Long noncoding RNA H19 interacts with polypyrimidine tract‐binding protein 1 to reprogram hepatic lipid homeostasis

H19 is an imprinted long noncoding RNA abundantly expressed in embryonic liver and repressed after birth. We show that H19 serves as a lipid sensor by synergizing with the RNA‐binding polypyrimidine tract‐binding protein 1 (PTBP1) to modulate hepatic metabolic homeostasis. H19 RNA interacts with PTBP1 to facilitate its association with sterol regulatory element‐binding protein 1c mRNA and protein, leading to increased stability and nuclear transcriptional activity. H19 and PTBP1 are up‐regulated by fatty acids in hepatocytes and in diet‐induced fatty liver, which further augments lipid accumulation. Ectopic expression of H19 induces steatosis and pushes the liver into a “pseudo‐fed” state in response to fasting by promoting sterol regulatory element‐binding protein 1c protein cleavage and nuclear translocation. Deletion of H19 or knockdown of PTBP1 abolishes high‐fat and high‐sucrose diet–induced steatosis. Conclusion: Our study unveils an H19/PTBP1/sterol regulatory element‐binding protein 1 feedforward amplifying signaling pathway to exacerbate the development of fatty liver. (Hepatology 2018;67:1768‐1783)