Ypel5 regulates liver development and function in zebrafish.

YPEL5 is a member of the YPEL gene family that is evolutionarily conserved in the eukaryotic species. To date, the physiological function of YPEL5 has not been yet assessed due to a paucity of genetic animal models. Here, using CRISPR/Cas9-mediated genome editing, we generated a stable ypel5-/- mutant zebrafish line. Disruption of ypel5 expression leads to liver enlargement associated with hepatic cell proliferation. Meanwhile, hepatic metabolism and function are also dysregulated in ypel5-/- mutant as revealed by metabolomic and transcriptomic analysis. Mechanistically, Hnf4a is identified as a crucial downstream mediator and positively regulated by Ypel5. Hnf4a overexpression could largely rescue ypel5 deficiency-induced hepatic defects. Further, PPARα signaling mediates the regulation of Hnf4a by Ypel5 through directly binding to the transcriptional enhancer of Hnf4a gene. Herein, this work demonstrates an essential role for Ypel5 in hepatocyte proliferation and function, and provides the first in vivo evidence for a physiological role of the ypel5 gene in vertebrate.