Conserved long noncoding RNATILAMpromotes liver fibrosis through interaction with PML in hepatic stellate cells

Abstract

Background & AimsFibrosis 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 to 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 may provide targets for fibrotic therapies.MethodsWe identified lncRNATILAMas expressed nearCOL1A1in human HSCs and performed loss-of-function studies in human HSCs and liver organoids. Transcriptomic analyses of HSCs isolated from mice defined the murine ortholog ofTILAM. We then generatedTilam-deficient GFP reporter mice and quantified fibrotic responses to carbon tetrachloride (CCl4) and choline-deficient L-amino acid defined high fat diet (CDA-HFD). Co-precipitation studies, mass spectrometry, and gene expression analyses identified protein partners ofTILAM.ResultsTILAMis conserved between human and mouse HSCs and regulates expression of ECM proteins, including collagen.Tilamis selectively induced in HSCs during the development of fibrosisin vivo. In both male and female mice, loss ofTilamresults in reduced fibrosis in the setting of CCl4and CDA-HFD injury models.TILAMinteracts with promyelocytic leukemia protein (PML) to stabilize PML protein levels and promote the fibrotic activity of HSCs.ConclusionTILAMis activated in HSCs and interacts with PML to drive the development of liver fibrosis. Depletion ofTILAMmay serve as a therapeutic approach to combat the development of end stage liver disease.