Elizalde, M.; Urtasun, R. ; Azkona, M.; Latasa, M.; Goñi, S. ; García-Irigoyen, O.; Uriarte, I.; Segura, V. ; Collantes, M. ; Di-Scala, M. ; Lujambio, A. ; Prieto, J.; Ávila, M. ; Berasain, C. (Carmen). Splicing regulator SLU7 is essential for maintaining liver homeostasis. The Journal of Clinical Investigation, 2014, vol. 24, n.7, pp. 2909-2920
A precise equilibrium between cellular differentiation and proliferation is fundamental for tissue homeostasis.
Maintaining this balance is particularly important for the liver, a highly differentiated organ with systemic
metabolic functions that is endowed with unparalleled regenerative potential. Carcinogenesis in the liver
develops as the result of hepatocellular de-differentiation and uncontrolled proliferation. Here, we identified
SLU7, which encodes a pre-mRNA splicing regulator that is inhibited in hepatocarcinoma, as a pivotal gene
for hepatocellular homeostasis. SLU7 knockdown in human liver cells and mouse liver resulted in profound
changes in pre-mRNA splicing and gene expression, leading to impaired glucose and lipid metabolism, refractoriness
to key metabolic hormones, and reversion to a fetal-like gene expression pattern. Additionally, loss of
SLU7 also increased hepatocellular proliferation and induced a switch to a tumor-like glycolytic phenotype.
Slu7 governed the splicing and/or expression of multiple genes essential for hepatocellular differentiation,
including serine/arginine-rich splicing factor 3 (Srsf3) and hepatocyte nuclear factor 4α (Hnf4α), and was critical
for cAMP-regulated gene transcription. Together, out data indicate that SLU7 is central regulator of hepatocyte
identity and quiescence.