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AMPK Hyper-Activation Alters Fatty Acids Metabolism and Impairs Invasiveness of Trophoblasts in Preeclampsia.

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posted on 01.08.2019, 14:34 by X Yang, P Xu, F Zhang, L Zhang, Y Zheng, M Hu, L Wang, T-L Han, C Peng, L Wen, Y Zeng, R Gao, Y Xia, C Tong, Z Yang, H Qi, PN Baker
BACKGROUND/AIMS: Preeclampsia (PE) has long been assumed to be an ischemic disease of the placenta, although there is limited evidence as to how the ischemia impacts on the placenta. AMP-activated protein kinase (AMPK) is a key regulator of cellular energy metabolism and plays an important role in a variety of ischemic diseases by enhancing energy production. The present study investigated placental metabolism in PE, and the role of AMPK in regulating trophoblast function. METHODS: placentas from normal and PE complicated pregnancies were subjected to GC-MS to identify fatty acids (FA) metabolic fingerprints, and total FA oxidation was assessed by malondialdehyde (MDA) measurement. The AMPK-ACC signaling pathway was assessed by q-PCR and Western Blotting. HTR8/SVneo trophoblast cultures were exposed to different oxygenation conditions to establish an in vitro PE cell model; further analysis by GC-MS for metabolite profiling was then undertaken. Trophoblasts invasion was assessed by a matrigel transwell assay in the presence/absence of AMPK expression and after manipulations of AMPK activity, and then further validated by human villi outgrowth experiments. RESULTS: AMPK phosphorylation and MDA production were significantly elevated in placentas from pregnancies complicated by PE. Metabolism of cis double bond FA was inhibited while trans double bond FA metabolism was promoted in PE placentas. HTR8/SVneo cell culture conditions of persistent low oxygenation mimicked the hyper-activation of AMPK and enhanced the FA oxidation that was observed in PE. AMPK activation impaired trophoblast invasion, while AMPK inhibition promoted trophoblast invasion. CONCLUSION: PE complicated placentas are associated with AMPK hyper-activation and consequent alterations in FA oxidation, which inhibit trophoblast invasion.

Funding

National Natural Sciences Foundation of China (81671488 and 81871189 to C.T; 81771613 and 81520108013 to H.Q), National Health and Family Planning Commission (201402006 to H.Q), Ministry of Science and Technology (2016YFC1000407 to H.Q), Chongqing Municipal Education Commission (CXTDX201601014 to H.Q, KJ1500223 to C.T), Commission of Science and Technology of Chongqing Municipality (cstc2017jcyjBX0045 to C.T), Chongqing Entrepreneurship and Innovation Supporting Program for Returned Overseas Students (cx2017104 to C.T), and Chongqing Medical University (CYYQ201507 to C.T).

History

Citation

Cellular Physiology and Biochemistry, 2018, 49 (2), pp. 578-594

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES

Version

VoR (Version of Record)

Published in

Cellular Physiology and Biochemistry

Publisher

Karger

eissn

1421-9778

Acceptance date

20/08/2018

Copyright date

2018

Available date

01/08/2019

Language

en