Figure 5.

Emerging therapeutic targets for the treatment of cholestasis. Inhibitors of NTCP may reduce the bile acid uptake by hepatocytes and subsequent toxicity. FXR agonists may upregulate hepatocyte efflux of bile constituents through BSEP, MRP2, MRP3, MRP4, and OSTα/β. UCDA, molecular chaperones such as 4-phenylbutyrate or other agents may reduce the toxic bile acid burden of the hepatocyte and improve bile flow and fat absorption. PPARα agonists may induce canalicular MDR3 expression and phospholipid secretion protecting cholangiocytes against bile acid toxicity. Alternatively, another strategy that would reduce hepatocyte bile acid levels is the inhibition of bile acid synthesis through suppressing CYP7A1 by FGF19 agonists, FXR agonists, or short interfering RNAs. In the ileal enterocyte, inhibiting ASBT will increase fecal excretion of bile acids, lower the bile acid pool size, change bile acid composition and alter enterocyte FXR signaling. In the cholangiocyte, nor-UCDA may protect the cholangiocyte from bile acid-induced injury by altering bile pH. 4-PB = 4-phenylbutyrate, BA = bile acid, PC = phosphatidylcholine, Bili = conjugated bilirubin, Cl = chloride, PS= phosphotidylserine, UDCA = ursodeoxycholic acid.