Dysregulation of Plasmalogen Homeostasis Impairs Cholesterol Biosynthesis

Honsho, Masanori; Abe, Yuichi; Fujiki, Yukio

doi:10.1074/jbc.m115.656983

Cited by 53 publications

(40 citation statements)

References 77 publications

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“…However, AG did not significantly increase bile acids or Cyp7a1 expression (http://onlinelibrary.wiley.com/doi/10.1002/hep.29039/suppinfo). Given that increased cellular plasmalogen level has been reported to reduce cholesterol biosynthesis, we tested whether AG reduces hepatic FC level. However, AG did not change hepatic FC level in MCDD‐fed mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice

et al. 2017

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Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat, the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of free cholesterol (FC) in the liver. Cyclodextrin-induced depletion of FC transactivated Δ-6 desaturase by increasing Srebp2 expression in cultured hepatocytes. DHA, the major product of Δ-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat siRNA treatment significantly decreased Pparα expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor alkyl glycerol (AG) prevented hepatic steatosis and NASH through a PPARα-dependent increase in fatty acid oxidation. Gnpat+/− mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. Conclusions Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis via GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH.

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Section: Resultsmentioning

confidence: 99%

Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice

et al. 2017

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“…In line with the importance of plasmalogens for membrane properties, their deprivation strongly impairs cholesterol trafficking [88,89] resulting in accumulation of free cholesterol but reduced levels of esterified cholesterol in ether lipid-deficient mouse and human fibroblasts as well as Chinese hamster ovary (CHO) cells [44, 51,88]. Interestingly, plasmalogen levels also seem to have a direct effect on cholesterol homeostasis, as recently shown by an inverse correlation between the amount of plasmalogen and the extent of cholesterol biosynthesis [90].…”

Section: The Importance Of Plasmalogens As Membrane Constituentsmentioning

confidence: 96%

From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

2017

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The emerging diverse roles of ether (phospho)lipids in nervous system development and function in health and disease are currently attracting growing interest. Plasmalogens, a subgroup of ether lipids, are important membrane components involved in vesicle fusion and membrane raft composition. They store polyunsaturated fatty acids and may serve as antioxidants. Ether lipid metabolites act as precursors for the formation of glycosyl-phosphatidyl-inositol anchors; others, like platelet-activating factor, are implicated in signaling functions. Consolidating the available information, we attempt to provide molecular explanations for the dramatic neurological phenotype in ether lipid-deficient human patients and mice by linking individual functional properties of ether lipids with pathological features. Furthermore, recent publications have identified altered ether lipid levels in the context of many acquired neurological disorders including Alzheimer's disease (AD) and autism. Finally, current efforts to restore ether lipids in peroxisomal disorders as well as AD are critically reviewed.

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“…However, more recently, Honsho et al . described how both the elevation and the decrease in the levels of ether lipids could affect cholesterol homeostasis through the regulation of the stability of squalene monooxygenase (SQLE). This work proposes a crosstalk between the two metabolic pathways, which was confirmed by the work of Kaddurah‐Daouk et al .…”

Section: Crosstalk Of Ether Lipids With Other Lipid Classesmentioning

confidence: 99%

On the road to unraveling the molecular functions of ether lipids

Jiménez‐Rojo

Riezman

2019

FEBS Letters

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Ether lipids are glycerolipids further classified into alkyl‐ether and alkenyl‐ether (also termed plasmalogens) lipids. The two ether lipid subclasses share the first steps of their synthesis. However, alkyl‐ether and alkenyl‐ether lipids differ in their structure and physico‐chemical properties (featuring different head groups) and, thus, probably in their functions. Ether lipids have intermittent distribution across the evolutionary tree and defects in their synthesis have been shown to perturb cellular homeostasis and lead to disease in humans. Here, we review their structure, their interactions with other lipids, and their potential roles in cellular functions, such as membrane homeostasis and membrane trafficking. Moreover, we discuss still unclear aspects of these lipids such as their subcellular distribution, and the need to unravel their molecular functions as well as how novel tools to study lipid biology will help clarify these aspects.

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Dysregulation of Plasmalogen Homeostasis Impairs Cholesterol Biosynthesis

Cited by 53 publications

References 77 publications

Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice

Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice

From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

On the road to unraveling the molecular functions of ether lipids

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