251 may play a modulate role in pathogenesis of the hepatic steatosis and suggest that CB1R antagonist has potential clinical applications in obesity-induced hepatic lipogenesis and that should be explored.