Department of Physiology and Neurobiology and the Institute for Systems Genomics, University of Connecticut, Storrs, CT.
Veterans Affairs Connecticut Healthcare System, West Haven, CT.
Hepatology. 2018 May;67(5):1768-1783. doi: 10.1002/hep.29654. Epub 2018 Mar 25.
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.
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).
H19 是一种印迹长非编码 RNA，在胚胎肝脏中大量表达，出生后被抑制。我们表明，H19 通过与 RNA 结合多嘧啶 tract 结合蛋白 1（PTBP1）协同作用，充当脂质传感器，调节肝脏代谢稳态。H19 RNA 与 PTBP1 相互作用，促进其与固醇调节元件结合蛋白 1c mRNA 和蛋白的结合，导致稳定性和核转录活性增加。脂肪酸在肝细胞中和饮食诱导的脂肪肝中上调 H19 和 PTBP1，进一步加剧脂质积累。异位表达 H19 通过促进固醇调节元件结合蛋白 1c 蛋白切割和核易位，在响应禁食时诱导脂肪变性，并使肝脏进入“假性进食”状态。H19 缺失或 PTBP1 敲低可消除高脂肪和高蔗糖饮食诱导的脂肪变性。
我们的研究揭示了 H19/PTBP1/固醇调节元件结合蛋白 1 正反馈放大信号通路，加剧了脂肪肝的发展。（《肝脏病学》2018 年；67:1768-1783）。
