Vitamin D supplementation ameliorates ductular reaction, liver inflammation and fibrosis in mice by upregulating TXNIP in ductular cells

Ductular reaction is associated with liver disease progression, but there are no drugs targeting ductular reaction. Vitamin D deficiency is common in chronic liver diseases and related to disease progression, but the underlying mechanisms by which vitamin D regulates liver diseases progression remain unclear. Here, we show that vitamin D plasma levels are negatively correlated with the degree of ductular reaction in patients with chronic liver diseases. 1,25(OH)₂D_3, the active form of vitamin D, reduces 3,5-diethoxycarbonyl-1,4-dihydrocollidin (DDC)-induced ductular reaction, liver inflammation, and fibrosis in female mice and upregulates the vitamin D target gene, TXNIP (encoding thioredoxin-interacting protein), in ductular cells. Cholangiocyte-specific Txnip-knockout female mice are more susceptible to DDC-induced ductular reaction, inflammation, and fibrosis. Deletion of Txnip in cholangiocytes promotes proliferation and suppressed death. Furthermore, Txnip deficiency increases TNF-α and TGF-β secretion by cholangiocytes to stimulate Kupffer cells and hepatic stellate cells, consequently leading to inflammation and collagen deposition. Biliary Txnip deficiency abolishes the protective effects of vitamin D, and TXNIP overexpression attenuates DDC-induced ductular reaction and inflammation and fibrosis. Collectively, our findings identify new mechanism how vitamin D ameliorates liver diseases and suggest that the vitamin D/TXNIP axis is a therapeutic target for addressing ductular reaction and liver diseases.