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Perfluorooctanesulfonate Induces Hepatomegaly and Lipoatrophy in Mice through Phosphoenolpyruvate Carboxykinase-Mediated Glyceroneogenesis Inhibition
journal contribution
posted on 2020-02-05, 16:05 authored by Ling Wang, Huiming Cao, Zhen Zhou, Yu Pan, Guangliang Liu, Thanh Wang, Yawei Wang, Mingwei Xiao, Siyi Chen, Yong LiangPerfluorooctansulfonate
(PFOS) is a persistent organic pollutant
that has attracted a great deal of attention due to toxic effects
such as its lipid metabolism-disrupting potential. Exposure to PFOS
can cause hepatomegaly and lipoatrophy in mice, but the underlying
mechanisms are still unknown. Considering that glyceroneogenesis is
the essential pathway for balancing the triglyceride (TG) cycle between
liver and white adipose tissue (WAT), we speculate that PFOS acts
via glyceroneogenesis inhibition to alter TG metabolism in the two
tissues. Combining gene expression, protein expression, an enzyme
activity assay, and molecular docking analysis, we report here that
PFOS can interact with cytosolic phosphoenolpyruvate carboxykinase
(PEPCK), the rate-limiting enzyme of glyceroneogenesis. Specifically,
by repression of PEPCK, PFOS can inhibit the glyceroneogenesis process
and thus decrease the glyceroneogenesis-derived glycerol level, leading
to a reduced re-esterified TG level and causing atrophy in WAT. Moreover,
in PFOS-exposed liver tissue, despite the fact that free glycerol
and fatty acids released from WAT were being used for TG synthesis,
the export of TG slowed. This eventually resulted in the continuous
lipolysis of WAT and accumulation of lipid in the liver. PEPCK can
be used as a key biomarker to assess the lipid metabolism disorders
induced by other conventional and emerging per- and polyfluoroalkyl
substances.
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Phosphoenolpyruvate Carboxykinase-Mediated Glyceroneogenesis Inhibition Perfluorooctansulfonateenzyme activity assaycytosolic phosphoenolpyruvate carboxykinasePerfluorooctanesulfonate Induces HepatomegalyPFOS-exposed liver tissuerate-limiting enzymegene expressionPFOS actsre-esterified TG levelglyceroneogenesis inhibitionlipid metabolism-disruptingWATglyceroneogenesis processlipid metabolism disordersdocking analysisglyceroneogenesis-derived glycerol levelTG metabolismPEPCKadipose tissuepolyfluoroalkyl substancesprotein expressionTG synthesis
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