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Lipoprotein(a) (Lp[a]) is a causal genetic risk factor for atherosclerotic cardiovascular disease (ASCVD). There are limited long-term follow-up data from large U.S. population cohorts. This study examined the relationship of Lp(a) with ASCVD outcomes in a large, pooled, multi-ethnic U.S. cohort. The study included data on Lp(a) and ASCVD outcomes from 5 U.S. prospective studies: MESA (Multi-Ethnic Study of Atherosclerosis), CARDIA (Coronary Artery Risk Development in Young Adults), JHS (Jackson Heart Study), FHS-OS (Framingham Heart Study-Offspring), and ARIC (Atherosclerosis Risk In Communities). Lp(a) levels were classified on the basis of cohort-specific percentiles. Multivariable Cox regression related Lp(a) with composite incident ASCVD events by risk group and diabetes status. The study included 27,756 persons without previous ASCVD who were aged 20 to 79 years, including 55.0% women, 35.6% Black participants, and 7.6% patients with diabetes, with mean follow-up of 21.1 years. Compared with Lp(a) levels <50th percentile, Lp(a) levels in the 50th to <75th, 75th to <90th, and ≥90th percentiles had adjusted HRs of 1.06 (95% CI: 0.99-1.14), 1.18 (95% CI: 1.09-1.28), and 1.46 (95% CI: 1.33-1.59), respectively for ASCVD events. Elevated Lp(a) predicted incident ASCVD events similarly by risk group, sex, and race or ethnic groups, but more strongly in patients with vs without diabetes (interaction P = 0.0056), with HRs for Lp(a) levels ≥90th percentile of 1.92 (95% CI: 1.50-2.45) and 1.41 (95% CI: 1.28-1.55), respectively. Lp(a) also individually predicted myocardial infarction, revascularization, stroke, and coronary heart disease death, but not total mortality. The study shows, in a large U.S. pooled cohort, that higher Lp(a) levels are associated with an increased ASCVD risk, including in patients with diabetes. [Display omitted] [ABSTRACT FROM AUTHOR]

This study aimed to investigate the lipid-lowering activity of LFBEP-C1 in high glucose-fed Caenorhabditis elegans (C. elegans). In this study, the fermented barley protein LFBEP-C1 was prepared and tested for its potential anti-obesity effects on C. elegans. The worms were fed Escherichia coli OP50 (E. coli OP50), glucose, and different concentrations of LFBEP-C1. Body size, lifespan, movement, triglyceride content, and gene expression were analyzed. The results were analyzed using ANOVA and Tukey's multiple comparison test. Compared with the model group, the head-swing frequency of C. elegans in the group of LFBEP-C1 at 20 μg/mL increased by 33.88%, and the body-bending frequency increased by 27.09%. This indicated that LFBEP-C1 improved the locomotive ability of C. elegans. The average lifespan of C. elegans reached 13.55 days, and the body length and width of the C. elegans decreased after LFBEP-C1 intake. Additionally, LFBEP-C1 reduced the content of lipid accumulation and triglyceride levels. The expression levels of sbp-1 , daf-2 , and mdt-15 significantly decreased, while those of daf-16 , tph-1 , mod-1 , and ser-4 significantly increased after LFBEP-C1 intake. Changes in these genes explain the signaling pathways that regulate lipid metabolism. LFBEP-C1 significantly reduced lipid deposition in C. elegans fed a high-glucose diet and alleviated the adverse effects of a high-glucose diet on the development, lifespan, and exercise behavior of C. elegans. In addition, LFBEP-C1 regulated lipid metabolism mainly by mediating the expression of genes in the sterol regulatory element-binding protein, insulin, and 5-hydroxytryptamine signaling pathways. [ABSTRACT FROM AUTHOR]

Anti-inflammatory activities of catechin-rich green tea extract (GTE) in obese rodents protect against metabolic endotoxemia by decreasing intestinal permeability and absorption of gut-derived endotoxin. However, translation to human health has not been established. We hypothesized that GTE would reduce endotoxemia by decreasing gut permeability and intestinal and systemic inflammation in persons with metabolic syndrome (MetS) compared with healthy persons. A randomized, double-blind, placebo-controlled, crossover trial in healthy adults (n = 19, 34 ± 2 years) and adults with MetS (n = 21, 40 ± 3 years) examined 4-week administration of a decaffeinated GTE confection (890 mg/d total catechins) on serum endotoxin, intestinal permeability, gut and systemic inflammation, and cardiometabolic parameters. Compared with the placebo, the GTE confection decreased serum endotoxin (P =.023) in both healthy persons and those with MetS, while increasing concentrations of circulating catechins (P <.0001) and γ-valerolactones (P =.0001). Fecal calprotectin (P =.029) and myeloperoxidase (P =.048) concentrations were decreased by GTE regardless of health status. Following the ingestion of gut permeability probes, urinary lactose/mannitol (P =.043) but not sucralose/erythritol (P >.05) was decreased by GTE regardless of health status. No between-treatment differences (P >.05) were observed for plasma aminotransferases, blood pressure, plasma lipids, or body mass nor were plasma tumor necrosis factor-α, interleukin-6, or the ratio of lipopolysaccharide-binding protein/soluble cluster of differentiation-14 affected. However, fasting glucose in both study groups was decreased (P =.029) by the GTE confection compared with within-treatment arm baseline concentrations. These findings demonstrate that catechin-rich GTE is effective to decrease circulating endotoxin and improve glycemic control in healthy adults and those with MetS, likely by reducing gut inflammation and small intestinal permeability but without affecting systemic inflammation. • A novel green tea extract (GTE) confection was provided to healthy adults and adults with metabolic syndrome. • GTE increased circulating catechins and valerolactones regardless of health status. • GTE decreased intestinal inflammation and small intestinal permeability. • GTE decreased circulating endotoxin. • GTE decreased fasting glucose without affecting systemic inflammation. • Gut-level benefits by GTE support research translation for cardioprotection by green tea. Healthy adults and adults with metabolic syndrome were randomized to a placebo or GTE (1 g; 890 mg catechins) confection for 1 month and then crossed-over to the alternative treatment following a 1-month washout. Regardless of health status, the GTE confection decreased fecal biomarkers of intestinal inflammation (calprotectin and myeloperoxidase) and small intestinal permeability based on a differential sugar absorption test while decreasing serum endotoxin. Abbreviations: GTE, green tea extract; MetS, metabolic syndrome [Display omitted] [ABSTRACT FROM AUTHOR]

Kimchi is a traditional fermented food that contains abundant nutrients and functional ingredients with various health benefits. We previously reported that kimchi active components suppress hepatic steatosis caused by endoplasmic reticulum (ER) stress in vitro and in vivo. Therefore, we assessed the effect of kimchi on the inhibition of hepatic steatosis caused by ER stress in HepG2 cells and C57BL/6N mice to verify the hypothesis that kimchi may potentially inhibit nonalcoholic fatty liver disease. We investigated the effect of kimchi on cell viability and triglyceride concentrations in cells and on lipid profile, lipid accumulation, and expression of related genes in cells and mice with hepatic steatosis. A mechanistic study was also performed using the liver X receptor α agonist T0901317 and the AMP-activated protein kinase agonist AICAR. Kimchi was noncytotoxic and effectively reduced triglyceride concentrations and suppressed hepatic steatosis-related gene expression in cells and mice. Additionally, kimchi recovered weight loss, lowered the serum and liver tissue lipid profiles, suppressed lipid accumulation, and reduced the effects of T0901317 and AICAR on lipogenic gene expression in tunicamycin-treated mice. Our results highlight that kimchi could prevent hepatic steatosis caused by ER stress in cells and mice. ER stress commonly causes hepatic steatosis in vitro and in vivo. In this study, kimchi attenuated ER stress–induced hepatic steatosis in HepG2 cells and C57BL/6N mice. Kimchi inhibited hepatic steatosis by regulating the LXRα/AMPK pathway. Abbreviations: ACC, acetyl coenzyme-A carboxylase; AMPK, AMP-activated protein kinase; ER, endoplasmic reticulum; FAS, fatty acid synthase; GOT, oxaloacetic transaminase; GPT, glutamic pyruvic transaminase; H&E, hematoxylin and eosin; ORO, oil red O; LXRα, liver X receptor α; SCD-1, stearoyl-CoA desaturase-1; SREBP-1c, sterol regulatory element-binding transcription factor 1c. [Display omitted] [ABSTRACT FROM AUTHOR]

Heterozygous familial hypercholesterolemia (HeFH) predisposes to premature cardiovascular diseases. Since 2015, the European Atherosclerosis Society has advocated initiation of statins at 8–10 years of age and a low-density lipoprotein cholesterol (LDL-C) target of <135 mg/dL. Longitudinal data from large databases on pharmacological management of pediatric HeFH are lacking. Here, we describe treatment patterns and LDL-C goal attainment in pediatric HeFH using longitudinal real-world data. This was a retrospective and prospective multicenter cohort study (2015–2021) of children with HeFH, diagnosed genetically or clinically, aged <18 years, and followed up in the National French Registry of FH (REFERCHOL). Data on the study population as well as treatment patterns and outcomes are summarized as mean±SD. We analyzed the data of 674 HeFH children (age at last visit: 13.1 ± 3.6 years; 82.0 % ≥10 years; 52.5 % females) who were followed up for a mean of 2.8 ± 3.5 years. Initiation of lipid-lowering therapy was on average at 11.8 ± 3.0 years of age for a duration of 2.5 ± 2.8 years. At the last visit, among patients eligible for treatment (573), 36 % were not treated, 57.1 % received statins alone, 6.4 % statins with ezetimibe, and 0.2 % ezetimibe alone. LDL-C was 266±51 mg/dL before treatment and 147±54 mg/dL at the last visit (−44.7 %) in treated patients. Regarding statins, 3.3 %, 65.1 %, and 31.6 % of patients received high-, moderate-, and low-intensity statins, respectively. Overall, 59 % of children on statin therapy alone and 35.1 % on bitherapy did not achieve the LDL-C goal; fewer patients in the older age group did not reach the treatment goal. Pediatric patients with FH followed up in specialist lipid clinics in France receive late treatment, undertreatment, or suboptimal treatment and half of them do not reach the therapeutic LDL-C goal. Finding a more efficient framework for linking scientific evidence to clinical practice is needed. [ABSTRACT FROM AUTHOR]

The purpose of this study was to elucidate and compare styrene maleic acid copolymer (SMA)-coated lipid emulsions (SMA emulsions) uptake pathway in vascular endothelial cells and surrounding cancer cells under not only neutral but also acidic pH, which is often observed in tumor microenvironment. DiI-labeled SMA emulsions were prepared using 1-palmitoyl-2-oleoyl-sn‑glycero-3-phosphocholine and triolein. In murine melanoma B16-BL6 (B16) cells and human umbilical vein endothelial cells (HUVEC), DiI-labeled SMA emulsions uptake under near-neutral (pH 7.4) and acidic (pH 6.0) conditions was determined by fluorescent analysis. SMA emulsions were taken up more efficiently into HUVEC than B16 cells under acidic condition in a temperature-dependent manner. Uptake study using endocytosis inhibitors showed that SMA emulsions were taken up by macropinocytosis and clathrin-mediated endocytosis in B16 cells. In HUVEC, however, they were taken up by clathrin- and caveolae-independent, but dynamin-dependent pathway. SMA emulsions would be internalized efficiently into vascular endothelial cells as well as cancer cells under acidic microenvironment via different endocytosis pathways. SMA emulsions could be a promising drug delivery carrier for anti-angiogenic drugs. [Display omitted] • Uptake activity of SMA-coated lipid emulsions were higher in HUVEC than B16 cells at neutral pH. • Uptake activity of SMA-coated lipid emulsions were higher at acidic than neutral pH. • SMA-coated lipid emulsions were localized in lysosomes. • SMA emulsions were taken up by macropinocytosis and clathrin-mediated endocytosis in B16 cells. • SMA emulsions uptake were clathrin- and caveolae-independent, but dynamin-dependent in HUVEC. [ABSTRACT FROM AUTHOR]

All plasma membranes exhibit asymmetry, both in lipid distribution and protein topology. Cells invest significant free energy to uphold this asymmetry. Despite its critical physiological role, our quantitative understanding of membrane asymmetry is limited, due primarily to insufficient in vitro methods for creating asymmetric model membranes. New experimental protocols now allow for the preparation of vesicles with tailored, asymmetric lipid distributions. Leaflets with distinct lipid compositions can affect each other's properties, such as lateral diffusion, hydrocarbon chain ordering, and bending elasticity. Integral membrane proteins not only adapt to lipid asymmetry but also exhibit asymmetric topological orientations, which in turn can depend on lipid composition. Plasma membranes utilize free energy to maintain highly asymmetric, non-equilibrium distributions of lipids and proteins between their two leaflets. In this review we discuss recent progress in quantitative research enabled by using compositionally controlled asymmetric model membranes. Both experimental and computational studies have shed light on the nuanced mechanisms that govern the structural and dynamic coupling between compositionally distinct bilayer leaflets. This coupling can increase the membrane bending rigidity and induce order – or lipid domains – across the membrane. Furthermore, emerging evidence indicates that integral membrane proteins not only respond to asymmetric lipid distributions but also exhibit intriguing asymmetric properties themselves. We propose strategies to advance experimental research, aiming for a deeper, quantitative understanding of membrane asymmetry, which carries profound implications for cellular physiology. [ABSTRACT FROM AUTHOR]

The oleaginous yeast, Lipomyces starkeyi can have diverse industrial applications due to its remarkable capacity to use various carbon sources for the biosynthesis intracellular triacylglycerides (TAGs). In L. starkeyi , TAG synthesis is enhanced through upregulation of genes involved in citrate-mediated acyl-CoA synthesis and Kennedy pathways through the transcriptional regulator LsSpt23p. High expression of LsSPT23 can considerably enhance TAG production. Altering the regulatory factors associated with lipid production can substantially augment lipid productivity. In this study, we identified and examined the L. starkeyi homolog sucrose nonfermenting 1 SNF1 (LsSNF1) of YlSNF1 , which encodes a negative regulator of lipid biosynthesis in the oleaginous yeast Yarrowia lipolytica. The deletion of LsSNF1 enhanced TAG productivity in L. starkeyi , suggesting that LsSnf1p is a negative regulator in TAG production. The enhancement of TAG production following deletion of LsSNF1 can primarily be attributed to the upregulation of genes in the citrate-mediated acyl-CoA synthesis and Kennedy pathways, pivotal routes in TAG biosynthesis. The overexpression of LsSPT23 enhanced lipid productivity; strain overexpressing LsSPT23 and without LsSNF1 exhibited increased TAG production capacity per cell. LsSnf1p also has a significant role in the utilization of carbon sources, including xylose or glycerol, in L. starkeyi. Our study results elucidated the role of LsSnf1p in the negative regulation of TAG synthesis in L. starkeyi , which has not previously been reported. • Lipomyces starkeyi SNF1 homolog (LsSNF1) was identified and the LsSNF1 deletion mutant was constructed. • LsSnf1p had important roles in lipid production and carbon-source utilization in L. starkeyi. • The overexpression of LsSpt23p and without LsSnf1p exhibited increased TAG production capacity per cell. [ABSTRACT FROM AUTHOR]

• Exemestane administration significantly increased LDL-C. • Exemestane administration significantly decreased HDL-C and TC. • Exemestane prescription only lowered TG concentrations when it was administered for < 12 months. Postmenopausal women are prone to develop cardiovascular disorders. In addition, cardiovascular risk in women can be influenced by the long-term prescription of drugs that lead to estrogen deprivation, e.g., aromatase inhibitors, and that can cause dyslipidemia. Little is known about the impact of exemestane, an aromatase inhibitor, on serum lipids' concentration in women. Hence, we conducted a meta -analysis of randomized controlled trials (RCTs) to assess the influence of this pharmacological agent on the lipid profile in women. The Scopus, Web of Science, PubMed/Medline and EMBASE databases were searched by two surveyors for manuscripts published from the inception of these databases until April 3rd, 2023. No language restrictions were applied to the search. The random effects model was used to generate the combined results as weighted mean difference (WMD) and 95% confidence interval (CI). In total, 8 eligible RCTs were included in the meta -analysis. Overall results from the random effects model indicate that exemestane administration increases LDL-C (WMD: 4.42 mg/dL, 95 % CI: 0.44, 8.41, P = 0.02) and decreases HDL-C (WMD: −6.03 mg/dL, 95 % CI: −7.77, −4.29, P < 0.001) and TC (WMD: −5.40 mg/dL, 95 % CI: −9.95, −0.86, P = 0.02) levels, respectively. Moreover, exemestane prescription only lowered TG concentrations when it was administered for < 12 months (WMD: −14.60 mg/dL, 95 % CI: –23.57 to −5.62, P = 0.001). Currently available evidence suggests that the administration of exemestane in females increases LDL-C values and reduces HDL-C, TC, and, when prescribed for less than 12 months, TG concentrations. [ABSTRACT FROM AUTHOR]

Lipids have been previously implicated in the lifecycle of neuroinvasive viruses. However, the role of lipids in programmed cell death and the relationship between programmed cell death and lipid droplets (LDs) in neuroinvasive virus infection remains unclear. Here, we found that the infection of neuroinvasive virus, such as rabies virus and encephalomyocarditis virus could enhance the LD formation in N2a cells, and decreasing LDs production by targeting diacylglycerol acyltransferase could suppress viral replication. The lipidomics analysis revealed that arachidonic acid (AA) was significantly increased after reducing LD formation by restricting diacylglycerol acyltransferase, and AA was further demonstrated to induce ferroptosis to inhibit neuroinvasive virus replication. Moreover, lipid peroxidation and viral replication inhibition could be significantly alleviated by a ferroptosis inhibitor, ferrostatin-1, indicating that AA affected neuroinvasive virus replication mainly through inducing ferroptosis. Furthermore, AA was demonstrated to activate the acyl-CoA synthetase longchain family member 4-lysophosphatidylcholine acyltransferase 3-cytochrome P450 oxidoreductase axis to induce ferroptosis. Our findings highlight novel cross-talks among viral infection, LDs, and ferroptosis for the first time, providing a potential target for antiviral drug development. [ABSTRACT FROM AUTHOR]

While numerous observational studies have indicated an association between lipids and Sudden Sensorineural Hearing Loss (SSNHL), it remains uncertain whether dyslipidemia serves as a causal risk factor for SSNHL. Our objective is to elucidate the potential causal relationship between lipid levels and SSNHL through Mendelian randomization analysis. The primary and secondary lipid data used in this study were sourced from the UK Biobank (UKBB) and the Global Lipid Genetics Consortium results (GLGC), respectively. These datasets were obtained from large, publicly available genome-wide association studies (GWAS). The outcome data for sudden sensorineural hearing loss (SSNHL) were acquired from the Finnegan Biobank, consisting of 1491 cases and 196,592 controls. Subsequently, both single-variable Mendelian randomization (SVMR) and multivariate Mendelian randomization (MVMR) methods were employed to evaluate the causal relationship between lipids and the occurrence of SSNHL. Among the primary lipid data, SVMR analysis showed a significant correlation between high density lipoprotein cholesterol (HDL-C) (OR: 0.822, 95 %CI: 0.694–0.974, p = 0.023) and SSNHL, and triglycerides (TG) (OR: 0.997, 95 %CI: 0.836–1.188, p = 0.975), low density lipoprotein cholesterol (LDL-C) (OR: 1.067, 95 %CI: 0.861–1.322, p = 0.552) did not correlate with SSNHL. In the secondary lipid data, SVMR analysis showed that HDL-C (OR: 0.987, 95 %CI: 0.805–1.210, p = 0.903), TG (OR: 0.991, 95 %CI: 0.787–1.246, p = 0.937) and LDL-C (OR: 1.092, 95 % CI: 0.926–1.287, p = 0.294) did not correlate with SSNHL. MVMR analysis of the primary lipid data showed that HDL-cholesterol (OR: 0.755, 95 % CI: 0.596–0.956, p = 0.019) was significantly associated with SSNHL, while TG (OR: 0.808, 95 %CI: 0.611–1.068, p = 0.134) and LDL-C (OR: 1.146, 95 %CI: 0.869–1.511, p = 0.333) did not correlate with SSNHL, consistent with the results of SVMR. Inverse MR results showed that SSNHL did not correlate with TG (OR: 0.999, 95 %CI: 0.997–1.001, p = 0.835), HDL-C (OR: 1.001, 95 %CI: 0.998–1.003), LDL-C (OR: 0.999, 95 %CI: 0.997–1.002, p = 0.863). Mendelian randomization (MR) results suggest that decreased serum HDL-C levels are an independent risk factor for SSNHL. Monitoring and focusing on lipid levels may be of value in the prevention and treatment of SSNHL. [ABSTRACT FROM AUTHOR]

In neurodegeneration, neurons release lipids that accumulate in glial lipid droplets (LDs). But what controls lipid transport and how does this affect glia? A recent study by Li et al. discovered that the loss of neuronal AMP-activated protein kinase (AMPK) activity promotes lipid efflux, which drives a proinflammatory state in microglia. [ABSTRACT FROM AUTHOR]

Dyslipidemia is a leading contributor to atherosclerotic cardiovascular disease (ASCVD). There has been a significant improvement in the treatment of dyslipidemia in the past 10 years with the development of new pharmacotherapies. However adherence to guidelines and patients being prescribed appropriate therapy can be improved. The intent of this review is help enhance clinicians understanding of non-statin lipid lowering therapies in accordance with the 2022 American College of Cardiology Expert Consensus Clinical Decision Pathway (ECDP) on the Role of Non-statin Therapies for LDL-Cholesterol Lowering. We also present a single-center experience implementing a systematic inpatient protocol for lipid lowering therapy (LLT) for secondary prevention of ASCVD. We review the clinical trials for ezetimibe, evolocumab, alirocumab, inclisiran, bempedoic acid and summarize how the medications are implemented for use in the 2022 American College of Cardiology Expert Consensus Clinical Decision Pathway. We conducted a quality improvement retrospective chart analysis study to assess the proportion of patients admitted with non-ST-elevation myocardial infarction or ST-elevation myocardial infarction who underwent percutaneous coronary intervention and were prescribed LLT at discharge from 1/1/2018 to 08/20/2021. A structured inpatient lipid protocol was implemented with the aim of identifying very-high-risk patients, standardizing the initiation and escalation of LLT, and ensuring appropriate monitoring and follow-up. We identify patients admitted with ASCVD event, and obtain baseline LDL-C level. Our pharmacist reviews the patients in the cardiology units and will make recommendations for next step in management. For patients on statin with an LDL-C above 70mg/dL or not on a statin with an LDL-C above 150mg/dL, we maximize the statin and add a PCSK9 inhibitor on discharge. For patients on statin with an LDL-C below 70mg/dL or not on a statin with an LDL-C below 150mg/dL, we maximize the statin and add either ezetimibe or bempedoic acid. The inpatient case manager determines cost and coverage and communicates with the care management specialist to ensure follow up on authorization for medications. For very high risk patients, a referral is placed in the electronic medical record to our advanced lipid management program and the office calls patient to ensure follow up visit is scheduled with repeat lipid panel checked in 4-12 weeks. Cases are reviewed with the lipidologists, care managers, and nurses during a weekly lipid board to discuss treatment plans for the patients scheduled for the upcoming week. Prior to implementation, review of patients from 1/1/2018 to 08/20/2021, our analysis found that 92% of these patients were prescribed statin therapy, but only 66.2% of them had an LDL-C level below 70 mg/dL at their subsequent follow-up appointment. Frequent reassessment of the data is done to see compliance rate with medication and adherence to guidelines with hope to see improvement in percentage of patients with LDL-C at target. The 2022 ACC ECDP on the role of non-statin therapies for LDL-C lowering recommends aggressive combination therapy to lower LDL-C in very-high-risk patients. To effectively manage very-high-risk patients and ensure that they receive appropriate lipid-lowering therapy, it may be necessary to implement a structured inpatient protocol involving a multi-disciplinary approach in both the inpatient and outpatient setting. [ABSTRACT FROM AUTHOR]

Messenger RNA (mRNA)-based therapy shows immense potential for broad biomedical applications. However, the development of safe and efficacious mRNA delivery vectors remains challenging due to delivery barriers and inefficient intracellular payload release. Herein, we presented a simple strategy to boost the mRNA intracellular release by incorporation of anionic poly(γ-glutamic acid) (PGA) into an ionizable lipid-based LNP/mRNA. We systematically investigated the impact of PGA incorporation on mRNA transfection both in vitro and in vivo. The molecular weights and formulation ratios of PGA greatly affected the transfection efficacy of LNP/mRNA. From in vitro study, the optimized LNP/mRNA/PGA was formulated by incorporation of PGA with the molecular weight of 80 kDa or 200 kDa and the charge ratio (N/P/C) of 25/1/1. The optimized formulation achieved around 3-fold mRNA expression in HeLa cells compared to the bare LNP/mRNA. The intracellular releasing study using specific DNA probe revealed that this enhancement of transfection efficacy was attributed to the elevated mRNA release into cytoplasm. Moreover, the optimized LNP/mRNA/PGA achieved up to 5-fold or 3-fold increase of luciferase mRNA expression in vivo after being injected into mice systematically or intramuscularly, respectively. In addition, the incorporation of PGA did not significantly alter the biodistribution profile of the complexes on both organ and cellular levels. Therefore, our work provides a simple strategy to boost mRNA delivery, which holds great promise to improve the efficacy of mRNA therapeutics for various biomedical applications. The process of designing and screening potent mRNA carriers is complicated and time-consuming, while the efficacy is not always satisfying due to the delivery barriers and inefficient mRNA release. This work presented an alternative strategy to boost the mRNA delivery efficacy by incorporating an anionic natural polymer poly(γ-glutamic acid) (PGA) into LNP/mRNA complexes. The optimized LNP/mRNA/PGA achieved up to 3-fold and 5-fold increase in transfection efficacy in vitro and in vivo , respectively. Intracellular releasing analysis revealed that the enhancement of transfection efficacy was mainly attributed to the elevated intracellular release of mRNA. In addition, the incorporation of PGA did not alter the biodistribution or the biosafety profile of the complexes. These findings indicate that PGA incorporation is a promising strategy to improve the efficacy of mRNA therapeutics. [Display omitted] [ABSTRACT FROM AUTHOR]

Lipid metabolism play an essential role in occurrence and development of asthma, and it can be disturbed by phthalate esters (PAEs) and organophosphate flame retardants (OPFRs). As a chronic inflammatory respiratory disease, the occurrence risk of childhood asthma is increased by PAEs and OPFRs exposure, but it remains not entirely clear how PAEs and OPFRs contribute the onset and progress of the disease. We have profiled the serum levels of PAEs and OPFRs congeners by liquid chromatography coupled with mass spectrometry, and its relationships with the dysregulation of lipid metabolism in asthmatic, bronchitic (acute inflammation) and healthy (non-inflammation) children. Eight PAEs and nine OPFRs congeners were found in the serum of children (1 – 5 years old) from Shenzhen, and their total median levels were 615.16 ng/mL and 17.06 ng/mL, respectively. Moreover, the serum levels of mono-methyl phthalate (MMP), tri-propyl phosphate (TPP) and tri- n -butyl phosphate (TNBP) were significant higher in asthmatic children than in healthy and bronchitic children as control. Thirty-one characteristic lipids and fatty acids of asthma were screened by machine-learning random forest model based on serum lipidome data, and the alterations of inflammatory characteristic lipids and fatty acids including palmitic acids, 12,13-DiHODE, 14,21-DiHDHA, prostaglandin D2 and LysoPA(18:2) showed significant correlated with high serum levels of MMP, TPP and TNBP. These results imply PAEs and OPFRs promote the occurrence of childhood asthma via disrupting inflammatory lipid and fatty acid metabolism, and provide a novel sight for better understanding the effects of plastic additives on childhood asthma. [Display omitted] [ABSTRACT FROM AUTHOR]

Chaenomeles sinensis (Thouin) Koehne fruit is a rich source of medicinally and nutritionally important natural phytochemicals that benefit human health. Based on the information provided, we hypothesized that Chaenomeles sinensis (Thouin) Koehne fruit polyphenols (CSFP) possessed in vivo protective effect of on high-fat diet (HFD)–induced obesity and hepatic steatosis. Specific pathogen-free male C57BL/6J mice were randomly divided into 3 groups and fed with a low-fat diet, HFD, or HFD supplemented with CSFP by intragastric administration for 14 weeks. Obesity-related biochemical indexes and hepatic gene expression profile were determined. The findings of this study demonstrated notable reductions in body weight gain, serum triglycerides, total cholesterol, low-density lipoprotein cholesterol, and steatosis grade in the group supplemented with CSFP compared with the HFD group. Gene expression analysis provided insights into the molecular mechanisms, demonstrating that CSFP downregulated the expression of key genes involved in lipogenesis (e.g., Fas, Fads2, Scd1) and upregulated the genes associated with fatty acid oxidation (e.g., Pparα, Cpt1a, Acox1), while also suppressing genes implicated in cholesterol homeostasis (e.g., HMGCoR, Insig1, AdipoR2). These molecular changes suggest that CSFP exerts protective effects by modulating hepatic lipid metabolism pathways, thereby mitigating the metabolic derangements associated with HFD-induced obesity and hepatic steatosis. In mice with obesity, Chaenomeles sinensis (Thouin) Koehne fruit polyphenols downregulated the expression of key genes involved in lipogenesis and upregulated the genes associated with fatty acid oxidation, while also suppressing genes implicated in cholesterol homeostasis. The findings suggested that Chaenomeles sinensis (Thouin) Koehne fruit polyphenols may have beneficial effects on obesity-related molecular dysregulation. Abbreviations: Acox1 , acyl-coenzyme A oxidase 1; AdipoR2 , adiponectin receptor 2; Cpt1 a , carnitine palmitoyltransferase 1a; Fads2 , fatty acid desaturase 2; Fas , fatty acid synthase; HMGCoR , 3-hydroxy-3-methyl-glutaryl CoA reductase; Insig1 , insulin-induced gene 1; Pparα , peroxisome proliferator-activated receptor α; Scd1 , stearoyl-CoA desaturase 1. [Display omitted] [ABSTRACT FROM AUTHOR]

Exposure to bisphenol A (BPA) during gestation leads to fetal growth restriction (FGR), whereby the underlying mechanisms remain unknown. Here, we found that FGR patients showed higher levels of BPA in the urine, serum, and placenta; meanwhile, trophoblast ferroptosis was observed in FGR placentas, as indicated by accumulated intracellular iron, impaired antioxidant molecules, and increased lipid peroxidation products. To investigate the role of ferroptosis in placental and fetal growth, BPA stimulation was performed both in vivo and in vitro. BPA exposure during gestation was associated with FGR in mice; also, it induces ferroptosis in mouse placentas and human placental trophoblast. Pretreatment with ferroptosis inhibitor ferritin-1 (Fer-1) alleviated BPA-induced oxidative damage and cell death. Notably, BPA reduced the trophoblastic expression of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which regulated tissue growth and organ size. YAP or TAZ siRNA enhanced BPA-induced ferroptosis, suggesting that trophoblast ferroptosis is dependent on YAP/TAZ downregulation after BPA stimulation. Consistently, the protein levels of YAP/TAZ were also reduced in FGR placentas. Further results revealed that silencing YAP/TAZ promoted BPA-induced ferroptosis through autophagy. Pretreatment with autophagy inhibitor chloroquine (CQ) attenuated BPA-induced trophoblast ferroptosis. Ferritinophagy, an autophagic degradation of ferritin (FTH1), was observed in FGR placentas. Similarly, BPA reduced the protein level of FTH1 in placental trophoblast. Pretreatment with iron chelator desferrioxamine (DFO) and NCOA4 (an autophagy cargo receptor) siRNA weakened the ferroptosis of trophoblast after exposure to BPA, indicating that autophagy mediates ferroptosis in BPA-stimulated trophoblast by degrading ferritin. In summary, ferroptosis was featured in BPA-associated FGR and trophoblast injury; the regulation of ferroptosis involved the YAP/TAZ-autophagy-ferritin axis. [ABSTRACT FROM AUTHOR]

Accurately evaluating plaque characteristics is essential because lesions with lipid-rich plaque put patients at risk of thromboembolic complications from carotid artery stenting. Near-infrared spectroscopy (NIRS) is a diagnostic imaging modality that identifies lipid components from the near-infrared absorption pattern but does not reveal the distribution of calcification. The purpose of this study was to investigate the calcification characteristics of unstable carotid plaques, focusing on relationships between the calcification characteristics revealed by computed tomography angiography and the lipid core distribution derived from NIRS. Participants in this retrospective analysis comprised 35 patients (29 men, 6 women; mean age, 76.0 years; range, 52–89 years) who underwent carotid artery stenting in our institute between January 2021 and December 2022. We evaluated the thickness and length of carotid calcifications at the minimal lumen level from preoperative computed tomography angiography and analyzed the relationship with maximum lipid core burden index (max-LCBI) from NIRS. Strong negative linear correlations were observed between the thickness of calcification and max-LCBI at Area (any segment in a target lesion) (r = −0.795, P < 0.001), max-LCBI at minimal lumen area (r = −0.795, P < 0.001) and lipid core burden index (LCBI) at lesion (rate of LCBI in entire plaque lesion) (r = −0.788, P < 0.001), respectively. Significant negative linear correlations were observed between distribution of calcification length and max-LCBI at area (r = −0.429, P = 0.01), max-LCBI at minimal lumen area (r = −0.373, P = 0.027), and LCBI at lesion (r = −0.443, P = 0.008). Thin and ubiquitous carotid calcification was associated with LCBI values derived from NIRS indicative of carotid lipid plaque distribution, implying the possibility of predicting lesion instability. [ABSTRACT FROM AUTHOR]

The TetraEther indeX of 86 carbon atoms (TEX 86) is widely used as a proxy to reconstruct past sea surface temperatures. Most current applications of TEX 86 are primarily based on analyzing the composition of isoprenoid glycerol dialkyl glycerol tetraethers (isoGDGTs) that comprise TEX 86 in sediments, with the assumption that the sedimentary isoGDGTs are mainly derived from the surface mixed layer. Here we report on the variations in the isoGDGT distribution, archaeal abundance and community through the water column of the Western Pacific Ocean, directly testing the export depth of isoGDGTs and constraining the temperature records of TEX 86. Our data show that maximum isoGDGT concentrations occurred in subsurface waters (150–200 m) with maximum archaeal abundances. The ratio between isoGDGTs bearing 2 vs. 3 cyclopentane moieties, i.e. [2/3] ratio, increased with depth, which is likely related to the shift of the archaeal community from Ca. Nitrosopelagicus-dominance to norank_f__Nitrosopumilaceae -dominance. Models based on the [2/3] ratios in the water column predicted an average export depth of isoGDGTs to sediments of around 150–200 m, consistent with the robust relationship between the compiled sedimentary TEX 86 and the annual mean subsurface temperature. Taken together, our findings support that TEX 86 records subsurface rather than surface temperatures in the open ocean. [ABSTRACT FROM AUTHOR]

Over the last two decades, water-in-oil fat crystal stabilised Pickering emulsions have been increasingly studied for the controllable release of encapsulated (water-soluble) species. The stability inherent to Pickering emulsions has been shown to be enhanced by sintering to form an interfacial lipid 'shell' around the droplets, which improves the retention and prolongs the delivery of the enclosed species. Using a scraped surface heat exchanger/pin stirrer setup, the present work shows that processing conditions used to produced W/O emulsions with dispersed droplets enclosed in lipid shells, have a significant impact upon the subsequent release of NaCl enclosed within them. The best performing emulsion structure produced here is reported to retain about 98% of its initial salt load over a period of 100 days. NaCl release profiles were also used to calculate the interfacial rate constants for the transferal of salt across the lipid shells. Interfacial rate constants ranged from 5.5 to 3593.2xl0-3 nm2/s and were significantly (up to three orders of magnitude) lower than those reported in literature for similar systems. Analysis revealed that depending on the specific conditions employed, the processing environment can enhance or compromise lipid shell integrity. Overall, the current study offers significant direction in terms of the optimum processing requirements that are necessary to produce fat-continuous emulsion microstructures that can successfully regulate the release of NaCl, paving the way for the successful development of food formulations of controlled salt-perception. [ABSTRACT FROM AUTHOR]

XK-related 8 (XKR8), in complex with the transmembrane glycoprotein basigin, functions as a phospholipid scramblase activated by the caspase-mediated cleavage or phosphorylation of its C-terminal tail. It carries a putative phospholipid translocation path of multiple hydrophobic and charged residues in the transmembrane region. It also has a crucial tryptophan at the exoplasmic end of the path that regulates its scrambling activity. We herein investigated the tertiary structure of the human XKR8-basigin complex embedded in lipid nanodiscs at an overall resolution of 3.66 Å. We found that the C-terminal tail engaged in intricate polar and van der Waals interactions with a groove at the cytoplasmic surface of XKR8. These interactions maintained the inactive state of XKR8. Point mutations to disrupt these interactions strongly enhanced the scrambling activity of XKR8, suggesting that the activation of XKR8 is mediated by releasing the C-terminal tail from the cytoplasmic groove. We speculate that the cytoplasmic tail region of XKR8 functions as a plug to prevent the scrambling of phospholipids. [ABSTRACT FROM AUTHOR]

Eukaryotic elongation factor 1A1 (EEF1A1) is canonically involved in protein synthesis but also has noncanonical functions in diverse cellular processes. Previously, we identified EEF1A1 as a mediator of lipotoxicity and demonstrated that chemical inhibition of EEF1A1 activity reduced mouse liver lipid accumulation. These findings suggested a link between EEF1A1 and metabolism. Therefore, we investigated its role in regulating metabolic substrate preference. EEF1A1-deficient Chinese hamster ovary (2E2) cells displayed reduced media lactate accumulation. These effects were also observed with EEF1A1 knockdown in human hepatocyte-like HepG2 cells and in WT Chinese hamster ovary and HepG2 cells treated with selective EEF1A inhibitors, didemnin B, or plitidepsin. Extracellular flux analyses revealed decreased glycolytic ATP production and increased mitochondrial-to-glycolytic ATP production ratio in 2E2 cells, suggesting a more oxidative metabolic phenotype. Correspondingly, fatty acid oxidation was increased in 2E2 cells. Both 2E2 cells and HepG2 cells treated with didemnin B exhibited increased neutral lipid content, which may be required to support elevated oxidative metabolism. RNA-seq revealed a >90-fold downregulation of a rate-limiting glycolytic enzyme, hexokinase 2, which we confirmed through immunoblotting and enzyme activity assays. Pathway enrichment analysis identified downregulations in TNFA signaling via NFKB and MYC targets. Correspondingly, nuclear abundances of RELB and MYC were reduced in 2E2 cells. Thus, EEF1A1 deficiency may perturb glycolysis by limiting NFKB- and MYC-mediated gene expression, leading to decreased hexokinase expression and activity. This is the first evidence of a role for a translation elongation factor, EEF1A1, in regulating metabolic substrate utilization in mammalian cells. [ABSTRACT FROM AUTHOR]

Background: For many years, United States' dietary policy recommended limiting egg intake to no more than 3/wk in the belief that restricting dietary cholesterol would lower plasma cholesterol levels and thereby reduce the risk of cardiovascular disease. The evidence supporting these recommendations is controversial. Objectives: To examine the impact of eggs, a major contributor to dietary cholesterol intake, on lipid levels and to determine whether these egg effects are modified by other healthy dietary factors in adults. Methods: Males and females aged 30-64 y with available 3-d diet record data, without cardiovascular disease and not taking lipid- or glucose-lowering medications in the prospective Framingham Offspring cohort were included (n = 1852). Analysis of covariance models were used to compare mean follow-up lipid levels adjusting for age, sex, BMI, and dietary factors. Cox proportional hazard's models were used to estimate risk for elevated lipid levels. Results: Consuming -5 eggs/wk was not adversely associated with lipid outcomes. Among men, consuming -5 (compared with <0.5) eggs/wk was associated with an 8.6 mg/dL lower total cholesterol level and a 5.9 mg/dL lower LDL cholesterol level, as well as lower triglycerides. Overall, higher egg intake combined with higher dietary fiber (compared with lower intakes of both) was associated with the lowest total cholesterol, LDL cholesterol, and LDL cholesterol-to-HDL cholesterol ratio. Finally, diets with higher (compared with lower) egg intakes in combination with higher total fish or fiber intakes, respectively, were associated with lower risks of developing elevated (>160 mg/dL) LDL cholesterol levels (hazard ratio: 0.61; 95% confidence interval: 0.44, 0.84; and HR: 0.70; 95% confidence interval: 0.49, 0.98, respectively). Conclusions: Higher egg intakes were beneficially associated with serum lipids among healthy adults, particularly those who consumed more fish and dietary fiber. [ABSTRACT FROM AUTHOR]

• As of August 18th, 2022, the COVID-19 pandemic has claimed over 6,400,000 lives worldwide and over 1,000,000 lives in the United States. • Prior retrospective studies exist in the literature, documenting that statins have a mortality benefit in patients hospitalized with COVID-19. These studies have focused on populations with a high proportion of Caucasians. • This retrospective study examines a population that is majority African American and found no benefit of statins in patients hospitalized with COVID-19 in mortality, survival time, need for ICU care, length of ICU stay, need for ventilator, duration of intubation, or need for dialysis. • Further research should be done examining the interplay between COVID-19, statins, and race/ethnicity to better elucidate whether statins have any beneficial effect in decreasing mortality caused by COVID-19. The COVID-19 pandemic has claimed over 6.4 million lives globally. Finding effective medications to reduce mortality in hospitalized COVID-19 patients remains critical. No previous study has been published on the effects of statin use in a majority African American COVID-19 patient population. This study aims to assess the relationship between in-hospital statin use and mortality in this population. A retrospective chart review of patients diagnosed with COVID-19 from March 2020 to June 2020 admitted to the Phoebe Putney Health System in Albany, Georgia, an early epicenter of the COVID-19 pandemic, was conducted. The outcomes of 735 hospitalized COVID-19 positive patients from over 40 counties in Georgia were analyzed. The primary outcome of interest was all-cause mortality, with secondary outcomes of interest of ICU care, length of ICU stay, need for mechanical ventilator, duration of intubation, and need for dialysis. Multivariate logistic regression and Cox proportional hazards analysis were conducted to examine the effect of in-hospital statin use and mortality. 186 of 735 total patients were prescribed statins in-hospital. 83.8% were African American. Multivariate logistic regression found in-hospital statin use was not significantly associated with the primary outcome – all-cause mortality (p=0.23). Similar findings were seen in need for ICU care, length of ICU stay, need for mechanical ventilator, duration of intubation, and need for dialysis (p>0.05). Additionally, results from a Cox proportional hazards model found in-hospital statin use was not associated with survival time. Sensitivity analysis conducted on only African American patients validated that in-hospital statin use was not associated with all-cause mortality in these patients. Of note, immunosuppression and severe disease presentation were associated with a six-fold increase in risk of mortality and the largest decreases in survival time. It is possible statins have no mortality benefit for this patient population, but further research beyond this association study would need to be conducted to determine this conclusively. From this study, the best clinical recommendation would be to continue statins for COVID-19 patients with pre-hospital statin use and to launch a randomized clinical trial to definitively determine the efficacy of statins in the treatment of hospitalized COVID-19 patients. [ABSTRACT FROM AUTHOR]

• A database of over 300,000 adolescents in a single practice was reviewed. • Universal pediatric lipid screening did not achieve expectations for FH detection. • Pharmacotherapy for FH in childhood is poorly utilized despite recommendations. • We suggest ways that metrics and oversight may improve pediatric FH screening rates. • Clarifying pediatric specialists and referral criteria may improve FH treatment. Familial hypercholesterolemia (FH) is an inherited condition that likely affects 1 in 300 people often requiring pharmacologic intervention in childhood. We hypothesized that current strategies for pediatric lipid screening fail to detect and treat most FH, but data analysis may suggest specific methods to improve outcomes. We retrospectively searched 392,129 patient records of 11–17-year-olds in Kaiser Permanente Southern California for data related to recommended universal pediatric lipid screening. We categorized subjects as Probable or Possible FH and evaluated FH pharmacotherapy status. 37% of the population received lipid screening with 0.13% (1 in 769) having Probable or Possible FH. Results at each step of the process showed progressive decreases in detection and treatment. We characterized 1 in 3448 subjects as Probable FH which is only 8.7% of cases expected from the prevalence of FH in the population. 45% of Probable FH cases received ongoing pharmacotherapy which is 1 in 7688 of the cohort (3.9% of expected cases). One major correctable reason for this drop-off was using obesity to target screening and treatment decisions rather than following the recommended universal screening. We found a strong association of obesity with screening (risk ratio (RR) 2.74 [confidence interval (CI) 2.71–2.76]), but not with FH (RR 0.72, CI 0.47–1.10). This current universal lipid screening strategy, likely typical of US practice, fails to detect and treat the supermajority of FH cases, increasing risk for adult coronary artery disease. To address the specific deficiencies we observed, we suggest improvements to detect and treat FH. [Display omitted] [ABSTRACT FROM AUTHOR]

Autophagy, which is responsible for removing damaged molecules, prevents their accumulation in cells, thus maintaining intracellular homeostasis. It is also responsible for removing the effects of oxidative stress, so its activation takes place during increased reactive oxygen species (ROS) generation and lipid peroxidation. Therefore, the aim of this review was to summarize all the available knowledge about the effect of protein modifications by lipid peroxidation products on autophagy activation and the impact of this interaction on the functioning of cells. This review shows that reactive aldehydes (including 4-hydroxynonenal and malondialdehyde), either directly or by the formation of adducts with autophagic proteins, can activate or prevent autophagy, depending on their concentration. This effect relates not only to the initial stages of autophagy, when 4-hydroxynonenal and malondialdehyde affect the levels of proteins involved in autophagy initiation and phagophore formation, but also to the final stage, degradation, when reactive aldehydes, by binding to the active center of cathepsins, inactivate their proteolytic functions. Moreover, this review also shows how little research exists on analyzing the impact of lipid peroxidation products and their protein adducts on autophagy. Such knowledge could be used in the therapy of diseases related to autophagy disorders. [Display omitted] • Lipid peroxidation products by forming adducts with proteins may regulate autophagy. • 4-HNE and MDA activate or prevent autophagy depending on their concentration. • 4-HNE/MDA affects proteins involved in autophagy initiation and phagophore creation. • 4-HNE by binding to cathepsins B and D inactivate their proteolytic activity. [ABSTRACT FROM AUTHOR]

Lipid biomarker analysis focused on steroids has shown to have great potential for discriminating between animal faecal inputs in archaeology. This is particularly interesting when applied to stabling deposits to assess herding strategies and livestock composition. Here we present the results of a sedimentary faecal biomarker study conducted at Belmaco Cave, a pre-European archaeological site in La Palma (Canary Islands). The site was occupied by indigenous pastoralist groups over the course of five centuries prior to the first arrival of the Europeans in the 15th century. Previous soil micromorphological data indicates recurrent sheep and/or goat penning and periodic burning of the pen in the central area of the cave. We selected bulk sediment samples from unburned, charred and ashed dung layers and carried out sterol, stanol and bile acid analysis. Our results suggest that the main source of faecal matter is sheep. We also found that even though charred and dung ash layers contained lower concentrations of the biomarker compounds, these were still sufficient to provide information on the origin of the faecal remains. These data add to our current knowledge of the aboriginal Canary Island pastoralist economy. [ABSTRACT FROM AUTHOR]

Rhodotorula kratochvilovae has shown to be a promising species for microbial oil production from lignin-derived compounds. Yet, information on R. kratochvilovae's detoxification and microbial oil production is scarce. This study investigated the growth and microbial oil production on the phenolic-containing effluent from poplar steam explosion and its detoxification with five R. kratochvilovae strains (EXF11626, EXF9590, EXF7516, EXF3697, EXF3471) and compared them with Cutaneotrichosporon oleaginosum. The R. kratochvilovae strains reached a maximum growth rate up to four times higher than C. oleaginosum. Furthermore, all R. kratochvilovae strains generally degraded phenolics more rapidly and to a larger extent than C. oleaginosum. However, the diluted substrate limited the lipid production by all strains as the maximum lipid content and titre were 10.5% CDW and 0.40 g/L, respectively. [Display omitted] • All R. kratochvilovae strains are preferred to C. oleaginosum for detoxification. • R. kratochvilovae strains grow rapidly on lignocellulosic effluent. • R. kratochvilovae strains removed at least 91% of the phenolics after seven days. • The yeasts produced mainly unsaturated fatty acids on the effluent. [ABSTRACT FROM AUTHOR]

Many metabolic diseases are caused by disorders of lipid homeostasis. CIDEC, a lipid droplet (LD)-associated protein, plays a critical role in controlling LD fusion and lipid storage. However, regulators of CIDEC remain largely unknown. Here, we established a homogeneous time-resolved fluorescence (HTRF)-based high-throughput screening method and identified LPXN as a positive regulatory candidate for CIDEC. LPXN and Hic-5, the members of the Paxillin family, are focal adhesion adaptor proteins that contribute to the recruitment of specific kinases and phosphatases, cofactors, and structural proteins, participating in the transduction of extracellular signals into intracellular responses. Our data showed that Hic-5 and LPXN significantly increased the protein level of CIDEC and enhanced CIDEC stability not through triacylglycerol synthesis and FAK signaling pathways. Hic-5 and LPXN reduced the ubiquitination of CIDEC and inhibited its proteasome degradation pathway. Furthermore, Hic-5 and LPXN enlarged LDs and promoted lipid storage in adipocytes. Therefore, we identified Hic-5 and LPXN as novel regulators of CIDEC. Our current findings also suggest intervention with Hic-5 and LPXN might ameliorate ectopic fat storage by enhancing the lipid storage capacity of white adipose tissues. [ABSTRACT FROM AUTHOR]

Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery, as demonstrated by the approval of patisiran for amyloidosis therapy in 2018. To illuminate the unique superiority of lipid nanovehicles in RNA delivery, in this review, we first introduce various RNA therapeutics, describe systemic delivery barriers, and explain the lipid components and methods used for lipid nanovehicle preparation. Then, we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to systemic RNA delivery. Finally, the current status and challenges of lipid nanovehicle-based RNA therapeutics in clinical applications are also discussed. Our objective is to provide a comprehensive overview showing how to utilize lipid nanovehicles to overcome multiple barriers to systemic RNA delivery, inspiring the development of more high-performance RNA lipid nanovesicles in the future. This review provides a comprehensive overview of how to design lipid nanovehicles to overcome multiple extracellular and intracellular barriers to systemic RNA delivery. [Display omitted] [ABSTRACT FROM AUTHOR]

This study investigated the time course of lipid accumulation during IVM and assessed the role of lipid modulators added during IVM on lipid content, nuclear maturation, oxidative stress, mitochondrial activity, gene expression, and cryosurvival of cat oocytes. First, the lipid content of immature COCs was compared to those subjected to different IVM duration times (24, 28, and 32 h). Then, the lipid content was investigated after the use of different lipid modulators [conjugated linoleic acid (CLA), forskolin (FSK), l -carnitine (LC)]. Subsequently, both the CONTROL group and MIX 18 (CLA+FSK+LC) were compared regarding nuclear maturation, mitochondrial activity, reactive oxygen 19 species (ROS), and glutathione (GSH) levels, to the expression of SDHA, GDF9, BMP15, ZAR-1, 20 PRDX1, SIRT1, and SIRT3 genes (normalized by ACTB and YWHAZ genes); and to vitrification and 21 post-warming viability assessment. When not using any lipid modulator, an increase (P < 0.05) in lipid content could be observed after 28 h of IVM. The MIX group showed the greatest (P < 0.05) reduction in oocyte lipid content after 28 h of IVM. No difference (P > 0.05) was observed in the MII rate in the CONTROL (45%) and MIX (41%) groups and in mitochondrial activity ((1.00 ± 0.35 A U vs 1.19 ± 0.14 A U). Although ROS and GSH levels were higher (P < 0.05) in MIX than in CONTROL, the redox balance (ROS/GSH) was greater (P < 0.05) in the latter (C:1.00 ± 0.20b vs M:0.26 ± 0.06 a A.U). The GDF9, HSP70, PRDX1 , and SIRT1 transcripts were downregulated (P < 0.05) in MIX-oocytes, compared to the CONTROL. After vitrification, MIX (74%) presented a higher (P < 0.05) viability compared to control (53%). In conclusion, MIX can reduce the total lipid content and improve viability after cryopreservation, however, it seems to affect the oocyte metabolism in a way that still needs to be better understood in the cat biological model. • The use of a cocktail (MIX) of lipid modulators during IVM was able to reduce the lipid content of cat oocytes. • The use of MIX did not impact the nuclear maturation rates of cat oocytes. • MIX increased GSH and ROS levels and reduced the redox balance. • MIX increased the oocyte viability after cryopreservation. [ABSTRACT FROM AUTHOR]

Polymeric prodrugs have been applied to control the delivery of various types of therapeutics. Similarly, conjugation of peptide therapeutics to lipids has been used to prolong systemic exposure. Here, we extend on these two approaches by conjugating brush polyethylene glycol (PEG) polymers with different lipid components including short-chain (1C2) or medium-chain (1C12) monoalkyl hydrocarbon tails, cholesterol (Cho), and diacylglycerols composed of two medium-chain (2C12) or long-chain (2C18) fatty acids. We uniquely evaluate the integration of these lipid-polymers into endogenous lipid trafficking pathways (albumin and lipoproteins) and the impact of lipid conjugation on plasma pharmacokinetics after intravenous (IV) and subcutaneous (SC) dosing to cannulated rats. The IV and SC elimination half-lives of Cho-PEG (13 and 22 h, respectively), 2C12-PEG (11 and 17 h, respectively) and 2C18-PEG (12 h for both) were prolonged compared to 1C2-PEG (3 h for both) and 1C12-PEG (4 h for both). Interestingly, 1C2-PEG and 1C12-PEG had higher SC bioavailability (40 % and 52 %, respectively) compared to Cho-PEG, 2C12-PEG and 2C18-PEG (25 %, 24 % and 23 %, respectively). These differences in pharmacokinetics may be explained by the different association patterns of the polymers with rat serum albumin (RSA), bovine serum albumin (BSA) and lipoproteins. For example, in pooled plasma (from IV pharmacokinetic studies), 2C18-PEG had the highest recovery in the high-density lipoprotein (HDL) fraction. In conclusion, the pharmacokinetics of brush PEG polymers can be tuned via conjugation with different lipids, which can be utilised to tune the elimination half-life, biodistribution and effect of therapeutics for a range of medical applications. Lipidation of therapeutics such as peptides has been employed to extend their plasma half-life by promoting binding to serum albumin, providing protection against rapid clearance. Here we design and evaluate innovative biomaterials consisting of brush polyethylene glycol polymers conjugated with different lipids. Importantly, we show for the first time that lipidated polymeric materials associate with endogenous lipoprotein trafficking pathways and this, in addition to albumin binding, controls their plasma pharmacokinetics. We find that conjugation to dialkyl lipids and cholesterol leads to higher association with lipid trafficking pathways, and more sustained plasma exposure, compared to conjugation to short and monoalkyl lipids. Our lipidated polymers can thus be utilised as delivery platforms to tune the plasma half-life of various pharmaceuticals. [Display omitted] [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH) is a prevalent metabolic disease, characterized by the hepatic steatosis, inflammation, and fibrosis, which is lack of effective treatment currently. Protectin D1 (PTD1), a lipid mediator from omega-3 fatty acid docosahexaenoic acid (DHA), has displayed wide pharmacological actions including anti-inflammation in a variety of diseases, but the role of PTD1 on NASH remains unclear. In this study, using the methionine and choline deficient (MCD) fed NASH model, we explored the effect and underlying mechanism of PTD1 on NASH in mice. Our results showed PTD1 improved MCD-induced steatosis, hepatocellular injury, inflammation and fibrosis. Furthermore, PTD1 inhibited MCD-induced activation of TLR4 downstream molecules (TAK1, p38 and p65) without affecting the levels of TLR4 and phosphorylated IRAK-1. Notably, the levels of IRAK-M protein and the binding between IRAK-M and TRAF6 in the liver were also increased by PTD1 in NASH mice. Moreover, IRAK-M knockout remarkedly reverted the beneficial effects of PTD1 on the NASH in mice. Thus, these results demonstrated that PTD1 could protect mice from NASH by inhibiting the activation of TLR4 downstream signaling pathway, which might be related to the upregulation of IRAK-M, indicating that PTD1 may provide a new treatment for NASH. [Display omitted] • Protectin D1 (PTD1) has shown the anti-inflammatory effect, but little is known about its role on Non-alcoholic steatohepatitis (NASH). • PTD1 improved steatosis, liver injury, hepatic inflammation and liver fibrosis in NASH mice. • PTD1 inhibited the activation of TLR4 downstream molecules (TAK1, p38 and p65) without affecting TLR4 and IRAK-1 phosphorylation levels in NASH mice. • PTD1 upregulated IRAK-M and IRAK-M knockout reversed the protective effect of PTD1 in NASH mice. • PTD1 could attenuate NASH by inhibiting the activation of TLR4 downstream signaling pathway, which is related to the upregulation of IRAK-M. [ABSTRACT FROM AUTHOR]

Lipids are important in multiple cellular functions, with most having structural or energy storage roles. However, a small fraction of lipids exert bioactive roles through binding to G protein-coupled receptors and induce a plethora of processes including cell proliferation, differentiation, growth, migration, apoptosis, senescence and survival. Bioactive signalling lipids are potent modulators of metabolism and energy homeostasis, inflammation, tissue repair and malignant transformation. All these events are involved in the initiation and progression of chronic liver diseases. In this review, we focus specifically on the roles of bioactive lipids derived from phospholipids (lyso -phospholipids) and poly-unsaturated fatty acids (eicosanoids, pro-resolving lipid mediators and endocannabinoids) in prevalent chronic liver diseases (alcohol-associated liver disease, non-alcoholic fatty liver disease, viral hepatitis and hepatocellular carcinoma). We discuss the balance between pathogenic and beneficial bioactive lipids as well as potential therapeutic targets related to the agonism or antagonism of their receptors. [ABSTRACT FROM AUTHOR]

Deep eutectic solvents (DES) can be a green alternative extraction technology for microalgae lipids, acting simultaneously as a pre-treatment agent and solvent. However, due to the low vapor pressure of both DES and lipid solute, the recovery of lipids and solvent regeneration remains difficult. In this study, we developed a novel strategy to separate the dissolved sunflower and model algae oil from imidazole/hexanoic acid DES by using polar antisolvents (water, methanol, and ethanol). The polarity and the amount of antisolvent influenced the lipid solubility in DES. While the water was the strongest antisolvent, the alcohols were easier to evaporate, ensuring easy DES regeneration. By adding small amounts of water and methanol, more than 90% of the lipids were recovered in the form of high-purity oils (>90%). In the case of ethanol, a large amount of ethanol was required, which diluted the solvent-rich phase and solubilized more lipids in it. Based on three repeated cycles with the selected antisolvent methanol, > 90% of the eutectic solvent could be regenerated. [ABSTRACT FROM AUTHOR]

Lipid nanoparticles (LNPs) hold great promise as carriers for developing drug delivery systems (DDSs) aimed at managing ischemic stroke (IS). Previous research has highlighted the vital role played by the lipid composition and biophysical characteristics of LNPs, influencing their interactions with cells and tissues. This understanding presents an opportunity to engineer LNPs tailored specifically for enhanced IS treatment. We previously introduced the innovative concept of reconstituted lipid nanoparticles (rLNPs), which not only retain the advantages of conventional LNPs but also incorporate lipids from the originating cell or tissue. Brain-derived rLNPs (B-rLNPs) exhibit significantly superior accumulation within the cerebral ischemic region when compared to liver-derived rLNPs (L-rLNPs). The homing effect of B-rLNPs was then employed to construct 3-n-butylphthalide (NBP) loaded DDS (B-rLNPs/NBP) for the treatment of IS. Our results demonstrated that compared with free NBP, B-rLNPs/NBP can significantly reduce infarct volume, neurological deficits, blood-brain barrier (BBB) leakage rate, brain water content, neutrophil infiltration, alleviate pathological structures, and improve the motor function in MCAO/R model. We also proved that B-rLNPs/NBP showed further reinforced protective effects on the same model than free NBP through the regulation of TLR4/MyD88/NF-κB (anti-inflammation) and Bax/Bcl-2 (anti-apoptosis) pathways. This study offers a promising tool towards improved IS treatment. [Display omitted] • B-rLNPs show selective homing to cerebral ischemic area. • B-rLNPs/NBP significantly improves the protective effect of NBP on MCAO/R model. • B-rLNPs/NBP functions through TLR4/MyD88/NF-κB and Bax/Bcl-2 pathways. [ABSTRACT FROM AUTHOR]

Nucleic acid therapeutics have demonstrated substantial potential in combating various diseases. However, challenges persist, particularly in the delivery of multifunctional nucleic acids. To address this issue, numerous gene delivery vectors have been developed to fully unlock the potential of gene therapy. The advancement of innovative materials with exceptional delivery properties is critical to propel the clinical translation of nucleic acid drugs. Cationic vector materials have received extensive attention, while zwitterionic materials remain relatively underappreciated in delivery. In this review, we outline a diverse range of zwitterionic material nucleic acid carriers, predominantly encompassing zwitterionic lipids, polymers and peptides. Their respective chemical structures, synthesis approaches, properties, advantages, and therapeutic applications are summarized and discussed. Furthermore, we highlight the challenges and future opportunities associated with the development of zwitterionic vector materials. This review will aid to understand the zwitterionic materials in aiding gene delivery, contributing to the continual progress of nucleic acid therapeutics. [Display omitted] [ABSTRACT FROM AUTHOR]

Fatty acid handling and complex lipid synthesis are altered in the kidney cortex of diabetic patients. We recently showed that inhibition of the renin-angiotensin system without changes in glycemia can reverse diabetic kidney disease (DKD) and restore the lipid metabolic network in the kidney cortex of diabetic (db/db) mice, raising the possibility that lipid remodeling may play a central role in DKD. However, the roles of specific enzymes involved in lipid remodeling in DKD have not been elucidated. In the present study, we used this diabetic mouse model and a proximal tubule epithelial cell line (HK2) to investigate the potential relationship between long-chain acyl-CoA synthetase 1 (ACSL1) and lipid metabolism in response to fatty acid exposure and inflammatory signals. We found ACSL1 expression was significantly increased in the kidney cortex of db/db mice, and exposure to palmitate or tumor necrosis factor-α significantly increased Acsl1 mRNA expression in HK-2 cells. In addition, palmitate treatment significantly increased the levels of long-chain acylcarnitines and fatty acyl CoAs in HK2 cells, and these increases were abolished in HK2 cell lines with specific deletion of Acsl1(Acsl1KO cells), suggesting a key role for ACSL1 in fatty acid β-oxidation. In contrast, tumor necrosis factor-α treatment significantly increased the levels of short-chain acylcarnitines and long-chain fatty acyl CoAs in HK2 cells but not in Acsl1KO cells, consistent with fatty acid channeling to complex lipids. Taken together, our data demonstrate a key role for ACSL1 in regulating lipid metabolism, fatty acid partitioning, and inflammation. [ABSTRACT FROM AUTHOR]

Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial fatty acid synthesis (mtFAS) pathway. mtFAS builds lipoic acid and longer saturated fatty acids, but its exact products, their ultimate destination in cells, and the cellular significance of the pathway are all active research questions. Moreover, why mitochondria need mtFAS despite their well-defined ability to import fatty acids is still unclear. The identification of patients with inborn errors of metabolism in mtFAS genes has sparked fresh research interest in the pathway. New mammalian models have provided insights into how mtFAS coordinates many aspects of oxidative mitochondrial metabolism and raise questions about its role in diseases such as obesity, diabetes, and heart failure. In this review, we discuss the products of mtFAS, their function, and the consequences of mtFAS impairment across models and in metabolic disease. Wedan et al. present a compiled summary of mitochondrial fatty acid synthesis in mammalian systems. The study of this pathway in human disease is just emerging and promises new mechanistic insight into the regulation of mitochondrial bioenergetics. [ABSTRACT FROM AUTHOR]

Autoinflammatory diseases (AIDs) are a group of rare monogenetic disorders characterized by recurrent episodes of fever and systemic inflammation. A major pathologic hallmark of AIDs is excessive inflammasome assembly and activation, often the result of gain-of-function mutations in genes encoding core inflammasome components, including pyrin and cryopyrin. Recent advances in lipidomics have revealed that dysregulated metabolism of lipids such as cholesterol and fatty acids, especially in innate immune cells, exerts complex effects on inflammasome activation and the pathogenesis of AIDs. In this review, we summarize and discuss the impact of lipids and their metabolism on inflammasome activation and the disease pathogenesis of the most common AIDs, including familial Mediterranean fever, cryopyrin-associated periodic syndromes, and mevalonate kinase deficiency. We postulate that lipids hold diagnostic value in AIDs and that dietary and pharmacologic intervention studies could represent a promising approach to attenuate inflammasome activation and AID progression. [ABSTRACT FROM AUTHOR]

It's a privilege to discuss preventive cardiology with 3 of the foremost U.S. leaders in this growing subspecialty. Preventive cardiology is the practice of primordial, primary, and secondary prevention of cardiovascular disease. It employs an integrated team of clinicians committed to preventing all forms of cardiovascular disease, including ischemic heart disease, heart failure, atrial fibrillation, and other conditions. Thus, contemporary preventive cardiology extends management beyond dyslipidemic risk reduction and now commonly includes treatment of hypertension, diabetes and other related cardiometabolic disorders, novel cardiovascular risk factors, thrombotic risk, some cardiac genetic disorders, and cardiac disorders specific to women's health, as well as attention to tobacco- and drug-related risks. Preventive cardiologists may simultaneously manage cardiac rehabilitation programs. Among significant innovations are the launch of the American Journal of Preventive Cardiology in 2020, increasing validation and use of coronary artery calcium scoring, prescription of obesity and diabetes pharmaceuticals by cardiologists, and focus on pregnancy as a natural cardiovascular stress test for women with implications for future cardiovascular events. A continuing major barrier is that reimbursement for preventive cardiology services currently does not match the value benefit which accrues to patients and society. Preventive care too often is added late in the course of disease management. In addition to ongoing pharmaceutical and lifestyle research, future directions include incorporation of specific training goals for preventive cardiology in general clinical cardiology training programs and support for registered dietitian reimbursement for services to patients with clinically manifest atherosclerosis. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) are essential for cellular pathophysiology. In two recent reports, Kim et al. and Boutagy et al. show that accumulation of LDs in endothelial cells (ECs) elevates blood pressure and accelerates progression of atherosclerosis. These findings identify a novel mechanism of EC lipid metabolism which drives cardiometabolic diseases. Lipid droplets (LDs) are essential for cellular pathophysiology. In two recent reports, Kim et al. and Boutagy et al. show that accumulation of LDs in endothelial cells (ECs) elevates blood pressure and accelerates progression of atherosclerosis. These findings identify a novel mechanism of EC lipid metabolism which drives cardiometabolic diseases. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunctions predominantly cause encephalomyopathies with muscle atrophy and neurodegeneration. However, their impact on other tissues, particularly the gastrointestinal tract, requires further investigation. In a recent report in Nature , Moschandrea et al. used mice deficient in the mitochondrial aminoacyl-tRNA synthetase DARS2 to investigate the role of enterocytic mitochondria in dietary lipid processing and transport. Their work sheds light on the development of gastrointestinal disorders as a result of mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

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