RRC ID 12705
Author Kumadaki S, Karasawa T, Matsuzaka T, Ema M, Nakagawa Y, Nakakuki M, Saito R, Yahagi N, Iwasaki H, Sone H, Takekoshi K, Yatoh S, Kobayashi K, Takahashi A, Suzuki H, Takahashi S, Yamada N, Shimano H.
Title Inhibition of ubiquitin ligase F-box and WD repeat domain-containing 7α (Fbw7α) causes hepatosteatosis through Krüppel-like factor 5 (KLF5)/peroxisome proliferator-activated receptor γ2 (PPARγ2) pathway but not SREBP-1c protein in mice.
Journal J Biol Chem
Abstract F-box and WD repeat domain-containing 7α (Fbw7α) 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, Fbw7α 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 Fbw7α in hepatic lipid metabolism. siRNA knockdown of Fbw7α in mice caused marked hepatosteatosis with the accumulation of triglycerides. However, inhibition of Fbw7α 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 Fbw7α function indicated that Fbw7α regulated the expression of peroxisome proliferator-activated receptor (PPAR) γ2 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 PPARγ2 by Fbw7α was mediated, at least in part, by the direct degradation of the Krüppel-like factor 5 (KLF5) protein, upstream of PPARγ2 expression. Hepatic Fbw7α contributes to normal fatty acid and triglyceride metabolism, functions that represent novel aspects of this cell growth regulator.
Volume 286(47)
Pages 40835-46
Published 2011-11-25
DOI 10.1074/jbc.M111.235283
PII S0021-9258(20)50434-1
PMID 21911492
PMC PMC3220464
MeSH Animals Cell Cycle / drug effects Cell Cycle / genetics Cell Proliferation / drug effects F-Box Proteins / genetics F-Box Proteins / metabolism* F-Box-WD Repeat-Containing Protein 7 Fatty Liver / genetics Fatty Liver / metabolism* Fatty Liver / pathology Fenofibrate / pharmacology Gene Knockdown Techniques Kruppel-Like Transcription Factors / metabolism* Lipid Metabolism / drug effects Lipid Metabolism / genetics Liver / drug effects Liver / metabolism Liver / pathology Male Mice Mice, Inbred C57BL PPAR gamma / deficiency PPAR gamma / genetics PPAR gamma / metabolism* Sterol Regulatory Element Binding Protein 1 / metabolism* Ubiquitin-Protein Ligases / deficiency Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism*
IF 4.238
Times Cited 16
DNA material AxCANCre (RDB01748)