RT Journal Article
SR Electronic
T1 7α,25-dihydroxycholesterol protects against liver X receptor-mediated steatosis through GPR183/EBI2 in human and mouse hepatocytes
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.120.264960
DO 10.1124/jpet.120.264960
A1 Jin Huang
A1 Seung-Jin Lee
A1 Saeromi Kang
A1 Man Ho Choi
A1 Dong-Soon Im
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/04/27/jpet.120.264960.abstract
AB Non-alcoholic fatty liver disease is recognized as the most common chronic liver disease. Hepatic steatosis is associated with obesity and type 2 diabetes. Oxycholesterols are metabolites of cholesterol and several of them can act on the G protein-coupled receptor, GPR183/EBI2. We found expression of GPR183 in human hepatoma cell lines and in vivo induction of GPR183 expression in mouse livers after high-fat diet feeding. Therefore, the role of oxycholesterols and GPR183 in hepatocytes was investigated by using an in vitro model of liver X receptor (LXR)-mediated hepatocellular steatosis. T0901317, a specific LXR activator, induced lipid accumulation in Hep3B human hepatoma cells. This lipid accumulation was inhibited by 7α,25-dihydroxycholesterol, the most potent agonist of GPR183. The protective effects of 7α,25-dihydroxycholesterol were inhibited by NIBR189, a specific GPR183 antagonist. T0901317 treatment induced expression of SREBP-1c, the key transcription factor for lipid synthesis. 7α,25-dihydroxycholesterol inhibited the induction of SREBP-1c proteins in a GPR183-dependent manner. Using specific inhibitors of cellular signaling components, 7α,25-dihydroxycholesterol-induced inhibition of lipid accumulation was found to be mediated through Gi/o proteins, p38 MAPKs, PI3K, and AMPK. Furthermore, the protective effect of 7α,25-dihydroxycholesterol was confirmed in HepG2 cells and mouse primary hepatocytes. Therefore, the present data suggest that 7α,25-dihydroxycholesterol-GPR183 signaling in hepatocytes may protect against lipid accumulation in the liver.SIGNIFICANCE STATEMENT Oxycholesterols, metabolites of cholesterol, act on the G protein-coupled receptor, GPR183/EBI2. GPR183 is expressed in human hepatoma cell lines and its expression is induced in vivo in mouse livers after high-fat diet feeding. Activation of GPR183 inhibits lipid accumulation in HepG2 cells and mouse primary hepatocytes through Gi/o proteins, p38 MAPKs, PI3K, and AMPK.