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The Journal of biological chemistry v.292 no.7, 2017년, pp.3016 - 3028   SCI SCIE
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Heat Shock Protein 90 Modulates Lipid Homeostasis by Regulating the Stability and Function of Sterol Regulatory Element-binding Protein (SREBP) and SREBP Cleavage-activating Protein

Kuan, Yen-Chou (From the Food Biochemistry Laboratory and ) ; Hashidume, Tsutomu (From the Food Biochemistry Laboratory and ) ; Shibata, Takahiro (the Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan, and ) ; Uchida, Koji (the Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan, and ) ; Shimizu, Makoto (From the Food Biochemistry Laboratory and ) ; Inoue, Jun (From the Food Biochemistry Laboratory and ) ; Sato, Ryuichiro (From the Food Biochemistry Laboratory and ) ;
  • 초록  

    Sterol regulatory element-binding proteins (SREBPs) are the key transcription factors that modulate lipid biosynthesis. SREBPs are synthesized as endoplasmic reticulum-bound precursors that require proteolytic activation in the Golgi apparatus. The stability and maturation of precursor SREBPs depend on their binding to SREBP cleavage-activating protein (SCAP), which escorts the SCAP-SREBP complex to the Golgi apparatus. In this study, we identified heat shock protein (HSP) 90 as a novel SREBP regulator that binds to and stabilizes SCAP-SREBP. In HepG2 cells, HSP90 inhibition led to proteasome-dependent degradation of SCAP-SREBP, which resulted in the down-regulation of SREBP target genes and the reduction in intracellular triglyceride and cholesterol levels. We also demonstrated in vivo that HSP90 inhibition decreased SCAP-SREBP protein, down-regulated SREBP target genes, and reduced lipids levels in mouse livers. We propose that HSP90 plays an indispensable role in SREBP regulation by stabilizing the SCAP-SREBP complex, facilitating the activation of SREBP to maintain lipids homeostasis.


  • 주제어

    cholesterol .   fatty acid .   heat shock protein 90 (HSP90) .   lipid metabolism .   proteasome .   SCAP .   SREBP.  

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