Peking University-led researchers have modified an existing treatment for liver disease that does not cause itchiness, a common side effect of existing treatments. Chronic itch is a debilitating symptom impacting the quality of life in patients with liver diseases like cholestasis. The human G-protein coupled receptor (hX4) activation by bile acids has been implicated in promoting the cholestasis itch, but the underlying mechanisms remain unclear.
In the paper, "Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch," published in Cell , researchers identified that 3-sulfated bile acids accumulate in cholestatic patients with itch symptoms and developed a modified version of obeticholic acid (sold as Ocaliva) that lacks a 3-hydroxyl group to counter these effects. The team collected plasma samples from cholestatic patients with and without itch in the initial research. Analysis of 28 types of bile acids using liquid chromatography-tandem mass spectrometry revealed elevated levels of 3-sulfated bile acids in patients experiencing itch.
Additional testing demonstrated that 3-sulfated bile acids have higher potency to activate hX4 than other bile acids. They assessed the activation of hX4 by various bile acids and found that 3-sulfated bile acids significantly enhanced receptor activation. Next, the team determined the cryo-electron microscopy structure of hX4 bound with 3-phosphate deoxycholic acid to see how bile acids activate hX4.