Estudio del papel fisiopatológico de Slu7 en el hígado

  1. Elizalde Arbilla, María
Dirigida per:
  1. Matias Antonio Ávila Zaragozá Director
  2. Maria del Carmen Berasain Lasarte Directora

Universitat de defensa: Universidad de Navarra

Fecha de defensa: 24 de de juny de 2014

Tribunal:
  1. Juan Sastre Belloch President/a
  2. María Jose Iraburu Elizalde Secretària
  3. Aranzazu Sanchez Muñoz Vocal
  4. Mª Luz Martínez Chantar Vocal
  5. María Dolores Odero de Dios Vocal
Departament:
  1. (FM) Medicina Interna

Tipus: Tesi

Teseo: 116815 DIALNET lock_openDadun editor

Resum

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 4? (Hnf4?), and was critical for cAMP-regulated gene transcription. Together, out data indicate that SLU7 is central regulator of hepatocyte identity and quiescence.