Insulin induces phosphorylation of pyruvate dehydrogenase through RhoA activation pathway in HepG2 cells

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Insulin is a critical signaling molecule in reducing blood glucose levels, and pyruvate dehydrogenase (PDH) is an essential enzyme in regulating glucose metabolism. However, the insulin effect on PDH function has not been well established. We observed that insulin attenuated the phosphorylation (p) of Ser264 (p-Ser264) in the PDH E1 subunit (PDHA1) in normal rat hepatocyte. In contrast, insulin induced an increase of p-Ser264 PDHA1 levels in hepatocellular carcinoma HepG2 and Huh7 cells. Insulin activated RhoA and Rho-dependent coiled coil kinase, an effector protein of active RhoA, which regulated p-Ser264 PDHA1 levels, along with both p-Ser9 and p-Tyr216 forms of glycogen synthase kinase-3 (GSK-3) in HepG2 cells. Only p-Tyr216 GSK-3, the active form was involved in an increase of p-Ser264 PDHA1. Akt was also engaged in p-Ser9 of GSK-3, but neither in p-Tyr216 of GSK-3 nor p-Ser264 of PDHA1 upon insulin. Reconstituted dephospho-mimic forms PDHA1 S264A and GSK-3 Y216F impaired, but wild-types PDHA1 and GSK-3 and phospho-mimic forms PDHA1 S264D and GSK-3 Y216E increased cell proliferation upon insulin through expression of c-Myc and cyclin D1. Therefore, we propose that insulin-mediated p-PDHA1 is involved in the regulation of HepG2 cell proliferation through RhoA signaling pathway.Islam, R., Kim, J.-G., Park, Y., Cho, J.-Y., Cap, K.-C., Kho, A.-R., Chung, W.-S., Suh, S.-W., Park, J.-B. Insulin induces phosphorylation of pyruvate dehydrogenase through RhoA activation pathway in HepG2 cells.
Publisher
FEDERATION AMER SOC EXP BIOL
Issue Date
2019-02
Language
English
Article Type
Article
Citation

FASEB JOURNAL, v.33, no.2, pp.2072 - 2083

ISSN
0892-6638
DOI
10.1096/fj.201800917R
URI
http://hdl.handle.net/10203/250470
Appears in Collection
BS-Journal Papers(저널논문)
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