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

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.

Nrf2 Enhances Cholangiocyte Expansion in Pten-Deficient Livers

“…It is also plausible that Nrf2 enhances the induction and differentiation of oval cells into cholangiocytes on the basis of the observation that Trop2-EpCAM double-positive cells, which are possible oval cells, are specifically induced in the livers of Pten::Keap1-Alb mice. Notably, similar phenotypes have been observed in the livers of Fbxw7 conditional-knockout mice (39). The increased Notch pathway activity due to Fbxw7 deficiency skewed the differentiation of hepatoblasts toward the cholangiocyte lineage.…”

Genetic and hormonal control of hepatic steatosis in female and male mice

“…Skp1a is another candidate gene and is a component of SCF complexes. These ubiquitination complexes have been shown to play a role in hepatic lipid accumulation (45). Heterogenous nuclear ribonucleoprotein A/B (Hnrnpab) has been shown to play a role in apolipoprotein B mRNA editing in a cultured human hepatoma cell line (46).…”

Biological roles of microRNAs in the control of insulin secretion and action

“…SREBP2 directly activates miR-182 and miR-96, which negatively regulate the expression of FBXW7 and INSIG-2, respectively. These genes affect nuclear SREBP levels and endogenous lipid synthesis (29), potentially leading to steatohepatitis (59). Furthermore, several miRNAs directly contribute to liver expression of miR-33 targets, including ABCA1 (target of miR-26, miR-128-2, miR-144) (1, 9, 27, 75), ABCG1 (target of miR-128-2) (1), and CPT1A (target of miR-370) (27).…”