Impaired plasmalogen synthesis dysregulates liver X receptor-dependent transcription in cerebellum
Impaired plasmalogen synthesis dysregulates liver X receptor-dependent transcription in cerebellum
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DOI：
10.1093/jb/mvz043
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发表时间：
2019-10-01
影响因子：
2.7
通讯作者：
Fujiki, Yukio
中科院分区：
文献类型：
--
作者：
Honsho, Masanori;Dorninger, Fabian;Fujiki, Yukio
乙醇胺缩醛原（PlsEtn）的合成是通过调节过氧化物酶体膜上脂肪酰基辅酶a还原酶1 （Far1）的稳定性来调控的，Far1是缩醛原合成中的一种限速酶。通过改变角鲨烯环氧化酶（SQLE）的稳定性，plasmalogen稳态失调损害了培养细胞中胆固醇的生物合成。然而，PlsEtn合成的调控和组织内浆醛原稳态的生理后果仍不清楚。在本研究中，我们发现表达缺乏C端区Pex14p的Pex14突变小鼠（Pex14(Delta C/Delta C)）的小脑中Far1的蛋白水平高于野生型小鼠，而非转录水平高于野生型小鼠，这表明PlsEtn水平的降低稳定了Far1。SQLE蛋白水平升高，而Pex14小脑（δ C/ δ C）和合成PlsEtn的初始酶二羟丙酮磷酸酰基转移酶缺乏小鼠的肝X受体（LXRs）的转录活性降低。LXRs是核受体超家族的配体激活转录因子。这些结果表明，小脑中缩醛原的减少更有可能损害胆固醇稳态，从而降低胆固醇稳态的主要调节因子LXRs的转录活性。
Synthesis of ethanolamine plasmalogen (PlsEtn) is regulated by modulating the stability of fatty acyl-CoA reductase 1 (Far1) on peroxisomal membrane, a rate-limiting enzyme in plasmalogen synthesis. Dysregulation of plasmalogen homeostasis impairs cholesterol biosynthesis in cultured cells by altering the stability of squalene epoxidase (SQLE). However, regulation of PlsEtn synthesis and physiological consequences of plasmalogen homeostasis in tissues remain unknown. In the present study, we found that the protein but not the transcription level of Far1 in the cerebellum of the Pex14 mutant mouse expressing Pex14p lacking its C-terminal region (Pex14(Delta C/Delta C)) is higher than that from wild-type mouse, suggesting that Far1 is stabilized by the lowered level of PlsEtn. The protein level of SQLE was increased, whereas the transcriptional activity of the liver X receptors (LXRs), ligand-activated transcription factors of the nuclear receptor superfamily, is lowered in the cerebellum of Pex14(Delta C/Delta C) and the mice deficient in dihydroxyacetonephosphate acyltransferase, the initial enzyme for the synthesis of PlsEtn. These results suggest that the reduction of plasmalogens in the cerebellum more likely compromises the cholesterol homeostasis, thereby reducing the transcriptional activities of LXRs, master regulators of cholesterol homeostasis.