Conserved long noncoding RNA TILAM promotes liver fibrosis in humans and mice.
Fibrosis is the common endpoint for all forms of chronic liver injury, and progression of fibrosis is responsible for the development of end stage liver disease and liver failure. The activation of hepatic stellate cells (HSCs) and their transition to HSC myofibroblasts is a key step in the disease process, as these cells are the primary source of the extracellular matrix (ECM) proteins, which form the fibrotic scar. Long noncoding (lnc) RNAs can regulate the activity of HSCs, and lncRNAs that promote the fibrotic activity of HSCs may provide targets for antifibrotic therapies. Here, we identified and defined the functional mechanisms of a conserved lncRNA that plays a critical role in promoting liver fibrosis. We found that TILAM is conserved between human and mouse HSCs, and regulates expression of type 1 collagen, a major component of the ECM. 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. Analysis of GFP expression revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. In both male and female mice, we also observed that loss of Tilam resulted in reduced fibrosis in the setting of injury induced by carbon tetrachloride (CCl4) and choline-deficient L-amino acid defined high fat diet (CDA-HFD). Finally, we found that TILAM interacts with PML to stabilize PML protein expression and promote the fibrotic activity of HSCs. Together, these results define an lncRNA conserved between humans and mice that is activated uniquely in HSCs to drive the development of fibrosis and could provide a therapeutic target to combat the development of end stage liver disease. Overall design: Comparative gene expression profiling analysis of RNA-seq data for Primary Hepatic stellate cells with siRNA or LNA treatment