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Involvement of geranylgeranylation of Rho and Rac GTPases in adipogenic and RANKL expression, which was inhibited by simvastatin

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Title: Involvement of geranylgeranylation of Rho and Rac GTPases in adipogenic and RANKL expression, which was inhibited by simvastatin
Authors: Baba, T. T / Ohara-Nemoto, Y. / Miyazaki, T. / Nemoto, T. K
Issue Date: 2-Dec-2013
Publisher: John Wiley & Sons, Ltd.
Citation: Cell Biochemistry & Function, 31(8), pp.652-659; 2013
Abstract: Simvastatin suppresses myoblast differentiation via inhibition of Rac GTPase, which is involved in the mevalonic acid pathway that produces cholesterol. Statins also inhibit adipogenic differentiation and receptor activator of NFκB ligand (RANKL) expression, possibly through the mevalonic acid pathway, although the involvement of that pathway and effector proteins in these cellular events has not been fully clarified. In the present study, we aimed to elucidate the mechanism of the effects of simvastatin on adipogenic differentiation and calcitriol‐induced RANKL expression in bone marrow stromal ST2 cells. Adipogenesis and mRNA up‐regulation of peroxisome proliferator–activated receptor γ and adipocyte fatty acid–binding protein were induced by troglitazone, and those events were efficiently inhibited by simvastatin. In addition, RANKL expression induced by calcitriol was abrogated by simvastatin in ST2 cells. The inhibitory effects of simvastatin were adequately compensated by the addition of either mevalonic acid or an intermediate of the mevalonic acid pathway, geranylgeranyl pyrophosphate, but not by another intermediate, farnesyl pyrophosphate. These findings suggest that protein geranylgeranylation is related to cellular differentiation in those two directions. Furthermore, inhibitor analysis demonstrated that Rac GTPase is involved in adipogenic differentiation, whereas Rho GTPase was found to be involved in RANKL expression. Taken together, the present findings suggest that geranylgeranylation of Rho family GTPase is involved in both adipogenesis and RANKL expression of stromal cells, while Rac GTPase is involved in adipogenesis and Rho GTPase in RANKL expression.
Keywords: adipogenesis / farnesyl pyrophosphate / geranylgeranyl pyrophosphate / mevalonic acid pathway / RANKL / Rho family / statin
URI: http://hdl.handle.net/10069/38713
ISSN: 02636484
DOI: 10.1002/cbf.2951
Rights: © 2013 John Wiley & Sons, Ltd. This is the peer reviewed version of the following article: Cell Biochemistry & Function, 31(8), pp.652-659; 2013, which has been published in final form at http://dx.doi.org/10.1002/cbf.2951. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Type: Journal Article
Text Version: author
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/38713

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