NR1H4 and cholestasis: This can likely be attributed to (1) bile acid micellization with cholesterol and phospholipids in bile; (2) the capability of cholangiocytes to secrete bicarbonate in the lumen [23] that, in the presence of glycoproteins and other mucus-like components, may form a glycocalyx on the cholangiocyte luminal side; evidence so far is limited to in vitro studies, but this bicarbonate shield (or umbrella) may protect against bile acid–induced injury [24]; (3) the expression of FXR and its target genes that may be orchestrated to prevent intracellular bile acid accumulation during cholestasis [25].