Journal of Lipid Research最新文献

Triglyceride (TG)/HDL-C ratio (THR) is a surrogate predictor of hyperinsulinemia. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among nondiabetic Europeans from the Long Life Family Study (n = 1,384). Subjects with diabetes or on dyslipidemia medications were excluded. ΔTHR was derived using growth curve modeling and adjusted for age, sex, field centers, and principal components. GWAS used a linear mixed model accounting for familial relatedness. GWLS employed haplotype-based identity-by-descent estimation with 0.5 cM average spacing. Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (P = 1.58e-9) for ΔTHR; this locus has been reported before influencing baseline THR levels. Our GWLS found significant linkage with a logarithm of the odds exceeding 3 on 3q28 (logarithm of the odds = 4.1). Using a subset of 25 linkage-enriched families, we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2 [eukaryotic translation initiation factor 4A2]/ADIPOQ-rs114108468, p = 5e-6, minor allele frequency = 1.8%; TPRG1-rs16864075, p = 3e-6, minor allele frequency = 8%; accounted for ∼28% and ∼29% of the linkage, respectively). While the former variant was associated with EIF4A2 (p = 7e-5)/ADIPOQ (P = 3.49e-2) transcriptional levels, the latter variant was not associated with TPRG1 (P = 0.23) transcriptional levels. Replication in the Framingham Heart Study Offspring Cohort observed modest effect of these loci on ΔTHR. Our approach discovered two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes. Our findings provided novel insights into the molecular regulation of insulin resistance.

Disease-specific sterols accumulate in the blood of patients with several rare lipid disorders. Biochemical measurement of these sterols is important for correct diagnosis and sometimes monitoring of treatment. Existing methods to measure sterols in blood, particularly plant sterols, are often laborious and time consuming. Partly as a result, clinical access to sterol measurements is limited in many parts of the world. A simple and rapid method to extract free sterols from human serum and quantitate their concentration using isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) without derivatization was developed. The method was designed to be compatible with routine workflows (e.g., 96-well format) in a clinical lab and extensively validated. Serum from at least 125 controls were analyzed and used to estimate the upper reference limits for sitosterol, campesterol, stigmasterol, desmosterol, 7-dehydrocholesterol (7DHC), lathosterol, and cholestanol. Serum from patients with the rare lipid disorders sitosterolemia (n = 7), Smith-Lemli-Opitz syndrome (SLOS; n = 1), and cerebrotendinous xanthomatosis (CTX; n = 1) were analyzed. All seven sitosterolemia patients had greatly elevated levels of free plant sterols (sitosterol, campesterol, and stigmasterol) compared to the controls. The SLOS serum contained massively increased concentrations of 7DHC. CTX serum contained greatly increased concentrations of cholestanol, as well as 7DHC and lathosterol. Spiking experiments indicated that the method is likely also useful for the diagnosis of desmosterolosis and lathosterolosis. The reported method is a relatively simple and fast LC-MS/MS method capable of quantitating diagnostically important sterols and differentiated patients with three rare lipid disorders from controls.

In this retrospective, case-control study, we tested the hypothesis that blood-lipid concentrations during the decade prior to cognitive symptom onset can inform risk prediction for Alzheimer's disease (AD) and stable mild cognitive impairment (MCI). Clinically well-characterized cases were diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria; MCI cases had been stable for ≥5 years; and controls were propensity matched to cases at symptom onset (MCI: 116 cases, 435 controls; AD: 215 cases, 483 controls). Participants were grouped based on (i) longitudinal trajectories and (ii) quintile of variability independent of the mean (VIM) for total cholesterol, HDL-C, low-density lipoprotein cholesterol, non-HDL-C, and ln(triglycerides). Risk models evaluated the contributions of lipid trajectory and VIM groups relative to APOE genotype or polygenic risk scores (PRSs) for AD and lipid levels and major lipoprotein confounders: age, lipid-lowering medications, comorbidities, and other longitudinal correlates of blood-lipid concentrations. In models with AD-PRS, higher MCI-risk was associated with the two lower HDL-C trajectories [odds ratios: 3.8(1.3-11.3; P = 0.014), 3.2(1.1-9.3; P = 0.038), relative to the high trajectory], and the lowest VIM quintile of non-HDL-C [odds ratio: 2.2 (1.3-3.8: P = 0.004), relative to quintiles 2-5]. Higher AD-risk was associated with the two lower HDL-C trajectories [odds ratios: 2.8(1.5-5.1; P = 0.001), 3.7 (2.0-7.0; P < 0.001)], and the lowest VIM quintile of total cholesterol [odds ratio: 2.5(1.5-4.0: P < 0.001)]. Inclusion of lipid-trajectory and VIM groups improved risk-model predictive performance independent of APOE and AD or lipid-level PRSs, providing important real-world perspectives on how longitudinal levels and variation of blood-lipid concentrations contribute to risk of cognitive decline.

High density lipoproteins (HDLs) are best known for their role in atherosclerotic cardiovascular diseases. However, efforts to reduce cardiovascular risk by increasing the concentration of cholesterol in HDL have failed, raising the question of whether HDL may have other, more central aspects to its role in health and disease. In epidemiological studies, low levels of HDL cholesterol are strongly associated with risk of infectious diseases and death from sepsis and, during sepsis, a larger decline in HDL cholesterol predicts a worse outcome. Many preclinical studies have examined strategies to augment HDL genetically or pharmacologically and have shown that this leads to protection from sepsis in animal models. Data in humans are more limited, but suggest a clinically relevant role of HDL in mediating the response to pathogen-associated lipids and preventing excessive inflammation. Collectively, these data raise the intriguing possibility that a clinically important biological function of HDL is as a component of the innate immune system and suggest that pharmacological manipulation of HDL may be a strategy to reduce the organ dysfunction and death that results from uncontrolled inflammation during sepsis. This review article discusses recent advances in our understanding of the role of HDL in sepsis.

Sphingolipid metabolism comprises a complex interconnected web of enzymes, metabolites, and modes of regulation that influence a wide range of cellular and physiological processes. Deciphering the biological relevance of this network is challenging as numerous intermediates of sphingolipid metabolism are short-lived molecules with often opposing biological activities. Here, we introduce clickable, azobenzene-containing sphingosines, termed caSphs, as light-sensitive substrates for sphingolipid biosynthesis. Photo-isomerization of the azobenzene moiety enables reversible switching between a straight trans- and curved cis-form of the lipid's hydrocarbon tail. Combining in vitro enzyme assays with metabolic labeling studies, we demonstrate that trans-to-cis isomerization of caSphs profoundly stimulates their metabolic conversion by ceramide synthases and downstream sphingomyelin synthases. These light-induced changes in sphingolipid production rates are acute, reversible, and can be implemented with great efficiency in living cells. Our findings establish caSphs as versatile tools for manipulating sphingolipid biosynthesis and function with the spatiotemporal precision of light.

Ceramides are important intermediates in sphingolipid metabolism and serve as signaling molecules with independent biological significance. Elevated cellular and circulating ceramide levels are consistently associated with pathological conditions including cardiometabolic diseases, neurological diseases, autoimmune diseases, and cancers. Although pharmacological inhibition of ceramide formation often protects against these diseases in animal models, pharmacological modulation of ceramides in humans remains impractical. Dietary interventions including the Mediterranean diet, lacto-ovo-vegetarian diet, calorie-restricted diet, restriction of dairy product consumption, and dietary supplementation with polyunsaturated fatty acids, dietary fibers, and polyphenols, all have beneficial effects on modulating ceramide levels. Mechanistic insights into these interventions are discussed. This article reviews the relationships between ceramides and disease pathogenesis, with a focus on dietary intervention as a viable strategy for lowering the concentration of circulating ceramides.

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of metabolic dysfunction-associated fatty liver disease metabolic dysfunction-associated steatohepatitis , characterized by hepatic steatosis, inflammation, and fibrosis. This study investigates the role and potential mechanisms of metallothionein 1B (MT1B) in MASH through bioinformatics analysis and experimental validation. quantitative reverse transcription PCR and Western blot analyses confirm that MT1B expression is significantly downregulated in liver tissues of MASH patients, in high-fat diet-induced mouse models, and in hepatocytes induced by FFAs. Further functional experiments show that upregulation of MT1B reduces intracellular triglycerides and total cholesterol levels, lipid droplet formation, and proinflammatory factors. In vivo experiments demonstrate that specific downregulation of hepatic MT1B expression via AAV8-shMT1B injection significantly increases triglyceride and total cholesterol levels, exacerbates lipid accumulation, and markedly elevates liver fibrosis and inflammatory factor expression. RNA-seq and bioinformatics analyses show that the AKT/PI3K pathway is significantly suppressed in MT1B-overexpressing cells. Further experiments indicate that AKT inhibition can reverse the lipid metabolism disorders and inflammatory responses caused by MT1B downregulation. Additionally, Zinc can promote the nuclear translocation of MTF1, leading to its binding to the MT1B promoter, thereby upregulating MT1B expression and ultimately mitigating MASH progression. These findings suggest that zinc-regulated MT1B plays a critical role in lipid metabolism and inflammatory responses by regulating the AKT/PI3K signaling pathway, influencing MASH progression.

The enzymatic oxidation of arachidonic acid is proposed to yield trihydroxytetraene species (termed lipoxins) that resolve inflammation via ligand activation of the formyl peptide receptor, FPR2. While cell and murine models activate signaling responses to synthetic lipoxins, primarily lipoxin A₄ (LXA₄), there are expanding concerns about the reported biological formation, detection, and signaling mechanisms ascribed to LXA₄ and related di- and tri-hydroxy ω-6 and ω-3 fatty acids. The generation and signaling actions of LXA₄ and its primary 15-oxo metabolite were assessed in control, lipopolysaccharide-activated, and arachidonic acid-supplemented RAW264.7 and bone marrow-derived macrophages. Despite the expression of catalytically active enzymes required for LXA₄ synthesis, both LXA₄ and its 15-oxo-LXA₄ metabolite were undetectable in all conditions. Moreover, synthetic LXA₄ and the membrane-permeable 15-oxo-LXA₄ methyl ester, which rapidly de-esterified to 15-oxo-LXA₄, displayed no ligand activity for the putative LXA₄ receptor FPR2. Alternatively, 15-oxo-LXA₄, an electrophilic α,β-unsaturated ketone, alkylates nucleophilic amino acids and can modulate redox-sensitive transcriptional regulatory protein and enzyme function. 15-oxo-LXA₄ activated nuclear factor (erythroid related factor 2)-like 2-regulated expression of anti-inflammatory and repair genes and inhibited NF-κB-regulated pro-inflammatory mediator expression. Synthetic LXA₄ showed no impact on these macrophage anti-inflammatory and repair responses. In summary, these data show an absence of macrophage LXA₄ formation and receptor-mediated signaling actions of synthetic LXA₄. Rather, if present in sufficient concentrations, LXA₄ and other mono- and poly-hydroxylated unsaturated fatty acids synthesized by macrophages would be readily oxidized to electrophilic α,β-unsaturated ketone products that modulate the redox-sensitive cysteine proteome via G-protein coupled receptor-independent mechanisms.

HDL-C is an established risk marker for coronary heart disease. We investigated sociodemographic, lifestyle, anthropometric/physiologic, and other predictors of HDL-C over 30 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a multicenter, longitudinal cohort with a baseline exam in 1985-86 and follow-up exams at least every five years through 2016. During exams, participants completed various questionnaires, anthropometric measurements, and blood collection. We performed multiple linear regression of HDL-C at each CARDIA exam in a cross-sectional analysis, and linear mixed-effects regression to assess the longitudinal change of HDL-C across exams, treating time as a linear predictor, separately in women and men. The sample size ranged from 5114 participants at baseline to 3358 at the Year 30 Exam. Just over half of the participants were women and just under half were Black. Several factors were positively associated with HDL-C longitudinally in both women and men: age, self-identified Black race, alcohol intake, physical activity, and energy intake, along with sex-specific associations with current oral contraceptive use, current hormone therapy, and post-menopausal status (women only), and homeostasis model assessment-estimated insulin resistance (HOMA-IR) (men only). Other factors were inversely associated with HDL-C concentration longitudinally in both women and men: cigarette smoking, intakes of carbohydrates and total fat, body mass index, and low-density lipoprotein cholesterol and triglyceride concentrations, along with sex-specific associations with HOMA-IR and parity >0 (women only). We corroborated associations of several factors with HDL-C concentration and provided evidence of associations with several factors not extensively investigated in previous studies.

Phosphatidic acid phosphatase (PAP) is an evolutionarily conserved eukaryotic enzyme that catalyzes the Mg²⁺-dependent dephosphorylation of phosphatidic acid to produce diacylglycerol. The product and substrate of PAP are key intermediates in the synthesis of triacylglycerol and membrane phospholipids. PAP activity is associated with lipid-based cellular defects indicating the enzyme is an important target for regulation. We identified that the antidepressant sertraline is a novel inhibitor of PAP. Using Saccharomyces cerevisiae Pah1 as a model PAP, sertraline inhibited the activity by a noncompetitive mechanism. Sertraline also inhibited the PAP activity of human lipin 1 (α, β, and γ), an orthologue of Pah1. The inhibitor constants of sertraline for the S. cerevisiae and human PAP enzymes were 7-fold and ∼2-fold, respectively, lower than those of propranolol, a commonly used PAP inhibitor. Consistent with the inhibitory mechanism of sertraline and propranolol, molecular docking of the inhibitors predicts that they interact with non-catalytic residues in the haloacid dehalogenase-like catalytic domain of Pah1. The Pah1-CC (catalytic core) variant, which lacks regulatory sequences, was inhibited by both drugs in accordance with molecular docking data. That Pah1 is a physiological target of sertraline in S. cerevisiae is supported by the observations that the overexpression of PAH1 rescued the sertraline-mediated inhibition of pah1Δ mutant cell growth, the lethal effect of overexpressing Pah1-CC was rescued by sertraline supplementation, and that a sublethal dose of the drug resulted in a 2-fold decrease in TAG content.