In this era of genomics, transcriptomics, and proteomics, metabolomics is emerging as an important component of the omics evolution ( 1 ). Of the four kinds of biological molecules that comprise the human body, i.e., nucleic acids, amino acids (proteins), carbohydrates (sugars), and lipids (fats), lipids stand out among the various cellular metabolites in the sheer number of distinct molecular species. Using state-of-the-art lipidomics approaches made possible by newly developed instrumentation, protocols, and bioinformatics tools ( 2 ), the LIPID MAPS Consortium Abstract The focus of the present study was to defi ne the human plasma lipidome and to establish novel analytical methodologies to quantify the large spectrum of plasma lipids. Partial lipid analysis is now a regular part of every patient's blood test and physicians readily and regularly prescribe drugs that alter the levels of major plasma lipids such as cholesterol and triglycerides. Plasma contains many thousands of distinct lipid molecular species that fall into six main categories including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterols, and prenols. The physiological contributions of these diverse lipids and how their levels change in response to therapy remain largely unknown. As a fi rst step toward answering these questions, we provide herein an in-depth lipidomics analysis of a pooled human plasma obtained from healthy individuals after overnight fasting and with a gender balance and an ethnic distribution that is representative of the US population. In total, we quantitatively assessed the levels of over 500 distinct molecular species distributed among the main lipid categories. As more information is obtained regarding the roles of individual lipids in health and disease, it seems likely that future blood tests will include an ever increasing number of these lipid molecules. -Quehenberger, O., A.
Summary Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions, but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent response pathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomic methods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formation within the peritoneal cavities of mice. Foam cell formation was associated with significant changes in hundreds of lipid species and unexpected suppression, rather than activation, of inflammatory gene expression. We provide evidence that regulated accumulation of desmosterol underlies many of the homeostatic responses observed in macrophage foam cells, including activation of LXR target genes, inhibition of SREBP target genes, selective reprogramming of fatty acid metabolism and suppression of inflammatory response genes. These observations suggest that macrophage activation in atherosclerotic lesions results from extrinsic, pro-inflammatory signals generated within the artery wall that suppress homeostatic and anti-inflammatory functions of desmosterol.
We report the lipidomic response of the murine macrophage RAW cell line to Kdo 2 -lipid A, the active component of an inflammatory lipopolysaccharide functioning as a selective TLR4 agonist and compactin, a statin inhibitor of cholesterol biosynthesis. Analyses of lipid molecular species by dynamic quantitative mass spectrometry and concomitant transcriptomic measurements define the lipidome and demonstrate immediate responses in fatty acid metabolism represented by increases in eicosanoid synthesis and delayed responses characterized by sphingolipid and sterol biosynthesis. Lipid remodeling of glycerolipids, glycerophospholipids, and prenols also take place, indicating that activation of the innate immune system by inflammatory mediators leads to alterations in a majority of mammalian lipid categories, including unanticipated effects of a statin drug. Our studies provide a systems-level view of lipid metabolism and reveal significant connections between lipid and cell signaling and biochemical pathways that contribute to innate immune responses and to pharmacological perturbations.The "omics" revolution has provided significant insight into the genes, mRNAs, and proteins of mammalian cells, biological systems, and disease (1-3). An important function of these macromolecular classes is the production of metabolites that in turn are used by cells for replication and function. Lipids comprise major structural and metabolic components of cells and have essential functions in the formation of membranes, energy production, and intracellular signaling. Despite the central role of lipids in mammalian cell function, there has been no systematic effort to define the lipid "parts list" of a mammalian cell or the changes in these lipids associated with cellular function and disease. Many biochemical pathways leading to the synthesis and degradation of major lipid categories are known, but how these pathways interact under normal and pathological conditions remains unexplored. Recent advances in mass spectrometry have made it possible to qualitatively and quantitatively analyze a majority of cellular lipids (4 -8). We report here a comprehensive systems-level analysis of a mammalian cell lipidome through temporal measurements.We characterized lipidomic responses of RAW264.7 (RAW) macrophages to a highly specific ligand for Toll-like receptor 4 (TLR4) 4 that mimics aspects of bacterial infection. This model is of particular interest because of the essential roles that alterations in macrophage lipid metabolism play in innate and adaptive immune responses and the development of chronic inflammatory and cardiovascular diseases. Recent studies further suggest that TLR signaling in macrophages is not only required for innate immunity against viral and bacterial pathogens but also contributes to the pathogenesis of atherosclerosis, diabetes, arthritis, and other inflammatory diseases (9). Although TLR4 signaling is known to exert profound effects on the macrophage transcriptome (10), proteome (11), and selected lipid species that...
Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming one of the most common forms of liver disease in Abstract The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. Recognition and timely diagnosis of these different stages, particularly NASH, is important for both potential reversibility and limitation of complications. Liver biopsy remains the clinical standard for defi nitive diagnosis. Diagnostic tools minimizing the need for invasive procedures or that add information to histologic data are important in novel management strategies for the growing epidemic of NAFLD. We describe an "omics" approach to detecting a reproducible signature of lipid metabolites, aqueous intracellular metabolites, SNPs, and mRNA transcripts in a double-blinded study of patients with different stages of NAFLD that involves profi ling liver biopsies, plasma, and urine samples. Using linear discriminant analysis, a panel of 20 plasma metabolites that includes glycerophospholipids, sphingolipids, sterols, and various aqueous small molecular weight components involved in cellular metabolic pathways, can be used to differentiate between NASH and steatosis. This identifi cation of differential biomolecular signatures has the potential to improve clinical diagnosis and facilitate therapeutic intervention of
Supplementary key words lipidome • membrane • lipopolysaccharide • mitochondria • endoplasmic reticulum • plasmalemma • nucleusLipids regulate and modify protein function and thus various biological processes by two distinct mechanisms. Signaling lipids, including free fatty acids, eicosanoids, sphingosine-1-phosphate, and lysophosphatidic acid, may be released from the sites of their generation in membranes and can subsequently affect receptors located remotely throughout tissues and cells [e.g., see ( 1-4 ) for reviews]. Structural lipids, which represent the bulk of the lipid in the organism, affect membrane-bound enzymes, transporters, and receptors in a local fashion by altering membrane properties or by specifi c binding to target proteins [reviewed in ( 5-8 )].A fundamentally accepted general concept of cell biology is the compartmentalization of biological processes within subcellular structures, termed organelles. Detailed information about the location of biochemical reactions is crucial for understanding their roles in cellular function and dysfunction. By the same token, knowing how different signaling and structural lipids affect cellular responses requires knowledge of their subcellular distribution. Traditional lipid analysis involves organic extraction of whole Abstract Lipids orchestrate biological processes by acting remotely as signaling molecules or locally as membrane components that modulate protein function. Detailed insight into lipid function requires knowledge of the subcellular localization of individual lipids. We report an analysis of the subcellular lipidome of the mammalian macrophage, a cell type that plays key roles in infl ammation, immune responses, and phagocytosis. Nuclei, mitochondria, endoplasmic reticulum (ER), plasmalemma, and cytoplasm were isolated from RAW 264.7 macrophages in basal and activated states. Subsequent lipidomic analyses of major membrane lipid categories identifi ed 229 individual/isobaric species, including 163 glycerophospholipids, 48 sphingolipids, 13 sterols, and 5 prenols. Major subcellular compartments exhibited substantially divergent glycerophospholipid profi les. Activation of macrophages by the Toll-like receptor 4-specifi c lipopolysaccharide Kdo 2 -lipid A caused significant remodeling of the subcellular lipidome. Some changes in lipid composition occurred in all compartments (e.g., increases in the levels of ceramides and the cholesterol precursors desmosterol and lanosterol). Other changes were manifest in specifi c organelles. For example, oxidized sterols increased and unsaturated cardiolipins decreased in mitochondria, whereas unsaturated ether-linked phosphatidylethanolamines decreased in the ER. We speculate that these changes may refl ect mitochondrial oxidative stress and the release of arachidonic acid from the ER in response to cell activation. Tissue cultureCells were maintained, treated, and fractionated as previously described ( 9 ). Briefl y, RAW264.7 cells were maintained between passages 4 and 24 at 37°C and 10% CO 2 . The me...
Background Patients with chronic obstructive pulmonary disease (COPD) are highly susceptible from respiratory exacerbations from viral respiratory tract infections. However, it is unclear whether they are at increased risk of COVID-19 pneumonia or COVID-19-related mortality. We aimed to determine whether COPD is a risk factor for adverse COVID-19 outcomes including hospitalization, severe COVID-19, or death. Methods Following the PRISMA guidelines, we performed a systematic review of COVID-19 clinical studies published between November 1 st , 2019 and January 28 th , 2021 (PROSPERO ID: CRD42020191491). We included studies that quantified the number of COPD patients, and reported at least one of the following outcomes stratified by COPD status: hospitalization; severe COVID-19; ICU admission; mechanical ventilation; acute respiratory distress syndrome; or mortality. We meta-analyzed the results of individual studies to determine the odds ratio (OR) of these outcomes in patients with COPD compared to those without COPD. Findings Fifty-nine studies met the inclusion criteria, and underwent data extraction. Most studies were retrospective cohort studies/case series of hospitalized patients. Only four studies examined the effects of COPD on COVID-19 outcomes as their primary endpoint. In aggregate, COPD was associated with increased odds of hospitalization (OR 4.23, 95% confidence interval [CI] 3.65–4.90), ICU admission (OR 1.35, 95% CI 1.02–1.78), and mortality (OR 2.47, 95% CI 2.18–2.79). Interpretation Having a clinical diagnosis of COPD significantly increases the odds of poor clinical outcomes in patients with COVID-19. COPD patients should thus be considered a high-risk group, and targeted for preventative measures and aggressive treatment for COVID-19 including vaccination.
SUMMARY The serine hydrolase α/β hydrolase domain 6 (ABHD6) has recently been implicated as a key lipase for the endocannabinoid 2-arachidonylglycerol (2-AG) in the brain. However, the biochemical and physiological function for ABHD6 outside of the central nervous system has not been established. To address this we utilized targeted antisense oligonucleotides (ASOs) to selectively knock down ABHD6 in peripheral tissues to identify in vivo substrates and to understand ABHD6's role in energy metabolism. Here we show that selective knockdown of ABHD6 in metabolic tissues protects mice from high fat diet-induced obesity, hepatic steatosis, and systemic insulin resistance. Using combined in vivo lipidomic identification and in vitro enzymology approaches we show that ABHD6 can hydrolyze several lipid substrates, positioning ABHD6 at the interface of glycerophospholipid metabolism and lipid signal transduction. Collectively, these data suggest that ABHD6 inhibitors may serve as novel therapeutics for obesity, nonalcoholic fatty liver disease, and type II diabetes.
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