Conserved long noncoding RNA TILAM promotes liver fibrosis through interaction with PML in hepatic stellate cells.

BACKGROUND AND AIMS: Fibrosis is the common endpoint for all forms of chronic liver injury, and progression of fibrosis leads to the development of end-stage liver disease. Activation of hepatic stellate cells (HSCs) and their transdifferentiation into myofibroblasts results in the accumulation of extracellular matrix (ECM) proteins that form the fibrotic scar. Long noncoding (lnc) RNAs regulate the activity of HSCs and provide targets for fibrotic therapies.

APPROACH AND RESULTS: We identified lncRNA TILAM located near COL1A1, expressed in HSCs, and induced with liver fibrosis in humans and mice. Loss-of-function studies in human HSCs and human liver organoids revealed that TILAM regulates expression of COL1A1 and other ECM genes. To determine the role of TILAM in vivo, we annotated the mouse ortholog (Tilam), generated Tilam-deficient GFP-reporter mice, and challenged these mice in two different models of liver fibrosis. Single-cell data and analysis of GFP expression in Tilam-deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Furthermore, loss of Tilam expression attenuated development of fibrosis in the setting of in vivo liver injury. Finally, we found that TILAM interacts with PML to regulate a feedback loop by which TGF-β2 reinforces TILAM expression and nuclear localization of PML to promote the fibrotic activity of HSCs.

CONCLUSIONS: TILAM is activated in HSCs with liver injury and interacts with PML to drive the development of fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end stage liver disease.