| Inhibition of Ubiquitin ligase F-box and WD repeat domain-containing 7{alpha} (Fbw7{alpha}) causes hepatosteatosis through the Kruppel-like factor 5 (KLF5)/PPAR{gamma}2 pathway, but not SREBP-1c in mice. | |
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MedLine Citation:
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PMID: 21911492 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 Fbwα in hepatic lipid metabolism. siRNA knockdown of Fbw7α in mice caused marked hepatosteatosis with the accumulation of triglycerides (TGs). 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 (Fsp27). 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 which represent novel aspects of this cell growth regulator. |
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Authors:
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Shin Kumadaki; Tadayoshi Karasawa; Takashi Matsuzaka; Masatsugu Ema; Yoshimi Nakagawa; Masanori Nakakuki; Ryo Saito; Naoya Yahagi; Hitoshi Iwasaki; Hirohito Sone; Kazuhiro Takekoshi; Shigeru Yatoh; Kazuto Kobayashi; Akimitsu Takahashi; Hiroaki Suzuki; Satoru Takahashi; Nobuhiro Yamada; Hitoshi Shimano |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-12 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: - ISSN: 1083-351X ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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University of Tsukuba, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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