Polyamine Pathway Inhibitor DENSPM Suppresses Lipid Metabolism in Pheochromocytoma Cell Line.

Pheochromocytomas (PCCs) are tumors arising from chromaffin cells in the adrenal medulla, and paragangliomas (PGLs) are tumors derived from extra-adrenal sympathetic or parasympathetic paraganglia; these tumors are collectively referred to as PPGL cancer. Treatment for PPGL primarily involves surgical removal of the tumor, and only limited options are available for treatment of the disease once it becomes metastatic. Human carriers of the heterozygous mutations in the succinate dehydrogenase subunit B (SDHB) gene are susceptible to the development of PPGL. A physiologically relevant PCC patient-derived cell line hPheo1 was developed, and SDHB_KD cells carrying a stable short hairpin knockdown of SDHB were derived from it. An untargeted metabolomic approach uncovered an overactive polyamine pathway in the SDHB_KD cells that was subsequently fully validated in a large set of human SDHB-mutant PPGL tumor samples. We previously reported that treatment with the polyamine metabolism inhibitor N1,N11-diethylnorspermine (DENSPM) drastically inhibited growth of these PCC-derived cells in culture as well as in xenograft mouse models. Here we explored the mechanisms underlying DENSPM action in hPheo1 and SDHB_KD cells. Specifically, by performing an RNAseq analysis, we have identified gene expression changes associated with DENSPM treatment that broadly interfere with all aspects of lipid metabolism, including fatty acid (FA) synthesis, desaturation, and import/uptake. Furthermore, by performing an untargeted lipidomic liquid chromatography-mass spectrometry (LC/MS)-based analysis we uncovered specific groups of lipids that are dramatically reduced as a result of DENSPM treatment. Specifically, the bulk of plasmanyl ether lipid species that have been recently reported as the major determinants of cancer cell fate are notably decreased. In summary, this work suggests an intersection between active polyamine and lipid pathways in PCC cells.

Sea Cucumber Phospholipids Regulate Cholesterol Metabolism in High-Fat Diet-Induced ApoE-/- Mice.

BACKGROUND: Sea cucumber phospholipids, marine-derived lipids with high nutritional functions, have been proven to exhibit various biological activities. However, it is unclear how sea cucumber phospholipids regulate cholesterol (Chol) metabolism in atherosclerosis. OBJECTIVES: This study aimed to investigate the effects and mechanism of sea cucumber phospholipids on the metabolism of Chol and cholesterol esters (CE) in ApoE-/- mice, including plasmenyl phosphatidylethanolamine (PE-P) and plasmanyl phosphatidylcholine (PC-O). METHODS: Male ApoE-/- mice were fed with Chow diet, high-fat diet (HFD), and HFD supplemented with PC-O or PE-P, respectively. We integrated a targeted lipidomics strategy to classify and compare the cholesteryl esters according to their fatty acid types, and then analyzed the individual cholesteryl ester molecular species in the liver and serum of mice. Furthermore, the Chol metabolism-related genes and pathways were analyzed in high-fat-induced ApoE-/- mice. RESULTS: Biochemical analysis showed that sea cucumber phospholipids significantly inhibit the generation of arterial plaque in ApoE-/- mice. Compared with the HFD group, PE-P significantly reduced the contents of SFA-CE and MUFA-CE in mice liver (P < 0.05), whereas PC-O particularly upregulated CE20:5 and CE22:6 in the serum of mice (P < 0.001). Furthermore, PC-O and PE-P inhibited the Chol synthesis pathway (Cyp7A1 and Cyp27A1), as well as promoted the catabolism of Chol by upregulating gene expressions of bile acid synthesis (Abcb11) and lysosomal activity (Lamp1), respectively. CONCLUSIONS: Sea cucumber phospholipids could ameliorate the atherosclerosis symptoms by regulating Chol metabolism. J Nutr 20xx;x:xx.

Tricky Isomers-The Evolution of Analytical Strategies to Characterize Plasmalogens and Plasmanyl Ether Lipids.

Typically, glycerophospholipids are represented with two esterified fatty acids. However, by up to 20%, a significant proportion of this lipid class carries an ether-linked fatty alcohol side chain at the sn-1 position, generally referred to as ether lipids, which shape their specific physicochemical properties. Among those, plasmalogens represent a distinct subgroup characterized by an sn-1 vinyl-ether double bond. The total loss of ether lipids in severe peroxisomal defects such as rhizomelic chondrodysplasia punctata indicates their crucial contribution to diverse cellular functions. An aberrant ether lipid metabolism has also been reported in multifactorial conditions including Alzheimer's disease. Understanding the underlying pathological implications is hampered by the still unclear exact functional spectrum of ether lipids, especially in regard to the differentiation between the individual contributions of plasmalogens (plasmenyl lipids) and their non-vinyl-ether lipid (plasmanyl) counterparts. A primary reason for this is that exact identification and quantification of plasmalogens and other ether lipids poses a challenging and usually labor-intensive task. Diverse analytical methods for the detection of plasmalogens have been developed. Liquid chromatography-tandem mass spectrometry is increasingly used to resolve complex lipid mixtures, and with optimized parameters and specialized fragmentation strategies, discrimination between ethers and plasmalogens is feasible. In this review, we recapitulate historic and current methodologies for the recognition and quantification of these important lipids and will discuss developments in this field that can contribute to the characterization of plasmalogens in high structural detail.

Etherglycerophospholipids and ferroptosis: structure, regulation, and location.

Two pioneering studies by Zou et al. and Cui et al. have reported that the synthesis of etherglycerophospholipids (etherPLs) sensitizes cells to ferroptosis. The location and regulation of etherPLs suggest that: (i) lipid peroxidation in the inner leaflet of the plasma membrane might be of importance in ferroptosis, and (ii) different etherPLs may differently sensitize cells to ferroptosis.

Anthracyclins Increase PUFAs: Potential Implications in ER Stress and Cell Death.

Metabolic and personalized interventions in cancer treatment require a better understanding of the relationship between the induction of cell death and metabolism. Consequently, we treated three primary liver cancer cell lines with two anthracyclins (doxorubicin and idarubin) and studied the changes in the lipidome. We found that both anthracyclins in the three cell lines increased the levels of polyunsaturated fatty acids (PUFAs) and alkylacylglycerophosphoethanolamines (etherPEs) with PUFAs. As PUFAs and alkylacylglycerophospholipids with PUFAs are fundamental in lipid peroxidation during ferroptotic cell death, our results suggest supplementation with PUFAs and/or etherPEs with PUFAs as a potential general adjuvant of anthracyclins. In contrast, neither the markers of de novo lipogenesis nor cholesterol lipids presented the same trend in all cell lines and treatments. In agreement with previous research, this suggests that modulation of the metabolism of cholesterol could be considered a specific adjuvant of anthracyclins depending on the type of tumor and the individual. Finally, in agreement with previous research, we found a relationship across the different cell types between: (i) the change in endoplasmic reticulum (ER) stress, and (ii) the imbalance between PUFAs and cholesterol and saturated lipids. In the light of previous research, this imbalance partially explains the sensitivity to anthracyclins of the different cells. In conclusion, our results suggest that the modulation of different lipid metabolic pathways may be considered for generalized and personalized metabochemotherapies.

Lipidomics Approach in High-Fat-Diet-Induced Atherosclerosis Dyslipidemia Hamsters: Alleviation Using Ether-Phospholipids in Sea Urchin.

Ether-phospholipids (ether-PLs) in sea urchins, especially eicosapentaenoic-acid-enriched plasmenyl phosphatidylethanolamine (PE-P) and plasmanyl phosphatidylcholine (PC-O), exhibit potential lipid-regulating effects. However, their underlying regulatory mechanisms have not yet been elucidated. Herein, we integrated an untargeted lipidomics strategy and biochemical analysis to investigate these mechanisms in high-fat-induced atherosclerotic hamsters. Dietary supplementation with PE-P and PC-O decreased total cholesterol and low-density lipoprotein cholesterol concentrations in serum. The lipid regulatory effects of PE-P were superior to those of PC-O. Additionally, 20 lipid molecular species, including phosphatidylethanolamine, cholesteryl ester, triacylglycerol, and phosphatidylinositol, were identified as potential lipid biomarkers in the serum of hamsters with PC-O and PE-P treatment (95% confidence interval; p < 0.05). The variations of lipids may be attributed to downregulation of adipogenesis genes and upregulation of lipid ß-oxidation genes and bile acid biosynthesis genes. The improved lipid homeostasis by ether-PLs in sea urchins might be a key pathway underlying the antiatherosclerosis effect.

Ether-linked lipids of Dermabacter hominis, a human skin actinobacterium.

Dermabacter hominis is a medically important actinobacterial inhabitant of human skin, although it is rarely implicated in infections. The lipid composition of D. hominis is revisited in this study in the context of its natural resistance to daptomycin, an antibiotic whose activity is influenced by membrane lipids. Thin layer chromatography and mass spectrometry revealed that this species contains phospholipids and glycolipids. Using electrospray ionization time of flight mass spectrometry (exact mass) and gas chromatography-mass spectrometry, the major phospholipid of D. hominis was identified as plasmanyl-phosphatidylglycerol (pPG), because it presented one alkyl chain and one acyl chain in the glycerol moiety of the molecule. The structure of the major glycolipid (GL1) was studied by combined gas-liquid chromatography, mass spectrometry and nuclear magnetic resonance, and was established as galactosyl-α-(1→2)-glucosyl-alkyl-acyl-glycerol. Lipid analyses showed differences between one daptomycin-resistant (DAP-R) strain and one daptomycin-sensitive (DAP-S) strain growing in the presence of the antibiotic: DAP-R tended to accumulate GL1 and to reduce pPG, whereas DAP-S maintained high proportions of pPG. The results demonstrate the existence of ether-linked lipids in D. hominis and reveal a differential distribution of phospholipids and glycolipids according to the sensitivity or resistance to daptomycin, although the mechanism(s) operating in the resistance to the antibiotic remain(s) to be elucidated.