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Physiological role of plasmalogen homeostasis in the liver - A link to cholesterol metabolism

Year: 2025
Type: article
Abstract: In mammals, plasmalogens are enriched in the brain, kidney, and heart, while the lowest amounts of plasmalogens are found in the liver. The physiological significance of the low level of plasmalogens in the liver remains unknown. Here, we used alkylglycerol, a precursor that is readily converted to plasmalogen upon exogenous administration, to study the effects of elevated liver plasmalogens on fatty acyl-CoA reductase (FAR1), a rate-limiting enzyme in plasmalogen biosynthesis. Indeed, oral administration of alkylglycerol in wild-type mice augmented plasmalogen levels in the liver and resulted in reduced FAR1 protein levels. Vice versa, we determined increased FAR1 levels in mice with diminished plasmalogen levels due to a genetic defect in plasmalogen biosynthesis. Together, these findings suggest a role of FAR1-mediated regulation of plasmalogen biosynthesis in liver physiology. Further experiments indicated that elevation of plasmalogens in the liver of wild-type mice reduces the protein level of squalene epoxidase, and further suppresses a liver X receptor-mediated transcription of genes encoding ATP-binding cassette transporters such as Abca1, Abcg5, and Abcg8. In the livers of plasmalogen-deficient mice, the expression of Abca1 appears to be reduced due to the suppressed function of the nuclear receptor protein hepatocyte nuclear factor 4. These aberrant expression of transporters causes reduced levels of high-density lipoprotein cholesterol in plasma derived from wild-type mice administered alkylglycerol and plasmalogen synthesis-deficient mice. Taken together, the present results suggest that the homeostasis of plasmalogens, mediated by the regulation of FAR1 protein levels in the liver, plays a physiologically important role in the synthesis of high-density lipoprotein.
DOI: 10.1016/j.bbalip.2025.159695
Authors: Masanori Honsho, Fabian Dorninger, Johannes Berger, Roshni R. Singaraja, Laia Trigueros-Motos, Yuichi Abe, Yukio Fujiki
Institutions: Kyushu University, Medical University of Vienna, Agency for Science, Technology and Research, National University of Singapore, National University Health System, University of Hyogo, Institute of Rheological Functions of Food
Language: English
Subfield: Biochemistry
Open Access status: hybrid
Estimated APC paid: $3,670
Funders: Naito Foundation, Takeda Science Foundation, Novartis Foundation, Takeda Foundation, Austrian Science Fund, Meiji Seika Pharma, NOVARTIS Foundation (Japan) for the Promotion of Science, Japan Society for the Promotion of Science
Awards: Biosynthetic pathways and physiological functions of choline plasmalogens, Peroxisome biogenesis and human disorders, Neurotransmitter Alterations in Ether Lipid Deficiency, G5641478263, Overcoming plasmalogen deficiency in peroxisomal disorders (PERescue), Role of plasmalogens in ether lipid-associated pathologies
OpenAlex ID: W4414920904
FWCI:
Cites: 55
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Related to: 10