Journal of Lipid Research最新文献

High-density lipoproteins (HDLs) are heterogeneous particles with pleiotropic functions including anti-inflammatory and anti-infectious effects. In clinical studies, lower HDL-associated cholesterol (HDL-C) concentration has been associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severity and mortality. A reduction in the number of HDL particles, particularly small ones has been observed with alterations in their protein and lipid composition impairing their functions. These observations have supported HDL supplementation with promising results in small preliminary studies. This review summarizes available evidence on these different aspects to better understand the two-way interaction between HDLs and Coronavirus disease 2019 (COVID-19) and guiding future HDL-based therapies for preparing the next pandemic.

Background: Plasma 1-H nuclear magnetic resonance (¹H-NMR) metabolomic measures have yielded significant insight into the pathophysiology of cardiometabolic disease, but their interrelated nature complicates causal inference and clinical interpretation. This study aimed to investigate the associations of unrelated ¹H-NMR metabolomic profiles with coronary artery disease (CAD) and ischemic stroke (ISTR).

Methods: Principal component analysis was performed on 168 ¹H-NMR metabolomic measures in 56,712 unrelated European participants from UK Biobank to retrieve uncorrelated principal components (PCs), which were used in Cox-proportional hazard models. For each outcome, two-sample Mendelian randomization (MR) analyses were then conducted based on three non-overlapping databases, followed by a meta-analysis.

Results: The first six PCs collectively explaining 88% of the total variance were identified. For CAD, results from Cox and MR analyses were generally directionally consistent. The pooled odds ratios (ORs) [95% CI] for CAD per one-SD increase in genetically-influenced PC1 and PC3 (both characterized by distinct ApoB-associated lipoprotein profiles) were 1.04 [1.03, 1.05] and 0.94 [0.93, 0.96], respectively. Besides, the pooled OR [95% CI] for CAD per one-SD increase in genetically-influenced PC4, characterized by simultaneously decreased small HDL and increased large HDL, and independent of ApoB, was 1.05 [1.03, 1.07]. For ISTR, increases of PC3 and PC5 (characterized by increased amino acids) were associated with a lower risk and a higher risk, respectively.

Conclusions: This study confirms associations of ApoB-associated lipoprotein profiles with CAD and ISTR, and highlights the possible existence of an ApoB-independent lipoprotein profile, characterized by a distinctive HDL sub-particle distribution, driving CAD.

Recent studies have shown that hyper-HDL-cholesterol (HDL-C) is associated with cardiovascular disease (CVD) risk and all-cause mortality, a phenomenon known as the HDL-C paradox. Several genes have been reported to show relationships between increased HDL-C and myocardial infarction (MI) risk. We investigated the genetic predisposition of lipid metabolism influencing MI. The study dataset was from the Korean Genome and Epidemiology cohort obtained from the National Biobank of Korea, with an initial population of 68,806 individuals. We categorized samples based on HDL-C levels into hypo-HDL-C (n = 25,884), normal HDL-C (n = 41,117), and hyper-HDL-C groups (n = 1,805). We conducted genome-wide association studies for each group and the total sample. Significant associations were defined using genome-wide significant level and suggestive level. The lead SNP of each locus was selected for further interpretation. This analysis included 2,014 (2.6%) MI patients. Using multivariable logistic regression, we evaluated the association of 7,877 SNPs in 9 loci. We identified 6 SNPs significantly related to both hypo- and hyper-HDL groups, one SNP associated with hyper-HDL, and 6 SNPs associated with hypo-HDL group. Additionally, we found three SNPs associated with MI prevalence in the hyper-HDL group, including one significant SNP and two suggestive SNPs. Contrary to the traditional view of HDL-C as protective, this study identified genetic variants that increase MI risk by more than six-fold. These SNPs could serve as essential markers for detecting MI risk based on lipid profiles, pending replication in other cohorts.

Metabolic reprogramming is often observed in sepsis-associated microglial cells. However, little is known about the aberrant metabolic genes involved in neuroinflammation and lipid accumulation in microglial cells of sepsis-associated encephalopathy (SAE). Here, we show that hexokinase 2 (HK2) is upregulated and strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Downregulation of HK2 lowered the activation of NOD-like receptor signaling family pyrin domain containing 3, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) by interferon-stimulated gene 15 (ISG15). Notably, siISG15 effectively down-regulated the expression of ACSL4 in lipopolysaccharide-induced BV2 cells. Our findings provide new mechanistic insights of HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2.

Lipid metabolism plays a critical role in lymphatic endothelial cell (LEC) development and vessel maintenance. Altered lipid metabolism is associated with loss of lymphatic vessel integrity, which compromises organ function, protective immunity, and metabolic health. Thus, understanding how lipid metabolism affects LECs is critical for uncovering the mechanisms underlying lymphatic dysfunction. Protein palmitoylation, a lipid-based post-translational modification, has emerged as a critical regulator of protein function, stability, and interaction networks. Insulin, a master regulator of systemic lipid metabolism, also regulates protein palmitoylation. However, the role of insulin-driven palmitoylation in LEC biology remains unexplored. To examine the role of palmitoylation in LEC function, we generated the first palmitoylation proteomics profile in human LECs, validated insulin-regulated targets and determined the role of palmitoylation in LEC barrier function. In unstimulated condition, palmitoylation occurred primarily on proteins involved in vesicular and membrane trafficking, and in translation initiation. Insulin treatment, instead, enriched palmitoylation of proteins involved in LEC integrity, namely junctional proteins such as claudin 5, along with small GTPases and ubiquitination enzymes. We also investigated the role of the long-chain fatty acid transporter CD36, a major mediator of palmitate uptake into cells, in regulating optimal lymphatic protein palmitoylation. CD36 silencing in LECs increased by 2-fold palmitoylation of proteins involved in inflammation and immune cell activation. Overall, our findings provide novel insights into the intricate relationship between lipid modification and LEC function, suggesting that insulin and palmitoylation play a critical role in lymphatic endothelial function.

Mammalian cells synthesize hundreds of different variants of their prominent membrane lipid phosphatidylcholine (PC), all differing in the side chain composition. This batch is constantly remodeled by the Lands cycle, a metabolic pathway replacing one chain at the time. Using the alkyne lipid lyso-phosphatidylpropargylcholine (LpPC), a precursor and intermediate in PC synthesis and remodeling, we study both processes in brain endothelial bEND3 cells. A novel method for multiplexed sample analysis by mass spectrometry is developed that offers high throughput and molecular species resolution of the propargyl-labeled PC lipids. Their time resolved profiles and kinetic parameters of metabolism demonstrate the plasticity of the PC pool and the acute handling of lipid influx in endothelial cells differs from that in hepatocytes. Side chain remodeling as a form of lipid cycling adapts the PC pool to the cells need and maintains lipid homeostasis. We estimate that endothelial cells possess the theoretical capacity to remodel up to 99% of their PC pool within 3.5 h using the Lands cycle. However, PC species are not subjected stochastically to this remodeling pathway as different species containing duplets of saturated, omega-3 and omega-6 side chains show different decay kinetics. Our findings emphasize the essential function of Lands cycling for monitoring and adapting the side chain composition of PC in endothelial cells.

Free fatty acids like palmitic acid (PA) are elevated in obesity and diabetes and dysregulate monocyte and macrophage functions, contributing to enhanced inflammation in these cardiometabolic diseases. Epigenetic mechanisms regulating enhancer functions play key roles in inflammatory gene expression, but their role in PA-induced monocyte/macrophage dysfunction is unknown. We found that PA treatment altered the epigenetic landscape of enhancers and super-enhancers (SEs) in human monocytes. Integration with RNA-seq data revealed that PA-induced enhancers/SEs correlated with PA-increased expression of inflammatory and immune response genes, while PA-inhibited enhancers correlated with downregulation of phagocytosis and efferocytosis genes. These genes were similarly regulated in macrophages from mouse models of diabetes and accelerated atherosclerosis, human atherosclerosis, and by infectious agents. PA-regulated enhancers/SEs harbored SNPs associated with diabetes, obesity, and body mass index indicating disease relevance. We verified increased chromatin interactions between PA-regulated enhancers/SEs and inflammatory gene promoters, and reduced interactions at efferocytosis genes. PA-induced gene expression was reduced by inhibitors of BRD4, and NF-κB. PA treatment inhibited phagocytosis and efferocytosis in human macrophages. Together, our findings demonstrate that PA-induced enhancer dynamics at key monocyte/macrophage enhancers/SEs regulate inflammatory and immune genes and responses. Targeting these PA-regulated epigenetic changes could provide novel therapeutic opportunities for cardiometabolic disorders.

n-3 (e.g., EPA/DHA) and n-6 (e.g., LA) fatty acids are suggested to have opposite effects on inflammation, but results are inconsistent and direct comparisons of n-3 and n-6 are lacking. In a double-blind, randomized crossover study, females (n=16) and males (n=23) aged 30-70 years with abdominal obesity were supplemented with 3-4g/d EPA/DHA (fish oil) or 15-20g/d LA (safflower oil) for 7 weeks, with a 9-week washout phase. Cytokines and chemokines (multiplex assay), acute-phase proteins (MALDI-TOF mass spectrometry), endothelial function (vascular reaction index (VRI)), blood pressure, fatty acid composition (RBCMs/serum/adipose tissue, GC-MS/MS) and adipose gene expression (microarrays, qPCR) were measured. While significant differences between treatments in relative change scores were found for systolic blood pressure (n-3 vs. n-6: -1.81% vs. 2.61%, p=0.003), no difference between n-3 and n-6 were found for any circulatory inflammatory markers. However, compared to baseline, n-3 was followed by reductions in circulating TNF (-24.9%, p<0.001), RANTES (-12.1%, p<0.001), and MIP-1β (-12.5%, p=0.014), and n-6 by lowered TNF (-18.8%, p<0.001), RANTES (-7.37%, p=0.027), MCP-1 (-7.81%, p=0.020), and MIP-1β (-14.2%, p=0.010). Adipose tissue showed significant treatment differences in weight percent of EPA (n-3 vs. n-6: 50.2%* vs. -1.38%, p<0.001, *: significant within-treatment change score), DHA (16.0%* vs. -3.67%, p<0.001), and LA (-0.033 vs. 4.91%*, p<0.001). Adipose transcriptomics revealed overall down-regulation of genes related to inflammatory processes after n-3 and up-regulation after n-6, partly correlating with changes in circulatory markers. These data point to tissue-specific pro-inflammatory effects of high n-6 intake, but a net systemic anti-inflammatory effect as for n-3.

Obesity is a prevalent global disease associated with various metabolic disorders. The expansion of white adipose tissue plays a pivotal role in regulating obesity-related metabolic dysfunctions. This study identified serum-defined colon cancer antigen 3 (SDCCAG3) as a novel key modulator of adipocyte metabolism. In adipose-specific SDCCAG3 knockout mice fed a high-fat diet, pathological expansion of adipose tissue, impaired glucose tolerance, insulin resistance, increased inflammatory markers, and augmented hepatic lipid accumulation were observed. Conversely, obesity models by specific overexpression of SDCCAG3 in adipose tissue confirmed that SDCCAG3 alleviated pathological expansion of adipose tissue, improved obesity-related metabolic disorders, with no observed changes in adipose tissue development under normal dietary conditions. Mechanistically, SDCCAG3 enhanced the stability of peroxisome proliferator-activated receptor gamma (PPARγ) by preventing its degradation via the ubiquitin-proteasome system through the SMAD specific E3 ubiquitin protein ligase 1 (SMURF1). Additionally, SDCCAG3 was subjected to negative transcriptional regulation by PPARγ, forming a SDCCAG3-PPARγ-SDCCAG3 loop that enhanced adipocyte lipid metabolism. Collectively, these findings demonstrated that SDCCAG3 functioned as a beneficial positive regulator of adipose tissue expansion and metabolic homeostasis, indicating its potential as a therapeutic target for metabolic diseases associated with nutrient excess.

Zellweger Spectrum Disorder (ZSD) is caused by defects in PEX genes, whose proteins are required for peroxisome assembly and function. Peroxisome dysfunction in ZSD causes multisystem effects, with progressive retinal degeneration (RD) among the most frequent clinical findings. However, much remains unknown about how peroxisome deficiency causes RD. To study RD pathophysiology in ZSD, we used the PEX1-p.Gly844Asp (G844D) mouse model, which represents the common human PEX1-p.Gly843Asp allele. We previously reported diminished retinal function, diminished functional vision, and neural retina structural defects in this model. Here, we investigate the retinal pigment epithelium (RPE) phenotype, examining morphological, inflammatory, and lipid changes at 1, 3, and 6 months of age. We report that RPE cells exhibit evident degeneration by 3 months that worsens with time, starts in the dorsal pole, and is accompanied by subretinal inflammatory cell infiltration. We match these events with imaging mass spectrometry for regional analysis of lipids in the RPE. We identified 47 lipid alterations preceding structural changes, 9 of which localize to the dorsal pole. 29 of these persist to 3 months, with remodeling of the dorsal pole lipid signature. 13 new alterations occur concurrent with histological changes. Abnormalities in peroxisome-dependent lipids detected by LC/MS/MS are exacerbated over time. This study represents the first characterization of RPE in a ZSD model, and the first in situ lipid analysis in peroxisome-deficient tissue. Our findings uncover potential lipid drivers of RD progression in ZSD, and identify candidate biomarkers for retinopathy progression and response to therapy.