Cannabinoid receptor 1 promotes hepatic lipid accumulation and lipotoxicity through the induction of SREBP-1c expression in zebrafish

Abstract

The activated cannabinoid receptor 1 (CB1R) is exclusively responsible for food intake and weight gain and regulates several pathological features associated with obesity in mammals. However, the precise role of CB1R in non-mammalian model systems is poorly understood. To investigate the functions of CB1R in zebrafish liver, we conditionally expressed CB1R proteins using a liver-specific Tet(off) transgenic system. In this study, we found hepatic lipid accumulation in CB1R transgenic zebrafish (CB) without doxycycline treatment (-Dox) and a suppression of CB1R expression, resulting in the loss of lipid accumulation in the livers of CB fish that received doxycycline treatment (+Dox). Oil Red O (ORO)-stained hepatocytes were predominant in the liver buds of CB-Dox larvae, indicating that CB1R functionally promotes lipid accumulation during CB hepatogenesis. More than 73% of CB-Dox adults showed increased lipid content, which leads, in turn, to steatosis. Liver histology and ORO staining of CB-Dox hepatocytes also indicated the accumulation of fatty droplets in the CB liver samples, consistent with the specific pathological features of liver steatosis or steatohepatitis. We also found that hepatic CB1R overexpression accompanies the stimulation of the lipogenic transcription factor SREBP-1c and its target enzymes, acetyl coenzyme-A carboxylase-1 (ACC1) and fatty acid synthase (FAS), and increases de novo fatty acid synthesis. This study is the first to report CB1R as a potential hepatic stimulator for zebrafish liver steatosis.