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.
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.
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Kumadaki
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Karasawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ema
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakakuki
authors.forename: Ryo
authors.initials: R
authors.lastname: Saito
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Hirohito
authors.initials: H
authors.lastname: Sone
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takekoshi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yatoh
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Takahashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011345:Fenofibrate / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D047495:PPAR gamma; D051780:Sterol Regulatory Element Binding Protein 1; D044767:Ubiquitin-Protein Ligases; D011345:Fenofibrate