Biology subjects

Newman, J. W.

Publications and source records attributed to Newman, J. W..

6 recordsLinked to original sources

bioRxiv2026

Metabolomics highlights cardiovascular risk factor links to sphingolipid and one-carbon metabolism in asymptomatic adults

Background: Metabolic perturbations associated with cardiovascular disease (CVD) risk factors prior to clinical disease manifestation may inform novel preventative measures. Here we characterize metabolome-wide associations with various cardiometabolic risk factors in an asymptomatic population to develop a mechanistic metabolic framework of preemergent metabolic shifts. Methods: Plasma was collected from a clinically healthy cross-sectional cohort (n = 361; Clinical Trials.gov ID: NCT02367287). Cohort mass spectrometry-based metabolomics (biocrates MxP(R) Quant 500 kits) were complemented with expanded lipidomic coverage for a sex/age-matched subset with LDLc difference > 60 mg/dL (n = 38). LDLc-focused partial least square regressions and discriminate analyses were performed, after false discovery rate corrections. Results: As LDLc levels increased, plasma sphingolipids and cholesteryl esters, and transulfuration products were higher, while ether-linked phosphatidylcholines serine, glycine, alanine, methionine were lower. The subset analysis further highlighted elevations in triglycerides and deoxyceramides with elevated LDLc. When adjusted for alanine concentrations, deoxyceramide concentrations increased as serine declined (p = 0.0012), and the deoxyceramide:ceramide ratios were higher in the high LDLc group (p = 0.039). Lower serine levels were also accompanied by parallel changes in glycine (p= 0.0004), and anti-parallel changes in transsulfuration pathway metabolites particularly when adjusted for ceramide levels. Notably, the alanine:serine ratio was more strongly associated with fasting triglycerides (r = 0.38; p <0.0001) than LDLc. Conclusions: Serine depletion by increased demands of sphingolipid, and possibly transsulfuration pathway, metabolism is associated with elevations in cytotoxic deoxyceramides and reductions in glycine and methionine availability for one-carbon metabolism. These changes were strongly associated with fasting triglycerides and insulin resistance, a key marker of residual CVD risk.

biochemistry↗

bioRxiv2024

ABCA1 and apoA-I dependent 12-hydroxyeicosatetraenoic acid efflux regulates macrophage inflammatory signaling

Aberrant high-density lipoprotein (HDL) function is implicated in inflammation-associated pathologies. While HDL ABCA1-mediated reverse cholesterol and phospholipid transport are well described, the movement of pro-/anti-inflammatory lipids has not been explored. HDL phospholipids are the largest reservoir of circulating arachidonic acid-derived oxylipins. Endotoxin-stimulation activates inflammatory cells leading to hydroxyeicosatetraenoic acid (HETE) production, oxylipins which are involved in inflammatory response coordination. Active signaling in the non-esterified (NE) pool is terminated by sequestration of HETEs as esterified (Es) forms and degradation. We speculate that an ABCA1-apoA-I-dependent efflux of HETEs from stimulated cells could regulate intracellular HETE availability. Here we test this hypothesis both in vitro and in vivo. In endotoxin-stimulated RAW-264.7 macrophages preloaded with d8-arachidonic acid we use compartmental tracer modeling to characterize the formation of HETEs, and their efflux into HDL. We found that in response to endotoxin: I) Cellular NE 12-HETE is positively associated with MCP-1 secretion (p<0.001); II) HETE transfer from NE to Es pools is ABCA1-depedent (p<0.001); III) Cellular Es HETEs are transported into media when both apoA-I and ABCA1 are present (p<0.001); IV) The stimulated efflux of HETEs >> arachidonate (p<0.001). Finally, in endotoxin challenged humans (n=17), we demonstrate that intravenous lipopolysaccharide (0.6 ng/kg body weight) resulted in accumulation of 12-HETE in HDL over a 168-hour follow-up. Therefore, HDL can suppress inflammatory responses in macrophages by regulating intracellular HETE content in an apoA-I/ABCA1 dependent manner. The described mechanism may apply to other oxylipins and explain anti-inflammatory properties of HDL. This newly defined HDL property opens new doors for the study of lipoprotein interactions in metabolic diseases.

molecular biology↗

bioRxiv2024

Blood-based targeted metabolipidomics reveals altered omega fatty acid-derived lipid mediators in relapsing-remitting multiple sclerosis patients

Unresolved and uncontrolled inflammation is considered a hallmark of pathogenesis in chronic inflammatory diseases like multiple sclerosis (MS), suggesting a defective resolution process. Inflammatory resolution is an active process partially mediated by endogenous metabolites of dietary polyunsaturated fatty acids (PUFA), collectively termed specialized pro-resolving lipid mediators (SPMs). Altered levels of resolution mediators have been reported in several inflammatory diseases and may partly explain impaired inflammatory resolution. Performing LC-MS/MS-based targeted lipid mediator profiling, we observed distinct changes in fatty acid metabolites in serum from 30 relapsing-remitting MS (RRMS) patients relative to 30 matched healthy subjects (HS). Robust linear regression revealed 12 altered lipid mediators after adjusting for confounders (p <0.05). Of these, 15d-PGJ2, PGE3, and LTB5 were increased in MS while PGF2a, 8,9-DiHETrE, 5,6-DiHETrE, 20-HETE, 15-HETE, 12-HETE, 12-HEPE, 14-HDoHE, and DHEA were decreased in MS compared to HS. In addition, 12,13-DiHOME and 12,13-DiHODE were positively correlated with expanded disability status scale values (EDSS). Using Partial Least Squares, we identified several lipid mediators with high VIP scores (VIP > 1: 32% - 52%) of which POEA, PGE3, DHEA, LTB5, and 12-HETE were top predictors for distinguishing between RRMS and HS (AUC =0.75) based on the XGBoost Classifier algorithm. Collectively, these findings suggest an imbalance between inflammation and resolution. Altogether, lipid mediators appear to have potential as diagnostic and prognostic biomarkers for RRMS.

biochemistry↗

bioRxiv2023

Illuminating the Function of the Orphan Transporter, SLC22A10 in Humans and Other Primates

SLC22A10 is classified as an orphan transporter with unknown substrates and function. Here we describe the discovery of the substrate specificity and functional characteristics of SLC22A10. The human SLC22A10 tagged with green fluorescent protein was found to be absent from the plasma membrane, in contrast to the SLC22A10 orthologs found in great apes. Estradiol-17{beta}-glucuronide accumulated in cells expressing great ape SLC22A10 orthologs (over 4-fold, p<0.001). In contrast, human SLC22A10 displayed no uptake function. Sequence alignments revealed two amino acid differences including a proline at position 220 of the human SLC22A10 and a leucine at the same position of great ape orthologs. Site-directed mutagenesis yielding the human SLC22A10-P220L produced a protein with excellent plasma membrane localization and associated uptake function. Neanderthal and Denisovan genomes show human-like sequences at proline 220 position, corroborating that SLC22A10 were rendered nonfunctional during hominin evolution after the divergence from the pan lineage (chimpanzees and bonobos). These findings demonstrate that human SLC22A10 is a unitary pseudogene and was inactivated by a missense mutation that is fixed in humans, whereas orthologs in great apes transport sex steroid conjugates.

pharmacology and toxicology↗

bioRxiv2022

Adipocytes reprogram glucose metabolism in cancer cells promoting metastasis

In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here, we systematically characterized the bi-directional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, [13C]-glucose isotope tracing, and gene expression analysis. We report that omental tumor explants and OvCa cells co-cultured with adipocytes divert part of the glucose from glycolysis and TCA cycle towards glycerol-3-phosphate (G3P) synthesis. Normoxic HIF1 protein, stabilized by adipokines, regulate this altered flow of glucose-derived carbons in cancer cells, resulting in increased synthesis of glycerophospholipids (GPL) and triacylglycerols. Blocking adipocyte-induced HIF1 expression increases lipid peroxidation levels in cancer cells and sensitizes them to ferroptosis-mediated cell death. Subsequently, the knockdown of HIF1 or G3P acyltransferase 3 (a regulatory enzyme of GPL synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis.

cancer biology↗

bioRxiv2020

Serum metabolomic biomarkers of perceptual speed in cognitively normal and mildly impaired subjects with fasting state stratification

Cognitive decline is associated with both normal aging and early pathologies leading to dementia. Here we used quantitative profiling of metabolites involved in the regulation of inflammation, vascular function, neuronal function and energy metabolism, including oxylipins, endocannabinoids, bile acids, and steroid hormones to identify metabolic biomarkers of mild cognitive impairment (MCI). Serum samples (n =210) were obtained from subjects with or without MCI opportunistically collected with incomplete fasting state information. To maximize power and stratify the analysis of metabolite associations with MCI by the fasting state, we developed an algorithm to predict subject fasting state when unknown (n =71). In non-fasted subjects, linoleic acid and palmitoleoyl ethanolamide levels were positively associated with perceptual speed. In fasted subjects, soluble epoxide hydrolase activity and tauro-alpha-muricholic acid levels were negatively associated with perceptual speed. Other cognitive domains showed associations with bile acid metabolism, but only in the non-fasted state. Importantly, this study shows unique associations between serum metabolites and cognitive function in the fasted and non-fasted states and provides a fasting state prediction algorithm based on measurable metabolites.

pathology↗