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.

Cannabinoid receptor signaling regulates liver development and metabolism

“…Srebfs promote fatty acid and cholesterol uptake and synthesis and can act downstream of EC signaling in the liver, with levels that can be regulated in zebrafish and mice by administration of the EC anandamide (Migliarini and Carnevali, 2008;Pai et al, 2013). In mice, modulation of dietary methionine can alter Srebf expression by feedback induction (Aissa et al, 2014).…”

Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis

“…A role for the cannabinoid receptor CB1 in obesity and energy homeostasis has been established in relation to food intake and energy balance (25,26). Activation of the CB1 receptor centrally and peripherally leads to altered energy balance and weight gain in model organisms (19,(27)(28)(29). Selective blockade of CB1 with rimonabant in human clinical trials demonstrated an effect on weight loss (30,31), but further evaluation of cardiovascular outcomes was limited by psychiatric side effects, including an apparent increase in suicide risk (32).…”

Elucidating cannabinoid biology in zebrafish (Danio rerio)

“…This suggests that CB signaling in the peripheral tissues of zebrafish has a role in metabolic-regulation that is conserved with rodents (Osei-Hyiaman et al, 2005b). To further examine this potential role, a transgenic line was recently developed to study the effects of hepatic cnr1 overexpression (Pai et al, 2013). Overexpression of cnr1 in the liver resulted in elevated hepatic expression of SREBP-1c, a transcription factor involved in lipogenesis, as well as a host of genes involved with the synthesis, transport, and storage of fatty acids.…”