Biology subjects

Meckelmann, S.

Publications and source records attributed to Meckelmann, S..

3 recordsLinked to original sources

bioRxiv2024

Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis

Aging hampers the regenerative potential of intestinal epithelium across species including humans, yet the underlying causes remain elusive. Here, using proteomic and metabolomic profiling of intestinal tissues together with functional assays, we characterized the temporal dynamics of regeneration following injury induced by 5-fluorouracil, a commonly used chemotherapeutic agent. Comparison of regeneration dynamics in mice of different ages revealed the emergence of a proteostasis stress signature and increased levels of polyamines following injury exclusively in old epithelia. Mechanistically, we show that delayed regeneration is an intrinsic feature of aged epithelial cells that display reduced protein synthesis and accumulation of ubiquitylated proteins. Notably, dietary restriction followed by re-feeding prior to injury increases polyamine pathway activation, enhances protein synthesis, and restores the regenerative capacity of aged intestines. Our findings highlight promising epithelial targets for interventions aimed at tackling the decline in tissue repair mechanisms associated with aging.

molecular biology↗

bioRxiv2020

Oxylipin metabolism is controlled by mitochondrial b-oxidation during bacterial inflammation.

Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial {beta}-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin {beta}-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-{gamma}. Last, dampening oxylipin levels by {beta}-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial {beta}-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation.

biochemistry↗

bioRxiv2019

Metabolic dysregulation of the lysophospholipid/autotaxin axis in the chromosome 9p21 gene SNP rs10757274

AimsCommon chromosome 9p21 SNPs increase coronary heart disease (CHD) risk, independent of \"traditional lipid risk factors\". However, lipids comprise large numbers of structurally-related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here we applied lipidomic and genomic approaches to three model systems, to characterize lipid metabolic changes in common Chr9p21 SNPs which confer [~]30% elevated CHD risk associated with altered expression of ANRIL, a long ncRNA.\n\nMethods and ResultsUntargeted and targeted lipidomics was applied to plasma samples from Northwick Park Heart Study II (NPHSII) homozygotes for AA or GG in rs10757274. Elevated risk GG correlated with reduced lysophosphospholipids (lysoPLs), lysophosphatidic acids (lysoPA) and autotaxin (ATX). Five other risk SNPs did not show this phenotype. Correlation and network analysis showed that lysoPL-lysoPA interconversion was uncoupled from ATX in GG, indicating metabolic dysregulation. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK293 cells was mined. Significantly-altered expression of several lysoPL/lysoPA metabolising enzymes was found (MBOAT2, PLA2G4C, LPCAT2, ACSL6, PNPLA2, PLBD1, PLPP1, PLPP2 and PLPPR2). Next, vascular smooth muscle cells differentiated from iPSCs of individuals homozygous for Chr9p21 risk SNPs were examined. Here, the presence of risk alleles was associated with altered expression of several lysoPL/lysoPA enzymes. Importantly, for several, deletion of the risk locus fully or partially reversed their expression to non-risk haplotype levels: ACSL3, DGKA, PLA2G2A, LPCAT2, LPL, PLA2G3, PNPLA3, PLA2G12A LIPC, LCAT, PLA2G6, ACSL1, MBOAT2.\n\nConclusionA Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their enzymatic metabolism. Lipid metabolites and genomic pathways associated with CHD pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.\n\nOne sentence summaryInflammatory phospholipid metabolism defines a cardiovascular disease SNP

physiology↗