title: Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPARγ agonist.
abstract: The cholesterol biosynthetic pathway produces not only sterols but also non-sterol mevalonate metabolites involved in isoprenoid synthesis. Mevalonate metabolites affect transcriptional and post-transcriptional events that in turn affect various biological processes including energy metabolism. In the present study, we examine whether mevalonate metabolites activate PPARγ (peroxisome-proliferator-activated receptor γ), a ligand-dependent transcription factor playing a central role in adipocyte differentiation. In the luciferase reporter assay using both GAL4 chimaera and full-length PPARγ systems, a mevalonate metabolite, FPP (farnesyl pyrophosphate), which is the precursor of almost all isoprenoids and is positioned at branch points leading to the synthesis of other longer-chain isoprenoids, activated PPARγ in a dose-dependent manner. FPP induced the in vitro binding of a co-activator, SRC-1 (steroid receptor co-activator-1), to GST (glutathione transferase)-PPARγ. Direct binding of FPP to PPARγ was also indicated by docking simulation studies. Moreover, the addition of FPP up-regulated the mRNA expression levels of PPARγ target genes during adipocyte differentiation induction. In the presence of lovastatin, an HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor, both intracellular FPP levels and PPARγ-target gene expressions were decreased. In contrast, the increase in intracellular FPP level after the addition of zaragozic acid, a squalene synthase inhibitor, induced PPARγ-target gene expression. The addition of FPP and zaragozic acid promotes lipid accumulation during adipocyte differentiation. These findings indicated that FPP might function as an endogenous PPARγ agonist and regulate gene expression in adipocytes.
authors: Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.
authors: Tsuyoshi
authors: T
authors: Goto
authors: Hiroyuki
authors: H
authors: Nagai
authors: Kahori
authors: K
authors: Egawa
authors: Young-Il
authors: YI
authors: Kim
authors: Sota
authors: S
authors: Kato
authors: Aki
authors: A
authors: Taimatsu
authors: Tomoya
authors: T
authors: Sakamoto
authors: Shogo
authors: S
authors: Ebisu
authors: Takahiro
authors: T
authors: Hohsaka
authors: Hiroh
authors: H
authors: Miyagawa
authors: Shigeru
authors: S
authors: Murakami
authors: Nobuyuki
authors: N
authors: Takahashi
authors: Teruo
authors: T
authors: Kawada
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