| First Author | Kumadaki S | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 47 | Pages | 40835-46 |
| PubMed ID | 21911492 | Mgi Jnum | J:180713 |
| Mgi Id | MGI:5306873 | Doi | 10.1074/jbc.M111.235283 |
| Citation | Kumadaki S, et al. (2011) Inhibition of ubiquitin ligase F-box and WD repeat domain-containing 7alpha (Fbw7alpha) causes hepatosteatosis through Kruppel-like factor 5 (KLF5)/peroxisome proliferator-activated receptor gamma2 (PPARgamma2) pathway but not SREBP-1c protein in mice. J Biol Chem 286(47):40835-46 |
| abstractText | F-box and WD repeat domain-containing 7alpha (Fbw7alpha) is the substrate recognition component of a ubiquitin ligase that controls the degradation of factors involved in cellular growth, including c-Myc, cyclin E, and c-Jun. In addition, Fbw7alpha degrades the nuclear form of sterol regulatory element-binding protein (SREBP)-1a, a global regulator of lipid synthesis, particularly during mitosis in cultured cells. This study investigated the in vivo role of Fbw7alpha in hepatic lipid metabolism. siRNA knockdown of Fbw7alpha in mice caused marked hepatosteatosis with the accumulation of triglycerides. However, inhibition of Fbw7alpha did not change the level of nuclear SREBP-1 protein or the expression of genes involved in fatty acid synthesis and oxidation. In vivo experiments on the gain and loss of Fbw7alpha function indicated that Fbw7alpha regulated the expression of peroxisome proliferator-activated receptor (PPAR) gamma2 and its target genes involved in fatty acid uptake and triglyceride synthesis. These genes included fatty acid transporter Cd36, diacylglycerol acyltransferase 1 (Dgat1), and fat-specific protein 27 (Cidec). The regulation of PPARgamma2 by Fbw7alpha was mediated, at least in part, by the direct degradation of the Kruppel-like factor 5 (KLF5) protein, upstream of PPARgamma2 expression. Hepatic Fbw7alpha contributes to normal fatty acid and triglyceride metabolism, functions that represent novel aspects of this cell growth regulator. |
