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Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver.
- Source :
-
Journal of Clinical Investigation . Jan2011, Vol. 121 Issue 1, p342-354. 13p. 1 Color Photograph, 1 Diagram, 6 Graphs. - Publication Year :
- 2011
-
Abstract
- E3 ubiquitin ligase complexes of the SCF type consist of ring-box 1 (Rbx1), cullin 1 (Cul1), S-phase kinase-associated protein 1 (Skp1), and a member of the F-box family of proteins. The identity of the F-box protein determines the substrate specificity of the complex. The F-box family member F-box- and WD repeat domain-containing 7 (Fbxw7; also known as Fbw7, SEL-10, hCdc4, and hAgo) targets for degradation proteins with wide-ranging functions, and uncovering its in vivo role has been difficult, because Fbxw7-/- embryos die in utero. Using two different Cre-loxP systems (Mx1-Cre and Alb-Cre), we generated mice with liver-specific null mutations of Fbxw7. Hepatic ablation of Fbxw7 resulted in hepatomegaly and steatohepatitis, with massive deposition of triglyceride, a phenotype similar to that observed in humans with nonalcoholic steatohepatitis. Both cell proliferation and the abundance of Fbxw7 substrates were increased in the Fbxw7-deficient liver. Long-term Fbxw7 deficiency resulted in marked proliferation of the biliary system and the development of hamartomas. Fbxw7 deficiency also skewed the differentiation of liver stem cells toward the cholangiocyte lineage rather than the hepatocyte lineage in vitro. This bias was corrected by additional loss of the Notch cofactor RBP-J, suggesting that Notch accumulation triggered the abnormal proliferation of the biliary system. Together, our results suggest that Fbxw7 plays key roles, regulating lipogenesis and cell proliferation and differentiation in the liver. [ABSTRACT FROM AUTHOR]
- Subjects :
- *UBIQUITIN
*LIGASES
*HUMAN beings
*MICE
*STEM cells
*TRIGLYCERIDES
*ENZYME metabolism
*ANIMAL experimentation
*BIOLOGICAL models
*CARRIER proteins
*CELL differentiation
*CELL physiology
*COMPARATIVE studies
*DNA probes
*ENZYMES
*EPITHELIAL cells
*FATTY liver
*GENE expression
*GENETIC disorders
*LIPID metabolism disorders
*LIVER
*RESEARCH methodology
*MEDICAL cooperation
*NUCLEOTIDES
*RESEARCH
*EVALUATION research
*PHYSIOLOGY
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 121
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 58077573
- Full Text :
- https://doi.org/10.1172/JCI40725