Splicing regulator SLU7 is essential for maintaining liver homeostasis Journal Article
| Authors: | Elizalde, M.; Urtasun, R.; Azkona, M.; Latasa, M. U.; Goñi, S.; García-Irigoyen, O.; Uriarte, I.; Segura, V.; Collantes, M.; Di Scala, M.; Lujambio, A.; Prieto, J.; Ávila, M. A.; Berasain, C. |
| Article Title: | Splicing regulator SLU7 is essential for maintaining liver homeostasis |
| Abstract: | 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. |
| Keywords: | signal transduction; adult; controlled study; unclassified drug; liver cell carcinoma; liver function; nonhuman; cell proliferation; animal cell; mouse; phenotype; animal tissue; cell survival; cell function; gene expression; animal experiment; protein; genetic transcription; liver; protein processing; upregulation; liver cell; loss of function mutation; lipid metabolism; sterol regulatory element binding protein 1; rna splicing; cell dedifferentiation; impaired glucose tolerance; lipid homeostasis; serine arginine rich protein; essential gene; human; priority journal; article; hepatocyte nuclear factor 4alpha; serine arginine rich splicing factor 3; slu7 protein; carbohydrate metabolism; disorders of lipid metabolism |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 124 |
| Issue: | 7 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2014-07-01 |
| Start Page: | 2909 |
| End Page: | 2920 |
| Language: | English |
| DOI: | 10.1172/jci74382 |
| PROVIDER: | scopus |
| PMCID: | PMC4071377 |
| PUBMED: | 24865429 |
| DOI/URL: | |
| Notes: | Export Date: 1 August 2014 -- CODEN: JCINA -- Source: Scopus |
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