1. Hepatic stellate cell activation: A source for bioactive lipids.
- Author
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Shmarakov, Igor O., Jiang, Hongfeng, Liu, Jing, Fernandez, Elias J., and Blaner, William S.
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VITAMIN A , *LIPIDS , *LIVER cells - Abstract
Abstract Hepatic stellate cells (HSCs) are non-parenchymal liver cells that characteristically contain multiple retinoid (vitamin A)-containing lipid droplets. In this study, we addressed the metabolic fate of non-retinoid lipids originating from lipid droplet loss during HSCs activation. UPLC/MS/MS and qRT-PCR were used to monitor the lipid composition and mRNA expression of selected genes regulating lipid metabolism in freshly isolated, overnight-, 3- and 7-day cultures or primary mouse HSCs. A preferential accumulation of specific C20-C24 fatty acid species, especially arachidonic (C20:4) and docosahexaenoic acids (C22:6), was revealed in culture-activated HSCs along with an upregulation of transcription of fatty acid desaturases (Scd1, Scd2) and elongases (Elovl5, Elovl6). This was accompanied with an enrichment of activated HSCs with 36:4 and 38:4 phosphatidylcholine species containing polyunsaturated fatty acids and associated accumulation of selective lipid mediators, including endocannabinoids and related N-acylethanolamides, as well as ceramides. An increase in 2-arachidonoylglycerol and N-arachydonoylethanolamide concentrations was observed along with an upregulation of Daglα mRNA expression in HSCs during culture activation. N-palmitoylethanolamide was identified as the most abundant endocannabinoid-like species in activated HSCs. An increase in total ceramide levels and enrichment with N-palmitoyl (C16:0), N-tetracosenoyl (C24:1), N-tetracosanoyl (C24:0) and N-docosanoyl (C22:0) ceramides was detected in activated HSC cultures and was preceded by increased mRNA expression of ceramide synthesizing enzymes (CerS2 , CerS5 and Smpd1). Our data suggest an active redistribution of non-retinoid lipids in HSCs underlying the formation of low abundance, highly bioactive lipid species that may affect signaling during HSC activation, as well as extracellularly within the liver. Graphical abstract Unlabelled Image Highlights • Culture-activated primary mouse HSCs are enriched with unesterified and phosphatidylcholine-incorporated AA and DHA. • 2-AG and AEA levels are increased during the early stage of HSCs activation. • 2-AG is the predominant endocannabinoid and PEA is the second most abundant endocannabinoid-like species in HSCs during culture activation. • During activation, HSC cultures are enriched with C16:0, C24:1, C24:0 and C22:0 ceramides. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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