Figure 1. DLAMs interact with the VDR and block TGF-β signaling by preventing binding to the SMAD3-binding element (SMADBE).

This prevention of binding prevents expression of profibrotic genes. The DLAMs do not affect classical 1,25(OH)₂D₃-VDR–potentiated actions on genes, such as Cyp24a1, due to interaction with VDRE. Cyp24a1 encodes 1,25(OH)₂D₃-24-hydroxylase, a mitochondrial enzyme that degrades 1,25(OH)₂D₃ and hence plays an important role in calcium homeostasis. Normally, TGF-β signals by binding to cell surface type I and type II serine/threonine receptors, which release phosphorylated SMAD3 into the cytosol, where it interacts with SMAD4, translocates to the nucleus, binds to the SMADBE in genes, and upregulates profibrotic gene expression. NCOA, nuclear coactivators; SRC, steroid receptor coactivator.