title: 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.
abstract: 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 demonstratedin vivothat 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.
authors.affiliation: From the Food Biochemistry Laboratory and.
authors.forename: Yen-Chou
authors.initials: YC
authors.lastname: Kuan
authors.affiliation: From the Food Biochemistry Laboratory and.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hashidume
authors.affiliation: the Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan, and.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: the Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan, and.
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.affiliation: From the Food Biochemistry Laboratory and.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: From the Food Biochemistry Laboratory and.
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.affiliation: From the Food Biochemistry Laboratory and aroysato@mail.ecc.u-tokyo.ac.jp.|the Nutri-Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Sato
mesh_terms: D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D055550:Protein Stability; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D051779:Sterol Regulatory Element Binding Proteins
keywords: SCAP; SREBP; cholesterol; fatty acid; heat shock protein 90 (HSP90); lipid metabolism; proteasome