Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver

E3 ubiquitin ligase complexes of the SCF type consist of ring-box 1 (Rbx1), cullin 1 (Cull), 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 Fbzw7(-/-) embryos die m 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 m 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 m 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 m 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