Trajectory of plasma lipidome associated with the risk of late-onset Alzheimer's disease: a longitudinal cohort study.

Background: Comprehensive lipidomic studies have demonstrated strong cross-sectional associations between the blood lipidome and late-onset Alzheimer's disease (AD) dementia and its risk factors, yet the longitudinal relationship between lipidome changes and AD progression remains unclear.

Methods: We employed longitudinal lipidomic profiling on 4730 plasma samples from 1517 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to investigate the temporal evolution of lipidomes among diagnostic groups. At baseline (n = 1393), participants were classified as stable diagnosis status including stable AD (n = 243), stable cognitive normal (CN; n = 337), and stable mild cognitive impairment (MCI; n = 413), or converters (AD converters: n = 329; MCI converters: n = 71).

Modulation of endogenous plasmalogens by genetic ablation of lysoplasmalogenase (Tmem86b) in mice.

Plasmalogens are a distinct subclass of glycerophospholipids that exhibit unique structural features, notably possessing a vinyl ether linkage at the sn1 position of the glycerol backbone. These specialized lipids play crucial roles in various biological functions. Although the biosynthetic pathway of plasmalogens has been well-characterized, their catabolism remains less studied.

Acute exposure to high-fat diet impairs ILC3 functions and gut homeostasis.

Prolonged exposure to a high-fat diet (HFD) exacerbates intestinal disease pathology, yet the early events preceding the development of gut inflammation remain poorly understood. Here, we show that within 48 h, HFD impairs intestinal group 3 innate lymphoid cells (ILC3s) and their capacity to produce interleukin-22 (IL-22), critical for maintaining gut homeostasis. This loss of function was associated with rapid dysbiosis, increased gut permeability, and reduced production of antimicrobial peptides, mucus, and tight-junction proteins.

Statin effects on the lipidome: Predicting statin usage and implications for cardiovascular risk prediction.

Statin therapy is a highly successful and cost-effective strategy for the prevention and treatment of cardiovascular diseases (CVD). Adjusting for statin usage is crucial when exploring the association of the lipidome with CVD to avoid erroneous conclusions. However, practical challenges arise in real-world scenarios due to the frequent absence of statin usage information.

Oncogenic small extracellular vesicles enriched in sphingosine-1-phosphate play a crucial role in pancreatic cancer progression.

Small extracellular vesicles (sEVs) from tumour cells mediate intercellular communication and signalling to regulate the progression of pancreatic ductal adenocarcinoma (PDAC). While we and others have shown that PDAC-derived sEVs comprise oncogenic protein and nucleic acid cargo, understanding the lipid landscape of these sEVs remains unknown. Lipids influence both the composition of sEVs and their roles in lipid metabolism and signalling pathways within the tumour microenvironment and tumorigenesis.

Beyond platelet activation: dysregulated lipid metabolism in defining risk and pathophysiology of VITT.

Background: VITT has emerged as a rare but serious adverse event linked primarily to adenoviral vector COVID-19 vaccinations, such as ChAdOx1-S (Oxford/AstraZeneca) vaccination. The syndrome is characterized by thrombosis with thrombocytopenia, elevated D-dimer, and pathologic platelet factor 4 antibodies within 42 days of vaccination.

Objectives: Despite dysregulated lipid metabolism underpinning many thrombotic conditions, the role of lipid alterations in VITT remains unexplored.

Reduced PI3K(p110α) induces atrial myopathy, and PI3K-related lipids are dysregulated in athletes with atrial fibrillation.

Background: Elucidating mechanisms underlying atrial myopathy, which predisposes individuals to atrial fibrillation (AF), will be critical for preventing/treating AF. In a serendipitous discovery, we identified atrial enlargement, fibrosis, and thrombi in mice with reduced phosphoinositide 3-kinase (PI3K) in cardiomyocytes. PI3K(p110α) is elevated in the heart with exercise and is critical for exercise-induced ventricular enlargement and protection, but the role in the atria was unknown.

An optimized plasmalogen modulating dietary supplement provides greater protection in a male than female mouse model of dilated cardiomyopathy.

We previously reported that plasmalogens, a class of phospholipids, were decreased in a setting of dilated cardiomyopathy (DCM). Plasmalogen levels can be modulated via a dietary supplement called alkylglycerols (AG) which has demonstrated benefits in some disease settings. However, its therapeutic potential in DCM remained unknown.

Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer's disease in humans.

Background: Alzheimer's disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear.

Method: In this post-hoc analysis of a randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome in the context of AD biomarkers, analyzing 784 lipid species across 47 classes using a targeted lipidomics platform.

Hepatic retinol dehydrogenase 11 dampens stress associated with the maintenance of cellular cholesterol levels.

Objective: Dysregulation of hepatic cholesterol metabolism can contribute to elevated circulating cholesterol levels, which is a significant risk factor for cardiovascular disease. Cholesterol homeostasis in mammalian cells is tightly regulated by an integrated network of transcriptional and post-transcriptional signalling pathways. Whilst prior studies have identified many of the central regulators of these pathways, the extended supporting networks remain to be fully elucidated.

Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36.

Lipids contribute to hematopoiesis and membrane properties and dynamics; however, little is known about the role of lipids in megakaryopoiesis. Here we show that megakaryocyte progenitors, megakaryocytes and platelets present a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake as well as de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production.

A lipidomic based metabolic age score captures cardiometabolic risk independent of chronological age.

Background: Metabolic ageing biomarkers may capture the age-related shifts in metabolism, offering a precise representation of an individual's overall metabolic health.

Methods: Utilising comprehensive lipidomic datasets from two large independent population cohorts in Australia (n = 14,833, including 6630 males, 8203 females), we employed different machine learning models, to predict age, and calculated metabolic age scores (mAge). Furthermore, we defined the difference between mAge and age, termed mAgeΔ, which allow us to identify individuals sharing similar age but differing in their metabolic health status.

Development and validation of a plasmalogen score as an independent modifiable marker of metabolic health: population based observational studies and a placebo-controlled cross-over study.

Background: Decreased levels of circulating ethanolamine plasmalogens [PE(P)], and a concurrent increase in phosphatidylethanolamine (PE) are consistently reported in various cardiometabolic conditions. Here we devised, a plasmalogen score (Pls Score) that mirrors a metabolic signal that encompasses the levels of PE(P) and PE and captures the natural variation in circulating plasmalogens and perturbations in their metabolism associated with disease, diet, and lifestyle.

Methods: We utilised, plasma lipidomes from the Australian Obesity, Diabetes and Lifestyle study (AusDiab; n = 10,339, 55% women) a nationwide cohort, to devise the Pls Score and validated this in the Busselton Health Study (BHS; n = 4,492, 56% women, serum lipidome) and in a placebo-controlled crossover trial involving Shark Liver Oil (SLO) supplementation (n = 10, 100% men).

A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility.

The cellular lipidome comprises thousands of unique lipid species. Here, using mass spectrometry-based targeted lipidomics, we characterize the lipid landscape of human and mouse immune cells ( www.cellularlipidatlas.

ACAD10 is not required for metformin's metabolic actions or for maintenance of whole-body metabolism in C57BL/6J mice.

Aim: Acyl-coenzyme A dehydrogenase family member 10 (ACAD10) is a mitochondrial protein purported to be involved in the fatty acid oxidation pathway. Metformin is the most prescribed therapy for type 2 diabetes; however, its precise mechanisms of action(s) are still being uncovered. Upregulation of ACAD10 is a requirement for metformin's ability to inhibit growth in cancer cells and extend lifespan in Caenorhabditis elegans.

Pitavastatin treatment remodels the HDL subclass lipidome and proteome in hypertriglyceridemia.

HDL particles vary in lipidome and proteome, which dictate their individual physicochemical properties, metabolism, and biological activities. HDL dysmetabolism in nondiabetic hypertriglyceridemia (HTG) involves subnormal HDL-cholesterol and apoAI levels. Metabolic anomalies may impact the qualitative features of both the HDL lipidome and proteome.

Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC.

The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH-driven HCC, the mouse fed a high-fat diet.

Administration of an LXR agonist promotes atherosclerotic lesion remodelling in murine inflammatory arthritis.

Objectives: The leading cause of mortality in patients with rheumatoid arthritis is atherosclerotic cardiovascular disease (CVD). We have shown that murine arthritis impairs atherosclerotic lesion regression, because of cellular cholesterol efflux defects in haematopoietic stem and progenitor cells (HSPCs), causing monocytosis and impaired atherosclerotic regression. Therefore, we hypothesised that improving cholesterol efflux using a Liver X Receptor (LXR) agonist would improve cholesterol efflux and improve atherosclerotic lesion regression in arthritis.

Estrogen receptor alpha deficiency in cardiomyocytes reprograms the heart-derived extracellular vesicle proteome and induces obesity in female mice.

Dysregulation of estrogen receptor alpha (ERα) has been linked with increased metabolic and cardiovascular disease risk. Here, we generate and characterize cardiomyocyte-specific ERα knockout (ERαHKO) mice to assess the role of ERα in the heart. The most striking phenotype was obesity in female ERαHKO but not male ERαHKO mice.

Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36.

Lipids contribute to hematopoiesis and membrane properties and dynamics, however, little is known about the role of lipids in megakaryopoiesis. Here, a lipidomic analysis of megakaryocyte progenitors, megakaryocytes, and platelets revealed a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake and de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production.

Comprehensive Targeted Lipidomic Profiling for Research and Clinical Applications.

Mass spectrometry remains one of the gold standard approaches in examining the lipidome in biological samples. Recently, advancements in chromatography and mass spectrometry approaches have enabled broad coverage of the lipidome. However, many limitations still exist, and lipidomic analysis often requires a fine balance between coverage of the lipidome, structural detail, and sample throughput.

Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease.

We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts.

Identification of novel lipid biomarkers in xmrk- and Myc-induced models of hepatocellular carcinoma in zebrafish.

Background: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and is accompanied by complex dysregulation of lipids. Increasing evidence suggests that particular lipid species are associated with HCC progression. Here, we aimed to identify lipid biomarkers of HCC associated with the induction of two oncogenes, xmrk, a zebrafish homolog of the human epidermal growth factor receptor (EGFR), and Myc, a regulator of EGFR expression during HCC.

Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer.

Background: Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC.