Lipid molecular timeline profiling reveals diurnal crosstalk between the liver and circulation

Sprenger, Richard R.; Hermansson, Martin; Neess, Ditte; Becciolini, Lena Sokol; Sørensen, Signe Bek; Fagerberg, Rolf; Ecker, Josef; Liebisch, Gerhard; Jensen, Ole N.; Vance, Dennis E.; Færgeman, Nils J.; Klemm, Robin W.; Ejsing, Christer S.

doi:10.1016/j.celrep.2021.108710

Cited by 38 publications

(35 citation statements)

References 53 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, MS ALL analysis is a lipidomics technology that affords high-fidelity identification and accurate quantification of molecular lipid species at a lipidome-wide level using high-resolution tandem mass spectrometry (MS/MS). 45,46 This analysis demonstrated a dose-dependent reduction in CerS2-specific ceramide products with VLCFAs, including Cer d18:1/24:1 and Cer d18:1/24:0 (Figure 2D). In addition, we observed an increase in the long-chain fatty acyl (LCFA)-containing ceramides, including Cer d18:1/16:0, Cer d18:1/ 18:0, and Cer d18:1/14:0.…”

Section: Potent Asos Reduce Cers2 Activitymentioning

confidence: 89%

Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death

et al. 2022

Self Cite

View full text Add to dashboard Cite

Emerging clinical data show that three ceramide molecules, Cer d18:1/16:0, Cer d18:1/24:1, and Cer d18:1/24:0, are biomarkers of a fatal outcome in patients with cardiovascular disease. This finding raises basic questions about their metabolic origin, their contribution to disease pathogenesis, and the utility of targeting the underlying enzymatic machinery for treatment of cardiometabolic disorders. Here, we outline the development of a potent N-acetylgalactosamine-conjugated antisense oligonucleotide engineered to silence ceramide synthase 2 specifically in hepatocytes in vivo. We demonstrate that this compound reduces the ceramide synthase 2 mRNA level and that this translates into efficient lowering of protein expression and activity as well as Cer d18:1/24:1 and Cer d18:1/24:0 levels in liver. Intriguingly, we discover that the hepatocyte-specific antisense oligonucleotide also triggers a parallel modulation of blood plasma ceramides, revealing that the biomarkers predictive of cardiovascular death are governed by ceramide biosynthesis in hepatocytes. Our work showcases a generic therapeutic framework for targeting components of the ceramide enzymatic machinery to disentangle their roles in disease causality and to explore their utility for treatment of cardiometabolic disorders.

show abstract

Section: Potent Asos Reduce Cers2 Activitymentioning

confidence: 89%

Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Unlike yeast cells, a sole methyltransferase, namely PE N -methyltransferase (PEMT), has been thought to be responsible for the PE-to-PC sequential methylation in hepatocytes ( Vance, 2014 ). However, Sprenger et al (2021) recently reported that PMME is highly accumulated in PEMT gene knockout mice, suggesting that, as well as in yeast cells, PE-to-PMME methylation and PMME-to-PC methylation are performed by different methyltransferases in mammalian cells. In mammals, PEMT is mainly expressed in the liver, which serves as the predominant site of PE-to-PC sequential methylation ( Vance, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Induction and Aggravation of the Endoplasmic-Reticulum Stress by Membrane-Lipid Metabolic Intermediate Phosphatidyl-N-Monomethylethanolamine

Ishiwata-Kimata

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Phosphatidylcholine (PC) is produced via two distinct pathways in both hepatocytes and yeast, Saccharomyces cerevisiae. One of these pathways involves the sequential methylation of phosphatidylethanolamine (PE). In yeast cells, the methyltransferase, Cho2, converts PE to phosphatidylmonomethylethanolamine (PMME), which is further modified to PC by another methyltransferase, Opi3. On the other hand, free choline is utilized for PC production via the Kennedy pathway. The blockage of PC production is well known to cause endoplasmic reticulum (ER) stress and activate the ER-stress sensor, Ire1, to induce unfolded protein response (UPR). Here, we demonstrate that even when free choline is sufficiently supplied, the opi3Δ mutation, but not the cho2 Δ mutation, induces the UPR. The UPR was also found to be induced by CHO2 overexpression. Further, monomethylethanolamine, which is converted to PMME probably through the Kennedy pathway, caused or potentiated ER stress in both mammalian and yeast cells. We thus deduce that PMME per se is an ER-stressing molecule. Interestingly, spontaneously accumulated PMME seemed to aggravate ER stress in yeast cells. Collectively, our findings demonstrate the multiple detrimental effects of the low-abundance phospholipid species, PMME.

show abstract

“…The metabolism of chylomicron PLs and TAGs after feeding milk fat thus contributes nitrogen bases and PUFAs to both the high PL turnover in the liver and to the lyso-PC formation that transports both fatty acids and nitrogen bases to extrahepatic tissues, including the brain. Recent studies have exemplified that analysis of time courses using stable isotopes ( 156 , 178 ) will clarify the nutritional, diurnal, and developmental regulations of these pathways in the near future.…”

Section: Discussionmentioning

confidence: 99%

Digestion and Absorption of Milk Phospholipids in Newborns and Adults

2021

View full text Add to dashboard Cite

Milk polar lipids provide choline, ethanolamine, and polyunsaturated fatty acids, which are needed for the growth and plasticity of the tissues in a suckling child. They may also inhibit cholesterol absorption by interacting with cholesterol during micelle formation. They may also have beneficial luminal, mucosal, and metabolic effects in both the neonate and the adult. The milk fat globule membrane contains large proportions of sphingomyelin (SM), phosphatidylcholine (PC), and phosphatidylethanolamine (PE), and some phosphatidylserine (PS), phosphatidylinositol (PI), and glycosphingolipids. Large-scale technical procedures are available for the enrichment of milk fat globule membrane (MFGM) in milk replacement formulations and food additives. Pancreatic phospholipase A2 (PLA2) and mucosal phospholipase B digest glycero-phospholipids in the adult. In the neonate, where these enzymes may be poorly expressed, pancreatic lipase-related protein 2 probably has a more important role. Mucosal alkaline SM-ase and ceramidase catalyze the digestion of SM in both the neonate and the adult. In the mucosa, the sphingosine is converted into sphingosine-1-phosphate, which is both an intermediate in the conversion to palmitic acid and a signaling molecule. This reaction sequence also generates ethanolamine. Here, we summarize the pathways by which digestion and absorption may be linked to the biological effects of milk polar lipids. In addition to the inhibition of cholesterol absorption and the generation of lipid signals in the gut, the utilization of absorbed choline and ethanolamine for mucosal and hepatic phospholipid synthesis and the acylation of absorbed lyso-PC with polyunsaturated fatty acids to chylomicron and mucosal phospholipids are important.

show abstract

Lipid molecular timeline profiling reveals diurnal crosstalk between the liver and circulation

Cited by 38 publications

References 53 publications

Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death

Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death

Induction and Aggravation of the Endoplasmic-Reticulum Stress by Membrane-Lipid Metabolic Intermediate Phosphatidyl-N-Monomethylethanolamine

Digestion and Absorption of Milk Phospholipids in Newborns and Adults

Contact Info

Product

Resources

About