Details

Autor(en) / Beteiligte

• Mukhopadhyay, Bani
• Liu, Jie
• Osei-Hyiaman, Douglas
• Godlewski, Grzegorz
• Mukhopadhyay, Partha
• Wang, Lei
• Jeong, Won-Il
• Gao, Bin
• Duester, Gregg
• Mackie, Ken
• Kojima, Soichi
• Kunos, George

Titel

Transcriptional Regulation of Cannabinoid Receptor-1 Expression in the Liver by Retinoic Acid Acting via Retinoic Acid Receptor-g

Ist Teil von

• The Journal of biological chemistry, 2010-06, Vol.285 (25), p.19002-19011

Erscheinungsjahr

2010

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Alcoholism can result in fatty liver that can progress to steatohepatitis, cirrhosis, and liver cancer. Mice fed alcohol develop fatty liver through endocannabinoid activation of hepatic CB sub(1) cannabinoid receptors (CB sub(1)R), which increases lipogenesis and decreases fatty acid oxidation. Chronic alcohol feeding also up-regulates CB sub(1)R in hepatocytes in vivo, which could be replicated in vitro by co-culturing control hepatocytes with hepatic stellate cells (HSC) isolated from ethanol-fed mice, implicating HSC-derived mediator(s) in the regulation of hepatic CB sub(1)R (Jeong, W. I., Osei-Hyiaman, D., Park, O., Liu, J., Batkai, S., Mukhopadhyay, P., Horiguchi, N., Harvey-White, J., Marsicano, G., Lutz, B., Gao, B., and Kunos, G. (2008) Cell Metab. 7, 227-235). HSC being a rich source of retinoic acid (RA), we tested whether RA and its receptors may regulate CB sub(1)R expression in cultured mouse hepatocytes. Incubation of hepatocytes with RA or RA receptor (RAR) agonists increased CB sub(1)R mRNA and protein, the most efficacious being the RARg agonist CD437 and the pan-RAR agonist TTNPB. The endocannabinoid 2-arachidonoylglycerol (2-AG) also increased hepatic CB sub(1)R expression, which was mediated indirectly via RA, because it was absent in hepatocytes from mice lacking retinaldehyde dehydrogenase 1, the enzyme catalyzing the generation of RA from retinaldehyde. The binding of RARg to the CB sub(1)R gene 5' upstream domain in hepatocytes treated with RAR agonists or 2-AG was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift and antibody supershift assays. Finally, TTNPB-induced CB sub(1)R expression was attenuated by small interfering RNA knockdown of RARg in hepatocytes. We conclude that RARg regulates CB sub(1)R expression and is thus involved in the control of hepatic fat metabolism by endocannabinoids.