Lipid Pool Research Articles

Simulating atherosclerotic plaque mechanics using polyvinyl alcohol (PVA) cryogel artery phantoms, ultrasound imaging and inverse finite element analysis.

The aim of this study is to demonstrate the potential of polyvinyl alcohol phantoms to simulate atherosclerotic features. In addition, a testing and simulation framework is developed for full PVA vessel material characterization using ring tensile testing and inflation testing combined with non-invasive ultrasound imaging and computational modelling. Strain stiffening behavior was observed in PVA through ring tensile tests, particularly at high (n=6) freeze-thaw cycles. Inflation testing of bi-layered phantoms featuring lipid pool inclusions demonstrated high strains at shoulder regions. The application of an inverse finite element framework successfully recovered boundaries and determined the shear moduli for the PVA wall to lie within the range 27 kPa to 53 kPa. The imaging-modelling framework presented facilitates the use and characterization of arterial mimicking phantoms to further explore plaque rupture. It also shows translational potential for non-invasive mechanical characterization of atherosclerotic plaques to improve the identification of clinically relevant metrics of plaque vulnerability.

Contribution of glucose and glutamine to hypoxia-induced lipid synthesis decreases, while contribution of acetate increases, during 3T3-L1 differentiation

The molecular mechanisms linking obstructive sleep apnea syndrome (OSA) to obesity and the development of metabolic diseases are still poorly understood. The role of hypoxia (a characteristic feature of OSA) in excessive fat accumulation has been proposed. The present study investigated the possible effects of hypoxia (4% oxygen) on de novo lipogenesis by tracking the major carbon sources in differentiating 3T3-L1 adipocytes. Gas-permeable cultuware was employed to cultivate 3T3-L1 adipocytes in hypoxia (4%) for 7 or 14 days of differentiation. We investigated the contribution of glutamine, glucose or acetate using 13C or 14C labelled carbons to the newly synthesized lipid pool, changes in intracellular lipid content after inhibiting citrate- or acetate-dependent pathways and gene expression of involved key enzymes. The results demonstrate that, in differentiating adipocytes, hypoxia decreased the synthesis of lipids from glucose (44.1 ± 8.8 to 27.5 ± 3.0 pmol/mg of protein, p < 0.01) and partially decreased the contribution of glutamine metabolized through the reverse tricarboxylic acid cycle (4.6% ± 0.2–4.2% ± 0.1%, p < 0.01). Conversely, the contribution of acetate, a citrate- and mitochondria-independent source of carbons, increased upon hypoxia (356.5 ± 71.4 to 649.8 ± 117.5 pmol/mg of protein, p < 0.01). Further, inhibiting the citrate- or acetate-dependent pathways decreased the intracellular lipid content by 58% and 73%, respectively (p < 0.01) showing the importance of de novo lipogenesis in hypoxia-exposed adipocytes. Altogether, hypoxia modified the utilization of carbon sources, leading to alterations in de novo lipogenesis in differentiating adipocytes and increased intracellular lipid content.

The microbiome diversifies N -acyl lipid pools - including short-chain fatty acid-derived compounds.

N -acyl lipids are important mediators of several biological processes including immune function and stress response. To enhance the detection of N -acyl lipids with untargeted mass spectrometry-based metabolomics, we created a reference spectral library retrieving N -acyl lipid patterns from 2,700 public datasets, identifying 851 N -acyl lipids that were detected 356,542 times. 777 are not documented in lipid structural databases, with 18% of these derived from short-chain fatty acids and found in the digestive tract and other organs. Their levels varied with diet, microbial colonization, and in people living with diabetes. We used the library to link microbial N -acyl lipids, including histamine and polyamine conjugates, to HIV status and cognitive impairment. This resource will enhance the annotation of these compounds in future studies to further the understanding of their roles in health and disease and highlight the value of large-scale untargeted metabolomics data for metabolite discovery.

Constraining the sources of archaeal tetraether lipids in multiple cold seep provinces of the Cascadia Margin

Archaeal isoprenoid glycerol dialkyl glycerol tetraether lipid (iGDGT) abundance profiles and carbon isotopic compositions reflect the relative distributions of archaeal sources, including planktonic, benthic, and methane-cycling contributions. Here, we analyze the carbon isotope ratios of iGDGTs purified from sediments of three different cold seep sites in Cascadia Margin, off the coast of Washington, USA. Together with relative abundance and glycerol configurations, we use the carbon isotope ratios to estimate the contributions of multiple archaeal sources to the sedimentary iGDGT assemblages and their impact on values of the TEX86 and methane indices. Using a Bayesian mixing model, we robustly characterize three potential endmembers by determining their characteristic lipid distributions, inferred contributions to the total sediment inventory, and carbon isotopic signatures. Despite the geographic proximity of the sample locations, we find site-specific heterogeneity in relative iGDGT abundances and δ13C values. Planktonic and benthic methane-cycling sources predominate in all cases (contributing > 98 % of iGDGTs), while benthic non-methane cycling archaea contribute minimally to the sedimentary lipid pool. Environments with higher methane influence show an increased presence of anti-parallel iGDGTs, indicating that methane-cycling archaea may dominantly or exclusively synthesize iGDGTs in this configuration. Our results quantify the relationship between the methane index (MI) and methane impact in systems dominated by planktonic and benthic methane-cycling archaea. Within the framework of the TEX86 temperature proxy, this permits a quantitative demonstration that it is overly simplistic to apply a MI cutoff threshold as a binary indicator to determine methane influence, and caution is needed when taking this approach in paleoclimate reconstructions.

Effect of Colchicine on Coronary Plaque Stability in Acute Coronary Syndrome as Assessed by Optical Coherence Tomography: The COLOCT Randomized Clinical Trial.

Colchicine has been approved to reduce cardiovascular risk in patients with coronary heart disease on the basis of its potential benefits demonstrated in the COLCOT (Colchicine Cardiovascular Outcomes Trial) and LoDoCo2 (Low-Dose Colchicine 2) studies. Nevertheless, there are limited data available about the specific impact of colchicine on coronary plaques. This was a prospective, single-center, randomized, double-blind clinical trial. From May 3, 2021, until August 31, 2022, a total of 128 patients with acute coronary syndrome aged 18 to 80 years with lipid-rich plaque (lipid pool arc >90°) detected by optical coherence tomography were included. The subjects were randomly assigned in a 1:1 ratio to receive either colchicine (0.5 mg once daily) or placebo for 12 months. The primary end point was the change in the minimal fibrous cap thickness from baseline to the 12-month follow-up. Among 128 patients, 52 in the colchicine group and 52 in the placebo group completed the study. The mean age of the 128 patients was 58.0±9.8 years, and 25.0% were female. Compared with placebo, colchicine therapy significantly increased the minimal fibrous cap thickness (51.9 [95% CI, 32.8 to 71.0] μm versus 87.2 [95% CI, 69.9 to 104.5] μm; difference, 34.2 [95% CI, 9.7 to 58.6] μm; P=0.006), and reduced average lipid arc (-25.2° [95% CI, -30.6° to -19.9°] versus -35.7° [95% CI, -40.5° to -30.8°]; difference, -10.5° [95% CI, -17.7° to -3.4°]; P=0.004), mean angular extension of macrophages (-8.9° [95% CI, -13.3° to -4.6°] versus -14.0° [95% CI, -18.0° to -10.0°]; difference, -6.0° [95% CI, -11.8° to -0.2°]; P=0.044), high-sensitivity C-reactive protein level (geometric mean ratio, 0.6 [95% CI, 0.4 to 1.0] versus 0.3 [95% CI, 0.2 to 0.5]; difference, 0.5 [95% CI, 0.3 to 1.0]; P=0.046), interleukin-6 level (geometric mean ratio, 0.8 [95% CI, 0.6 to 1.1] versus 0.5 [95% CI, 0.4 to 0.7]; difference, 0.6 [95% CI, 0.4 to 0.9]; P=0.025), and myeloperoxidase level (geometric mean ratio, 1.0 [95% CI, 0.8 to 1.2] versus 0.8 [95% CI, 0.7 to 0.9]; difference, 0.8 [95% CI, 0.6 to 1.0]; P=0.047). Our findings suggested that colchicine resulted in favorable effects on coronary plaque stabilization at optical coherence tomography in patients with acute coronary syndrome. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04848857.

Deciphering the complex mechanics of atherosclerotic plaques: A hybrid hierarchical theory-microrheology approach

Understanding the viscoelastic properties of atherosclerotic plaques at rupture-prone scales is crucial for assessing their vulnerability. Here, we develop a Hybrid Hierarchical theory-Microrheology (HHM) approach, enabling the analysis of multiscale mechanical variations and distribution changes in regional tissue viscoelasticity within plaques across different spatial scales. We disclose a universal two-stage power-law rheology in plaques, characterized by distinct power-law exponents (αshort and αlong), which serve as mechanical indexes for plaque components and assessing mechanical gradients. We further propose a self-similar hierarchical theory that effectively delineates plaque heterogeneity from the cytoplasm, cell, to tissue levels. Moreover, our proposed multi-layer perceptron model addresses the viscoelastic heterogeneity and gradients within plaques, offering a promising diagnostic strategy for identifying unstable plaques. These findings not only advance our understanding of plaque mechanics but also pave the way for innovative diagnostic approaches in cardiovascular disease management. Statement of significanceOur study pioneers a Hybrid Hierarchical theory-Microrheology (HHM) approach to dissect the intricate viscoelasticity of atherosclerotic plaques, focusing on distinct components including cap fibrosis, lipid pools, and intimal fibrosis. We unveil a universal two-stage power-law rheology capturing mechanical variations across plaque structures. The proposed hierarchical model adeptly captures viscoelasticity changes from cytoplasm, cell to tissue levels. Based on the newly proposed markers, we further develop a machine learning (ML) diagnostic model that sets precise criteria for evaluating plaque components and heterogeneity. This work not only reveals the comprehensive mechanical heterogeneity within plaques but also introduces a mechanical marker-based ML strategy for assessing plaque conditions, offering a significant leap towards understanding and diagnosing atherosclerotic risks.

Pathogenesis of human atheroma necrotic core: degradation of connective tissue fibers and possible involvement of cathepsin K

BackgroundAtheroma is a serious atherosclerotic lesion related to plaque rupture, thrombosis, and ischemic disease. To clarify the pathogenesis of human atheroma, particularly the formation of the liponecrotic tissue in the necrotic core, the distribution of connective tissue fibers, such as collagen and elastic fibers, and related substances was investigated in this study.MethodsAtherosclerotic lesions in human coronary arteries were classified into three categories: pathologic intimal thickening (PIT), atheroma with lipid core (ALC), and atheroma with necrotic core (ANC). PIT and ALC consisted of the lipid pool and the lipid core, respectively. The necrotic core of ANC was composed of a lipid core-like region and liponecrotic tissue containing amorphous materials and lacking cells and connective tissue fibers. The distribution of collagen type I, elastin, C-terminal crosslinked telopeptide of collagen type I (CTX-I), and cathepsin K (CatK) was investigated through immunohistochemistry. CTX-I is a fragmented peptide consisting of the C-terminal region of collagen type I that is generated by CatK. The distribution of denatured and unfolded collagen chains was also investigated through collagen hybridizing peptide staining.ResultsCollagen type I, denatured and unfolded collagen chains, and elastin were positively stained in the PIT, ALC, and lipid core-like region of ANC. However, they were negatively stained in the liponecrotic tissue of ANC. CTX-I and CatK were positively stained in all four regions, and their grade of staining appeared to show a positive relationship. Both CTX-I and CatK demonstrated higher staining grades in the liponecrotic tissue. These findings suggested that pre-existing collagen type I was severely degraded by CatK, resulting in the production of CTX-I in the liponecrotic tissue, and that pre-existing elastin was also degraded in this region. CatK was mainly found in macrophage foam cells, many of which were localized within and around the liponecrotic tissue.ConclusionsThis study suggests that the liponecrotic tissue in the necrotic core of human atheroma is formed by severe degradation of pre-existing connective tissue fibers and consequent collapse of tissue structure. This degradation is likely caused by proteolytic enzymes, such as CatK, secreted by macrophage foam cells.

Interactions between lipid metabolism and the microbiome in aquatic organisms: A review

Marine organisms' lipid metabolism contributes to marine ecosystems by producing a variety of lipid molecules. Historically, research focused on the lipid metabolism of the organisms themselves. Recent microbiome studies, however, have revealed that gut microbial communities influence the amount and type of lipids absorbed by organisms, thereby altering the organism's lipid metabolism. This has highlighted the growing importance of research on gut microbiota. This review highlights mechanisms by which gut microbiota facilitate lipid digestion and diversify the lipid pool in aquatic animals through the accelerated degradation of exogenous lipids and the transformation of lipid molecules. We also assess how environmental factors and pollutants, along with the innovative use of probiotics, interact with the gut microbiome to influence lipid metabolism within the host. We aim to elucidate the complex interactions between lipid metabolism and gut microbiota in aquatic animals by synthesizing current research and identifying knowledge gaps, providing a foundation for future explorations.

Impact of fish oil supplementation on plasma levels of highly unsaturated fatty acid-containing lipid classes and molecular species in American football athletes

BackgroundPrevious studies have linked sports-related concussions and repeated subconcussive head impacts in contact sport athletes to elevated brain injury biomarkers. Docosahexaenoic acid (DHA), the primary omega-3 (n-3) highly unsaturated fatty acid (HUFA) in the brain, has shown neuroprotective effects in animal models after brain injury, but clinical research has shown mixed results.MethodsWe conducted a randomized, double-blind, placebo-controlled study on 29 Division 1 collegiate American football players, exploring the impact of DHA (2.5 g) and eicosapentaenoic acid (EPA) (1.0 g) supplied as ethyl esters, on levels of plasma lipids shown to cross the blood-brain barrier. Dietary intake data was collected using food frequency questionnaires (FFQ). Complex lipids and unesterified fatty acids were isolated from plasma, separated via reversed-phase liquid chromatography and analyzed by targeted lipidomics analysis.ResultsFFQ results indicated that participants had low dietary n-3 HUFA intake and high omega-6 (n-6):n-3 polyunsaturated fatty acids (PUFA) and HUFA ratios at baseline. After DHA + EPA supplementation, plasma lysophosphatidylcholine (LPC) containing DHA and EPA significantly increased at all timepoints (weeks 17, 21, and 26; p < 0.0001), surpassing placebo at Weeks 17 (p < 0.05) and 21 (p < 0.05). Phosphatidylcholine (PC) molecular species containing DHA or EPA, PC38:6 PC36:6, PC38:7, PC40:6, and PC40:8, increased significantly in the DHA + EPA treatment group at Weeks 17 (and 21. Plasma concentrations of non-esterified DHA and EPA rose post-supplementation in Weeks 17 and 21.ConclusionsThis study demonstrates that n-3 HUFA supplementation, in the form of ethyl esters, increased the DHA and EPA containing plasma lipid pools the have the capacity to enrich brain lipids and the potential to mitigate the effects of sports-related concussions and repeated subconcussive head impacts.Trial RegistrationAll deidentified data are available at ClinicalTrials.gov #NCT0479207.

Cannabigerol-A useful agent restoring the muscular phospholipids milieu in obese and insulin-resistant Wistar rats?

Numerous strategies have been proposed to minimize obesity-associated health effects, among which phytocannabinoids appear to be effective and safe compounds. In particular, cannabigerol (CBG) emerges as a potent modulator of the composition of membrane phospholipids (PLs), which plays a critical role in the development of insulin resistance. Therefore, here we consider the role of CBG treatment on the composition of PLs fraction with particular emphasis on phospholipid subclasses (e.g., phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylinositol (PI)) in the red gastrocnemius muscle of Wistar rats fed the standard or high-fat, high-sucrose (HFHS) diet. The intramuscular PLs content was determined by gas-liquid chromatography and based on the composition of individual FAs, we assessed the stearoyl-CoA desaturase 1 (SCD1) index as well as the activity of n-3 and n-6 polyunsaturated fatty acids (PUFAs) pathways. Expression of various proteins engaged in the inflammatory pathway, FAs elongation, and desaturation processes was measured using Western blotting. Our research has demonstrated the important association of obesity with alterations in the composition of muscular PLs, which was significantly improved by CBG supplementation, enriching the lipid pools in n-3 PUFAs and decreasing the content of arachidonic acid (AA), which in turn influenced the activity of PUFAs pathways in various PLs subclasses. CBG also inhibited the local inflammation development and profoundly reduced the SCD1 activity. Collectively, restoring the PLs homeostasis of the myocyte membrane by CBG indicates its new potential medical application in the treatment of obesity-related metabolic disorders.

Circulating Omega-3 Polyunsaturated Fatty Acids Levels in Coronary Heart Disease: Pooled Analysis of 36 Observational Studies.

Prospective studies and retrospective case-control studies analyzing n-3 PUFA levels in CHD, published up to 30 July 2022, were selected. A random effects meta-analysis was used for pooled assessment, with relative risks (RRs) expressed as 95% confidence intervals (CIs) and standardized mean differences expressed as weight mean differences (WMDs). Subgroup and meta-regression analyses were conducted to assess the impact of n-3 PUFA exposure interval on the CHD subtype variables of the study. We included 20 prospective studies (cohort and nested case-control) and 16 retrospective case-control studies, in which n-3 PUFAs were measured. Higher levels of n-3 PUFAs (ALA, EPA, DPA, DHA, EPA + DHA, total n-3 PUFAs) were associated with a reduced risk of CHD, with RRs (95% CI) of 0.89 (0.81, 0.98), 0.83 (0.72, 0.96); 0.80 (0.67,0.95), 0.75 (0.64, 0.87), 0.83 (0.73, 0.95), and 0.80 (0.70, 0.93), respectively, p < 0.05. CHD patients had significantly lower n-3 PUFA levels compared to healthy controls (p < 0.05). In the subgroup analysis, a significant inverse trend was found for both fatal CHD and non-fatal CHD with n-3 PUFA (EPA + DHA) levels. Also, the link between n-3 PUFA levels in erythrocytes with total CHD was generally stronger than other lipid pools. n-3 PUFAs are significantly related to CHD risk, and these findings support the beneficial effects of n-3 PUFAs on CHD.

Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes

Despite opposing insulin sensitivity and cardiometabolic risk, both athletes and patients with type 2 diabetes have increased skeletal myocyte fat storage: the so-called “athlete’s paradox”. In a parallel non-randomised, non-blinded trial (NCT03065140), we characterised and compared the skeletal myocyte lipid signature of 29 male endurance athletes and 30 patients with diabetes after undergoing deconditioning or endurance training respectively. The primary outcomes were to assess intramyocellular lipid storage of the vastus lateralis in both cohorts and the secondary outcomes were to examine saturated and unsaturated intramyocellular lipid pool turnover. We show that athletes have higher intramyocellular fat saturation with very high palmitate kinetics, which is attenuated by deconditioning. In contrast, type 2 diabetes patients have higher unsaturated intramyocellular fat and blunted palmitate and linoleate kinetics but after endurance training, all were realigned with those of deconditioned athletes. Improved basal insulin sensitivity was further associated with better serum cholesterol/triglycerides, glycaemic control, physical performance, enhanced post insulin receptor pathway signalling and metabolic sensing. We conclude that insulin-resistant, maladapted intramyocellular lipid storage and turnover in patients with type 2 diabetes show reversibility after endurance training through increased contributions of the saturated intramyocellular fatty acid pools. Clinical Trial Registration: NCT03065140: Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity (MISTY)

Abstract 1056: Overexpression Of Lysosomal Acid Lipase

Background: Previous evidence suggests arterial smooth muscle cells (SMCs) comprise the majority of atherosclerotic lesion foam cells in human and mouse atheromas, have reduced expression of ABCA1 and lysosomal acid lipase (LAL) compared to macrophages, and retain cholesteryl esters in lysosomes rather than in the cytoplasm as in macrophage foam cells. Exogenous LAL can increase cholesterol efflux from SMC foam cells despite low ABCA1. Hypothesis: Overexpression of LAL increases cholesterol efflux from SMC foam cells by ABCA1-dependent and -independent mechanisms. Methods: Human vascular SMCs were transfected with 500 MOI AdV- LIPA or AdV- mCherry (adenovirus) control for 6 h and cholesterol loaded using 100 μg/ml aggregated LDL (agLDL) for 24 h. LAL activity was measured by specific enzymatic assay and location of stored cholesteryl esters (CE) was determined using LAMP-1 (lysosome marker) and BODIPY (neutral lipid) staining by confocal microscopy. Cholesterol efflux to 10 μg/ml apoliprotein A-I (ApoA-I) or 100 μg/ml HDL was determined following ABCA1 siRNA treatment or control, with cholesterol mass determined using Amplex Red assay. Student’s t test was used for statistical analysis of LAL activity, and Mann-Whitney U Test for analysis of colocalization of lipid pools. Results: LAL activity increased 1.67-fold 72 h after transfection with AdV- LIPA compared to SMCs transfected with AdV- mCherry (n=5, p = 0.001). Increased LAL expression in the absence of cholesterol acceptor resulted in a shift in CE storage from lysosomes to non-lysosomal compartments (Pearson correlation coefficient for BODIPY/LAMP-1 colocalization 0.27 in AdV- LIPA vs. 0.47 in AdV- mCherry SMCs, n=103, p &lt; 0.00001). Preliminary cholesterol efflux studies indicate SMCs overexpressing LAL release cholesterol by both ABCA1-dependent and -independent mechanisms. Conclusion: Our study provides evidence that despite low ABCA1 and LAL expression, SMC foam cells mobilize lysosomal cholesterol for cellular trafficking and efflux following supplementation with LAL. Further studies will examine changes in gene expression and the mechanism of ABCA1-independent efflux following LAL supplementation in SMC foam cells.

Abstract 2070: Myeloid Smyd2 Deficiency Exacerbates Atherosclerosis Via Promoting Plaque Necrosis And Calcification

Introduction: The accumulation of lipoprotein-laden macrophages within arterial walls marks the earliest phase of atherosclerotic cardiovascular disease, giving rise to foam cells. Here, we aim to define the previously unexplored role of myeloid specific SMYD2 (a histone lysine methyltransferase) in atherosclerosis and plaque formation. Methods: Myeloid-specific Smyd2 knockout mice in ApoE -/- background (Smyd2 mKO ApoE -/- ) and their littermate controls (Smyd2 fl/fl ApoE -/- ) were subjected to Western diet (WD) feeding for up to 26 weeks. Atherosclerotic plaque distribution was examined by en-face Oil Red O (ORO) staining of freshly collected aortas. Hematoxylin &amp; Eosin (H&amp;E) staining on brachiocephalic artery (BCA) tissues were performed to determine total plaque size, lipid pool area, and necrotic core area. Plaque calcification was determined by von Kossa staining and Alizarin Red S staining. Primary bone marrow derived macrophages (BMDMs) isolated from Smyd2 fl/fl ApoE -/- and Smyd2 mKO ApoE -/- mice and cultured RAW 246.7 cells (with Smyd2 knock-down) were used for in vitro studies including calcification assay, PR-PCR, and Western blot analysis. Results: Myeloid Smyd2 deficient mice demonstrated significantly increased aortic plaque burden on ORO staining as compared to control mice following WD feeding, though with slower WD-induced body weight gain relative to Smyd2 fl/fl ApoE -/- control mice. H&amp;E staining of BCA indicated that there was significant reduction in total lumen and lipid core area, while significantly increased total plaque and necrotic core in Smyd2 mKO ApoE -/- mice. Myeloid Smyd2 deletion promotes plaque calcification in mice fed with WD, and in cultured BMDMs and RAW 246.7 cells treated with calcification promoting media. Gene expression analysis of key calcification factors of aortic tissues and cultured cells showed significant upregulation of Sox9 and Msx2 genes in aortas of WD-fed Smyd2 mKO ApoE -/- mice and cultured Smyd2 deficient cells, as compared to controls. Conclusion: We delineated the consequences of Smyd2 deficiency in macrophages on atherosclerotic plaque development, particularly its impact on plaque necrosis and calcification.

Current Insights into the Effects of Dietary α-Linolenic Acid Focusing on Alterations of Polyunsaturated Fatty Acid Profiles in Metabolic Syndrome.

The plant-derived α-linolenic acid (ALA) is an essential n-3 acid highly susceptible to oxidation, present in oils of flaxseeds, walnuts, canola, perilla, soy, and chia. After ingestion, it can be incorporated in to body lipid pools (particularly triglycerides and phospholipid membranes), and then endogenously metabolized through desaturation, elongation, and peroxisome oxidation to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with a very limited efficiency (particularly for DHA), beta-oxidized as an energy source, or directly metabolized to C18-oxilipins. At this moment, data in the literature about the effects of ALA supplementation on metabolic syndrome (MetS) in humans are inconsistent, indicating no effects or some positive effects on all MetS components (abdominal obesity, dyslipidemia, impaired insulin sensitivity and glucoregulation, blood pressure, and liver steatosis). The major effects of ALA on MetS seem to be through its conversion to more potent EPA and DHA, the impact on the n-3/n-6 ratio, and the consecutive effects on the formation of oxylipins and endocannabinoids, inflammation, insulin sensitivity, and insulin secretion, as well as adipocyte and hepatocytes function. It is important to distinguish the direct effects of ALA from the effects of EPA and DHA metabolites. This review summarizes the most recent findings on this topic and discusses the possible mechanisms.

3AcFNP-59 for Positron Emission Tomography Imaging of Cholesterol Trafficking and Utilization.

Cholesteryl ester analogues of [18F]FNP-59 have the ability to provide information on cholesterol trafficking and utilization at earlier time points than those of [18F]FNP-59 or [131I]NP-59. It is well-known that free cholesterol and cholesteryl esters have differing distribution profiles and that they can be interconverted enzymatically. Substitution of the ester influences the rate of cholesterol ester hydrolysis and the subsequent mixing of cholesterol esters with the lipid pool in the body. This can be utilized by preparing esters that are more readily taken up by lipoprotein, are quickly hydrolyzed and mixed with the endogenous lipid pool and delivered to tissues of interest more quickly than free cholesterol analogues that require esterification for lipoprotein association. The acetyl ester of FNP-59 demonstrated the preferred uptake properties and response to adrenal cortical manipulation, indicating its ability to image hormone production. Finally, dosimetry studies were conducted in preparation for the clinical translation of [18F]3AcFNP-59.

Phosphorus drives adaptive shifts in membrane lipid pools and synthesis between soils

Phospholipids are key constituents of microbial membranes and account for a substantial fraction of microbial P, while P-free betaine lipids provide a pathway for membrane synthesis independent of P. The aim of this study was to test if modulation of relative amounts of phospholipids vs P-free betaine lipids is a response to P availability. To examine responses of membrane lipids to P availability, we added P or P + C to an extremely P-poor sandstone-derived soil (total P = 41 μg g−1) and a higher P shale-derived soil (total P = 201 μg g−1). By using D2O labelling and LC-MS we were able to disentangle membrane lipid synthesis dependent on P (i.e. 2H incorporation into phospholipids) from membrane lipid synthesis independent of P (i.e. 2H incorporation into P-free betaine lipids). In unamended soils, P-free betaine lipids were almost 60% of the membrane lipid pool of the P-poor sandstone-derived soil, but only 10% of the higher-P shale-derived soil. Hence, to produce a unit of membrane lipid, the microbial population of sandstone soil required only 54% as much P as the microbial population of shale soil. Four days after adding P to the sandstone soil, phospholipids accounted for a larger proportion of the pool and synthesis of membrane lipids while pool and synthesis of P-free betaine lipids decreased. The increased allocation to phospholipids in sandstone soil amended with P likely reflected amelioration of P limitation given that P addition did not affect pools or synthesis of phospholipids versus betaine lipids in the higher-P shale soil. Collectively these data support the idea that having membranes with a high proportion of P-free betaine lipids is a key adaptive trait of microbial populations of P-poor soil, while the plasticity afforded by membrane lipid remodelling enables short-term fine-tuning of membrane lipid composition to P availability.

Predicting Endothelium-Dependent Diastolic Function (FMD) and Its Correlation with the Degree of Coronary Artery Disease (CAD) and Plaque Vulnerability for Cardiovascular Events.

This study aims to investigate the correlation between vascular endothelium-dependent diastolic function (FMD) and the degree of coronary artery disease (CAD), plaque vulnerability, and its predictive value for cardiovascular events. Initially, patients (n=100) who were admitted from January 2020 to January 2021 and intended to undergo percutaneous coronary intervention (PCI) were selected. Further, FMD in all patients was determined before the procedure and divided into a high-FMD group (≥4.2%) and a low-FMD group (<4.2%). Further, the data of two groups, including general information, coronary artery lesions, and plaque fibrous cap, were compared. Finally, the relationship between FMD and the degree of coronary artery lesions and plaque vulnerability was analyzed. No significant differences were observed concerning general information, number of coronary arteries-associated branches, lesion type, involvement of the left main stem (LM), the proportion of chronic occluded lesions (CTO), and lipid pool angle between the low-FMD group and the high-FMD group (P > 0.05). Nevertheless, the degree of stenosis of the lesions in the low-FMD group was significantly higher than in the high-FMD group (P < 0.05). In addition, the thickness of the fibrous cap was considerably lower than that in the high-FMD group (P < 0.05). Moreover, the incidence rate of TCFA was significantly higher than the high-FMD group (P < 0.05). The correlation analysis showed that FMD was significantly negatively correlated with the degree of coronary artery lesion stenosis and TCFA (P < 0.05) and positively correlated with the fibrous cap thickness (P < 0.05). Overall, a negative correlation between FMD and the degree of coronary stenosis, plaque vulnerability, and a high predictive value for post-PCI cardiovascular events suggested that FMD could be a critical diagnostic marker for CAD.

Association of insulin resistance with the accumulation of saturated intramyocellular lipid: A comparison with other fat stores.

It has been shown using proton magnetic resonance spectroscopy (1H MRS) that, in a group of females, whole-body insulin resistance was more closely related to accumulation of saturated intramyocellular lipid (IMCL) than to IMCL concentration alone. This has not been investigated in males. We investigated whether age- and body mass index-matched healthy males differ from the previously reported females in IMCL composition (measured as CH2:CH3) and IMCL concentration (measured as CH3), and in their associations with insulin resistance. We ask whether saturated IMCL accumulation is more strongly associated with insulin resistance than other ectopic and adipose tissue lipid pools and remains a significant predictor when these other pools are taken into account. In this group of males, who had similar overall insulin sensitivity to the females, IMCL was similar between sexes. The males demonstrated similar and even stronger associations of IMCL with insulin resistance, supporting the idea that a marker reflecting the accumulation of saturated IMCL is more strongly associated with whole-body insulin resistance than IMCL concentration alone. However, this marker ceased to be a significant predictor of whole-body insulin resistance after consideration of other lipid pools, which implies that this measure carries no more information in practice than the other predictors we found, such as intrahepatic lipid and visceral adipose tissue. As the marker of saturated IMCL accumulation appears to be related to these two predictors and has a much smaller dynamic range, this finding does not rule out a role for it in the pathogenesis of insulin resistance.

Engineering peroxisomal biosynthetic pathways for maximization of triterpene production in Yarrowia lipolytica

Constructing efficient cell factories for product synthesis is frequently hampered by competing pathways and/or insufficient precursor supply. This is particularly evident in the case of triterpenoid biosynthesis in Yarrowia lipolytica, where squalene biosynthesis is tightly coupled to cytosolic biosynthesis of sterols essential for cell viability. Here, we addressed this problem by reconstructing the complete squalene biosynthetic pathway, starting from acetyl-CoA, in the peroxisome, thus harnessing peroxisomal acetyl-CoA pool and sequestering squalene synthesis in this organelle from competing cytosolic reactions. This strategy led to increasing the squalene levels by 1,300-fold relatively to native cytosolic synthesis. Subsequent enhancement of the peroxisomal acetyl-CoA supply by two independent approaches, 1) converting cellular lipid pool to peroxisomal acetyl-CoA and 2) establishing an orthogonal acetyl-CoA shortcut from CO2-derived acetate in the peroxisome, further significantly improved local squalene accumulation. Using these approaches, we constructed squalene-producing strains capable of yielding 32.8 g/L from glucose, and 31.6 g/L from acetate by employing a cofeeding strategy, in bioreactor fermentations. Our findings provide a feasible strategy for protecting intermediate metabolites that can be claimed by multiple reactions by engineering peroxisomes in Y. lipolytica as microfactories for the production of such intermediates and in particular acetyl-CoA-derived metabolites.