Journal
HEPATOLOGY
Volume 67, Issue 5, Pages 1768-1783Publisher
WILEY
DOI: 10.1002/hep.29654
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Funding
- National Institutes of Health [R01DK104656, R01DK080440, R01ES025909, R21AA022482, R21AA024935, HSN276201200017C]
- Department of Veterans Affairs Merit Award [1I01BX002634]
- National Natural Scientific Foundation of China [81572443]
- Yale Liver Center [P30 DK34989]
- National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK104656-01]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK104656, R01DK080440, P30DK034989] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES025909] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R21AA022482, R01AA026322, R21AA024935] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX002634] Funding Source: NIH RePORTER
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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)
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