Insulin‐mimetic action of bile acids via FXR

Farnesoid X receptor (FXR), a member of the orphan nuclear receptor superfamily, plays roles in diverse metabolic pathways including bile acids, lipids, glucose, and lipoproteins. We tested a signal transduction of FXR that integrated into the phosphoinositide 3-kinase (PI3K) pathway. In HepG2 cells and Caco-2 cells, FXR in the presence of GW4064 (synthetic FXR agonist) and CDCA (chenodeoxycholic acid, physiological FXR agonist) enhanced signals in PI3K that led to increase in glucose (GLC) uptake and glycogen synthase (GS) activity. Effects of FXR on GLC and GS were effectively reversed by LY200094. However, these positive effects were not observed in the presence of natural FXR antagonists such as LCA (lithocholic acid) and guggulsterone. We also confirmed that effects of FXR were comparable to those of insulin. In addition, FXR was coprecipitated in the presence of GW4064, but not insulin. We conclude that CDCA and GW4064 produce the insulin-mimetic action via FXR in the glucose metabolism in these cells.