Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver
Ichiro Onoyama, Atsushi Suzuki, Akinobu Matsumoto, Kengo Tomita, Hideki Katagiri, Yuichi Oike, Keiko Nakayama, Keiichi I. Nakayama
Ichiro Onoyama, Atsushi Suzuki, Akinobu Matsumoto, Kengo Tomita, Hideki Katagiri, Yuichi Oike, Keiko Nakayama, Keiichi I. Nakayama
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Research Article Hepatology

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.

Authors

Ichiro Onoyama, Atsushi Suzuki, Akinobu Matsumoto, Kengo Tomita, Hideki Katagiri, Yuichi Oike, Keiko Nakayama, Keiichi I. Nakayama

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Figure 3

Deposition of triglyceride and accumulation of SREBP1 in the Fbxw7-deficient liver.

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Deposition of triglyceride and accumulation of SREBP1 in the Fbxw7-defic...
(A) Triglyceride and total cholesterol concentrations in the livers of Mx1-Cre/Fbxw7+/F (control) and Mx1-Cre/Fbxw7F/F mice at 3 weeks after the final injection of pIpC, beginning at 8 weeks of age. Data are mean ± SD from 3 mice of each genotype. *P < 0.05. (B) Protein extracts of the livers of Mx1-Cre/Fbxw7+/F (control) and Mx1-Cre/Fbxw7F/F mice at 3 weeks after the final injection of pIpC, beginning at 8 weeks of age, were subjected to IB analysis with antibodies to the indicated proteins (left panel). Liver extracts of Fbxw7F/F (control) and Alb-Cre/Fbxw7F/F mice at 12 weeks of age were similarly analyzed (right panel). Three animals were examined for each genotype. Hsp90 was analyzed as a loading control. p-mTOR, phosphorylated mTOR. (C) RT and real-time PCR analysis of the indicated mRNAs in the livers of Mx1-Cre/Fbxw7+/F (control) and Mx1-Cre/Fbxw7F/F mice treated as in A. Normalized data are expressed relative to the corresponding value for control mice and are mean ± SD from 3 independent experiments. *P < 0.05. (D and E) Liver sections of Mx1-Cre/Fbxw7+/F (+/Δ) and Mx1-Cre/Fbxw7F/F (Δ/Δ) mice, treated as in A, were subjected to immunofluorescence staining with antibodies (D) to SREBP1 and (E) to SCD-1. CV, central vein. Scale bar: 100 μm.