Abstract
Plasmalogen biosynthesis is regulated by modulating fatty acyl-CoA reductase 1 stability in a manner dependent on cellular plasmalogen level. However, physiological significance of the regulation of plasmalogen biosynthesis remains unknown. Here we show that elevation of the cellular plasmalogen level reduces cholesterol biosynthesis without affecting the isoprenylation of proteins such as Rab and Pex19p. Analysis of intermediate metabolites in cholesterol biosynthesis suggests that the first oxidative step in cholesterol biosynthesis catalyzed by squalene monooxygenase (SQLE), an important regulator downstream HMG-CoA reductase in cholesterol synthesis, is reduced by degradation of SQLE upon elevation of cellular plasmalogen level. By contrast, the defect of plasmalogen synthesis causes elevation of SQLE expression, resulting in the reduction of 2,3-epoxysqualene required for cholesterol synthesis, hence implying a novel physiological consequence of the regulation of plasmalogen biosynthesis.
Highlights
Physiological significance of plasmalogen homeostasis remains unknown
We show that the cellular plasmalogen level regulates cholesterol synthesis by modulating squalene monooxygenase (SQLE) stability
Cholesterol synthesis is shown to be controlled at multiple steps, including sterol regulatory element-binding protein (SREBP)-mediated transcriptional regulation and post-translational regulation of HMG-CoA reductase (HMGCR), a rate-limiting enzyme of cholesterol synthesis (39, 40)
Summary
Physiological significance of plasmalogen homeostasis remains unknown. Results: Elevation of plasmalogens reduced cholesterol synthesis by enhancing degradation of squalene monooxygenase (SQLE), whereas SQLE was stabilized in the absence of plasmalogens. Conclusion: Plasmalogens regulate cholesterol synthesis by modulating the stability of SQLE. Significance: SQLE stability is modulated in response to the cellular level of plasmalogens, in addition to the acute changes of cholesterol level. Plasmalogen biosynthesis is regulated by modulating fatty acyl-CoA reductase 1 stability in a manner dependent on cellular plasmalogen level. Analysis of intermediate metabolites in cholesterol biosynthesis suggests that the first oxidative step in cholesterol biosynthesis catalyzed by squalene monooxygenase (SQLE), an important regulator downstream HMG-CoA reductase in cholesterol synthesis, is reduced by degradation of SQLE upon elevation of cellular plasmalogen level. The defect of plasmalogen synthesis causes elevation of SQLE expression, resulting in the reduction of 2,3epoxysqualene required for cholesterol synthesis, implying a novel physiological consequence of the regulation of plasmalogen biosynthesis. We report here a novel consequence of cellular plasmalogen level in cholesterol homeostasis
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