Lipid Levels Research Articles

Impact of Direct Measurement of Small Dense Low-Density Lipoprotein Cholesterol for Long-Term Secondary Prevention in Patients with Stable Coronary Artery Disease.

This study investigated whether directly measured small dense low-density lipoprotein cholesterol (D-sdLDL-C) can predict long-term coronary artery disease (CAD) events compared with low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apoB), and estimated small dense low-density lipoprotein cholesterol (E-sdLDL-C) determined by the Sampson equation in patients with stable CAD. D-sdLDL-C measured at Showa University between 2010 and 2022, and E-sdLDL-C were evaluated in 790 male and 244 female patients with stable CAD. CAD events, defined as sudden cardiac death, onset of acute coronary syndrome, and/or need for coronary revascularization, were monitored for 12 years. Cutoff lipid levels were determined by receiver operating characteristic curves. CAD events were observed in 238 male and 67 female patients. The Kaplan-Meier event-free survival curves showed that patients with D-sdLDL-C ≥32.1 mg/dL (0.83 mmol/L) had an increased risk for CAD events (P = 0.007), whereas risk in patients with E-sdLDL-C ≥36.2 mg/dL (0.94 mmol/L) was not increased. In the group with high D-sdLDL-C, the multivariable-adjusted hazard ratio (HR) was 1.47 (95% CI, 1.15-1.89), and it remained significant after adjustment for LDL-C, non-HDL-C, or apoB and in patients treated with statins. HRs for high LDL-C, non-HDL-C, or apoB were not statistically significant after adjustment for high D-sdLDL-C. Higher D-sdLDL-C was associated with enhanced risk of high LDL-C, non-HDL-C, and apoB (HR 1.73; 95% CI, 1.27-2.37). Higher D-sdLDL-C can predict long-term recurrence of CAD in stable CAD patients independently of apoB and non-HDL-C. D-sdLDL-C is an independent risk enhancer for secondary CAD prevention, whereas E-sdLDL-C is not. UMIN-CTR Clinical Trial Number: UMIN000027504.

Characterization of the gut microbiota in polycystic ovary syndrome with dyslipidemia

BackgroundPolycystic ovary syndrome (PCOS) is an endocrinopathy in childbearing-age females which can cause many complications, such as diabetes, obesity, and dyslipidemia. The metabolic disorders in patients with PCOS were linked to gut microbial dysbiosis. However, the correlation between the gut microbial community and dyslipidemia in PCOS remains unillustrated. Our study elucidated the different gut microbiota in patients with PCOS and dyslipidemia (PCOS.D) compared to those with only PCOS and healthy women.ResultsIn total, 18 patients with PCOS, 16 healthy females, and 18 patients with PCOS.D were enrolled. The 16 S rRNA sequencing in V3-V4 region was utilized for identifying the gut microbiota, which analyzes species annotation, community diversity, and community functions. Our results showed that the β diversity of gut microbiota did not differ significantly among the three groups. Regarding gut microbiota dysbiosis, patients with PCOS showed a decreased abundance of Proteobacteria, and patients with PCOS.D showed an increased abundance of Bacteroidota compared to other groups. With respect to the gut microbial imbalance at genus level, the PCOS.D group showed a higher abundance of Clostridium_sensu_stricto_1 compared to other two groups. Furthermore, the abundances of Faecalibacterium and Holdemanella were lower in the PCOS.D than those in the PCOS group. Several genera, including Faecalibacterium and Holdemanella, were negatively correlated with the lipid profiles. Pseudomonas was negatively correlated with luteinizing hormone levels. Using PICRUSt analysis, the gut microbiota community functions suggested that certain metabolic pathways (e.g., amino acids, glycolysis, and lipid) were altered in PCOS.D patients as compared to those in PCOS patients.ConclusionsThe gut microbiota characterizations in patients with PCOS.D differ from those in patients with PCOS and controls, and those might also be related to clinical parameters. This may have the potential to become an alternative therapy to regulate the clinical lipid levels of patients with PCOS in the future.

The effect and mechanism of inulin on atherosclerosis is mediated by the characteristic intestinal flora and metabolites.

Inflammation and hyperlipidemia can cause atherosclerosis. Prebiotic inulin has been proven to effectively reduce inflammation and blood lipid levels. Utilizing a mouse model induced by a high-fat diet, this study aimed to explore whether the characteristic intestinal flora and its metabolites mediate the effects of inulin intervention on atherosclerosis and to clarify the specific mechanism. Thirty apolipoprotein E-deficient (ApoE-/-) mice were randomly divided into three groups. They were fed with a normal diet, a high-fat diet or an inulin+high-fat diet for 16 weeks. The total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in the three groups were compared. The gross aorta and aortic sinus of mice were stained with oil red O, and the area of atherosclerotic plaque was observed and compared. The diversity and structure of the mouse fecal flora were detected by sequencing the V3-V4 region of the 16S rRNA gene, and the levels of metabolites in mouse feces were assessed by gas chromatography-mass spectrometry. The plasma lipopolysaccharide (LPS) levels and aortic inflammatory factors were measured by multi-index flow cytometry (CBA). ApoE-/- mice fed with the high-fat diet exhibited an increase of approximately 46% in the area of atherosclerotic lesions, and the levels of TC, TG and LDL-C were significantly increased (P < 0.05) compared with levels in the normal diet group. After inulin was added to the high-fat group, the area of atherosclerotic lesions, the level of serum LPS and aortic inflammation were reduced, and the levels of TC, TG and LDL-C were decreased (P < 0.05). Based on 16S rRNA gene detection, we found that the composition of the intestinal microbiota, such as Prevotella, and metabolites, such as L-arginine, changed significantly due to hyperlipidemia, and the dietary inulin intervention partially reversed the relevant changes. Inulin can inhibit the formation of atherosclerotic plaques, which may be related to the changes in lipid metabolism, the composition of the intestinal microbial community and its metabolites, and the inhibition of the expression of related inflammatory factors. Our study identified the relationships among the characteristic intestinal microbiota, metabolites and atherosclerosis, aiming to provide a new direction for future research to delay or treat atherosclerosis by changing the composition and function of the host intestinal microbiota and metabolites.

Regulatory patterns of Chinese patent medicine for lipid metabolism disorders in patients with type 2 diabetes mellitus complicated by ischemic stroke: A systematic review and network meta-analysis.

To investigate the regulatory patterns of Chinese patent medicine (CPM) interventions on lipid metabolism disorders in patients with type 2 diabetes mellitus (T2DM) complicated by ischemic stroke. Two researchers independently searched 8 major databases and created a comprehensive database containing all randomized controlled trials (RCTs) that investigated the application of "blood-activating and stasis-removing" CPM in the treatment of stroke combined with T2DM until October 1, 2022. The collected data were compiled and organized in Excel. Quality assessment was performed using the Cochrane 5.3 bias risk assessment tool, and the network meta-analysis was conducted using R software. A total of 12 articles were included in the final analysis, covering 4 types of CPM: Naoxintong Capsules (NXT), Tongmai Jiangtang Capsules, Tongxinluo Capsules (TXL), and Yindan Xinnaotong Soft Capsules. Among these, CPM formulations containing herbs with blood-activating and stasis-removing properties were the most commonly used. The results of the network meta-analysis are as follows: (1) the combination of 3 CPM formulations showed superior efficacy in improving total cholesterol levels compared to conventional Western medicine treatment (CT). In particular, Yindan Xinnaotong Soft Capsules + CT (surface under the cumulative ranking curve [SUCRA] = 97.24%) demonstrated the highest efficacy, followed by NXT + CT (SUCRA = 66.23%), and then TXL + CT (SUCRA = 55.16%). (2) TXL + CT treatment exhibited the most promising efficacy in improving triglyceride levels (P < .05), while the effects of the other 3 CPM formulations were not statistically significant. (3) In terms of improving low-density lipoprotein levels, NXT + CT (SUCRA = 82.27%) showed better efficacy than TXL + CT (SUCRA = 73.99%), while the effects of the other 2 CPM formulations were not statistically significant. (4) The combination of CPM formulations and CT resulted in a lower incidence of adverse reactions compared to CT (P < .05). The treatment of patients with T2DM complicated by ischemic stroke commonly involved the use of "blood-activating and stasis-removing" herbal medicines. These herbal medicines have shown effectiveness in regulating patients' blood lipid levels. However, it is crucial to acknowledge that the analysis was influenced by variations in the number and quality of RCTs involving different CPM formulations. Therefore, additional validation through large-scale, high-quality RCT studies is required.

Lipid Variability Induces Endothelial Dysfunction by Increasing Inflammation and Oxidative Stress.

This study investigates the impact of fluctuating lipid levels on endothelial dysfunction. Human aortic and umbilical vein endothelial cells were cultured under varying palmitic acid (PA) concentrations: 0, 50, and 100 μM, and in a variability group alternating between 0 and 100 μM PA every 8 hours for 48 hours. In the lipid variability group, cells were exposed to 100 μM PA during the final 8 hours before analysis. We assessed inflammation using real-time polymerase chain reaction, Western blot, and cytokine enzyme-linked immunosorbent assay (ELISA); reactive oxygen species (ROS) levels with dichlorofluorescin diacetate assay; mitochondrial function through oxygen consumption rates via XF24 flux analyzer; and endothelial cell functionality via wound healing and cell adhesion assays. Cell viability was evaluated using the MTT assay. Variable PA levels significantly upregulated inflammatory genes and adhesion molecules (Il6, Mcp1, Icam, Vcam, E-selectin, iNos) at both transcriptomic and protein levels in human endothelial cells. Oscillating lipid levels reduced basal respiration, adenosine triphosphate synthesis, and maximal respiration, indicating mitochondrial dysfunction. This lipid variability also elevated ROS levels, contributing to a chronic inflammatory state. Functionally, these changes impaired cell migration and increased monocyte adhesion, and induced endothelial apoptosis, evidenced by reduced cell viability, increased BAX, and decreased BCL2 expression. Lipid variability induce endothelial dysfunction by elevating inflammation and oxidative stress, providing mechanistic insights into how lipid variability increases cardiovascular risk.

Exploring the Mechanism of Fufang Danshen Tablet against Atherosclerosis by Network Pharmacology and Experimental Validation.

Atherosclerosis is the main pathological basis of cardiovascular diseases (CVDs). Fufang Danshen Tablet (FDT) is a traditional Chinese medicine that has been clinically used to treat CVDs for more than 40 years. Nevertheless, owing to the complexity of the ingredients, the pharmacological mechanism of FDT in the treatment of CVDs has not been fully elucidated. In this study, an integrated strategy of UFLC-Q-TOF-MS/MS, network pharmacology, molecular biology, and transcriptomics was used to elucidate the mechanisms of action of FDT in the treatment of atherosclerosis. In total, 22 absorbed constituents were identified in rat serum after oral administration of FDT. In silico, network pharmacology studies have shown that FDT regulates four key biological functional modules for the treatment of atherosclerosis: oxidative stress, cell apoptosis, energy metabolism, and immune/inflammation. In animal experiments, FDT exerted protective effects against atherosclerosis by reducing the plaque area and lipid levels in ApoE-/- mice. Furthermore, we found that FDT inhibited inflammatory macrophage accumulation by regulating the expression of Selp and Ccl2, which are both involved in monocyte adhesion and migration. The inhibition of monocyte recruitment by FDT is a new perspective to elucidate the anti-atherosclerotic mechanism of FDT, which has not been adopted in previous studies on FDT. Our results may help to elucidate the therapeutic mechanism of FDT against CVDs and provide potential therapeutic targets.

A CLASH OF CHOLESTEROL TITANS: STATIN–INTOLERANT VS. STATIN–TOLERANT PATIENTS ON PCSK9 INHIBITORS IN LONG TERM FOLLOW–UP

Abstract Introduction Statin intolerance remains a clinical challenge in the management of dyslipidemia. This study aimed to investigate whether patients with statin intolerance, receiving PCSK9 inhibitors, exhibit lipid profile improvement different from those obtained in those without statin intolerance. Methods In this monocentric outpatient study we enrolled 381 dyslipidemic patients receiving PCSK9 inhibitors. Statin intolerance was defined according to ESC criteria. Patients were divided into two groups, clinical data were collected, and lipid profiles were monitored regularly for a total of 36 months. Results Among the statin–intolerant patients, there was a higher proportion of women compared to those on statin therapy (38.6% vs 27.2% p = 0.051), although among intolerants the majority were men (69% vs 31% p = 0.023). Statin–intolerant patients had higher baseline total cholesterol (242±29.8 mg/dL vs 221±26.3 mg/dL p &amp;lt; 0.001) and LDL cholesterol (161.4±39.7 mg/dL vs 147±37.1 mg/dL p = 0.010). Interestingly, lipid reduction in both groups became comparable as early as 6 months (LDL 67±37 mg/dL vs 63±39 mg/dL p = 0.42) and continued to be similar at 12 and 36 months of follow–up (LDL 74±44 mg/dL vs 69±29 mg/dL p = 0.62). Conclusion PCSK9 inhibitors effectively lower lipid levels in both statin–intolerant and statin–tolerant dyslipidemic patients. Statin–intolerant patients seem to have similar management and can achieve cholesterol levels comparable to patients on statin therapy.

Sphingosine-1-phosphate promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH. Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH. CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage. S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.

Folic acid ameliorated the scopolamine-induced memory impairment in mice and the neuroprotective mechanisms

Current research on the neuroprotective regulatory mechanism of folic acid (FA) is limited to a single DNA methylation pathway. Consequently, this study aimed to explore the neuroprotective effect of FA on memory-impaired mice and its molecular mechanism. This study explored the preventive function of FA in enhancing memory impairment in scopolamine-induced mice using behavioral tests, histological staining techniques, Fourier transform infrared microscopy, immunofluorescence, and Western blotting. We found that FA improved behavioral performance, ameliorated oxidative stress, repaired neuronal damage in hippocampal CA1, CA3 regions and increased the number of Nissl body, increased unsaturated lipid levels, and activated long-term potentiation (LTP) pathway (p-CaMKII, p-CREB, BDNF) and synaptic plasticity (PSD95, Syn) in mice, which indicated that FA mitigates scopolamine-induced memory impairment by suppressing oxidative stress, upregulating the LTP pathway, and enhancing unsaturated lipid levels. These results suggested a preventive and dose-dependent effect of folic acid on memory impairment.

Dynamic Imaging of Lipid Droplets in Cells and Tissues by Using Dioxaborine Barbiturate-Based Fluorogenic Probes.

Lipids are essential for various cellular functions, including energy storage, membrane flexibility, and signaling molecule production. Maintaining proper lipid levels is important to prevent health problems such as cancer, neurodegenerative disorders, cardiovascular diseases, obesity, and diabetes. Monitoring cellular lipid droplets (LDs) in real-time with high resolution can provide insights into LD-related pathways and diseases owing to the dynamic nature of LDs. Fluorescence-based imaging is widely used for tracking LDs in live cells and animal models. However, the current fluorophores have limitations such as poor photostability and high background staining. Herein, we developed a novel fluorogenic probe based on a push-pull interaction combined with aggregation-induced emission enhancement (AIEE) for dynamic imaging of LDs. Probe 1 exhibits favorable membrane permeability and spectroscopic characteristics, allowing specific imaging of cellular LDs and time-lapse imaging of LD accumulation. This probe can also be used to examine LDs in fruit fly tissues in various metabolic states, serving as a highly versatile and specific tool for dynamic LD imaging in cellular and tissue environments.

Unveiling Metabolic Similarities of Entheses in Patients with Psoriasis and Psoriatic Arthritis Using Noninvasive In Vivo Molecular Imaging: Results From a Cross-sectional Exploratory Study.

We assessed and compared molecular tissue changes at the entheses in patients with psoriasis (PsO) and psoriatic arthritis (PsA) and in healthy controls (HCs) in vivo using multispectral optoacoustic tomography (MSOT) and described their relationship with clinical and ultrasound findings of enthesitis. A cross-sectional study (MSOT and Arthrosonography in PsA) in biologic disease-modifying antirheumatic drug-naïve patients with PsA and PsO and HCs was performed. Participants underwent clinical, ultrasonographic, and MSOT examination of six entheses (lateral humeral epicondyle, distal patellar tendon attachment, and Achilles tendon attachment). MSOT-measured hemoglobin (Hb), oxygen saturation (SO2), collagen, and lipid levels were quantified, and mean differences between groups were calculated using linear mixed effects models. MSOT-measured analytes were compared between entheses with and without clinical and ultrasound anomalies. Ninety participants were included (30 PsO, 30 PsA, and 30 HCs), 540 entheses were clinically assessed, and 540 ultrasound and 830 MSOT scans were obtained. Patients with PsA and PsO showed increased oxygenated Hb (PsA: P = 0.003; PsO: P = 0.054) and SO2 (PsA: P < 0.001; PsO: P = 0.001) levels and decreased collagen signals (PsA: P < 0.001; PsO: P < 0.001) compared with HCs, with more pronounced changes in PsA. Significantly lower collagen levels (P = 0.01) and increased lipids (P = 0.03) were recorded in tender entheses compared with nontender ones. Erosions and enthesophytes on ultrasound were associated with significant differences in SO2 (P = 0.014) and lipid signals (P = 0.020), respectively. Patients with PsA and PsO exhibit an analogous metabolic pattern at the entheses that is exacerbated in the presence of inflammation. These findings support the notion of a psoriatic disease spectrum characterized by common immunometabolic tissue changes.

Longitudinal analysis of vitamin D levels considering sunshine duration and suggestion for a standardised approach for vitamin D supplementation in children and adolescents with obesity

BackgroundChildren with obesity have low 25 hydroxy-vitamin D (25-OH-D3) levels compared to lean children. Recommendations on when to start vitamin D supplementation differ largely between countries. Longitudinal data on 25-OH-D3 levels to guide treatment decisions are scarce since they are largely influenced by solar radiation and are difficult to compare.MethodsWe carried out a retrospective analysis of multiple 25-OH-D3 and parathyroid hormone (PTH) measurements in a cohort of 543 patients without vitamin D supplementation. All measurements were taken at the local paediatric obesity clinic as documented in the German-Austrian-Swiss APV (Prospective Documentation of Overweight Children and Adolescents) registry from 2009 to 2019. Serial 25-OH-D3 and PTH levels were adjusted for sunshine duration over the last 30 days to account for seasonal variation, as well as for sex and body mass index (BMI). We further performed an exploratory analysis of the association of sunshine duration, sex, BMI SDS (standard deviation score), abnormal lipid levels or dysglycemia with the 25-OH-D3 trend.Results229 obese patients (mean BMI SDS: 2,58 (± 0,56), 53% females, mean age: 12 (± 3) years, range: 2–21 years) with two, 115 with three and 96 with four repeated 25-OH-D3 measurements were identified. Mean adjusted 25-OH-D3 (48.2 nmol/l) and PTH (34.9 ng/l) levels remained stable over 120 weeks. 5% of the patients had an elevated PTH > 65 ng/l. High total cholesterol ≥ 200 mg/dl and high triglycerides ≥ 130 mg/dl were associated with higher 25-OH-D3 levels.ConclusionWe propose a simple method to include sunshine duration in the analysis of 25-OH-D3 levels to minimise the bias of seasonal variation. Based on our data we established the pragmatic strategy of limiting vitamin D supplementation to patients with biochemical signs of mineralisation disorders such as elevated PTH and alkaline phosphatase (AP). In children with normal PTH and AP we recommend adjustment of calcium intake and increase of outdoor activity instead.

Clinical Observations on the Combined Use of Hyperbaric Oxygenation and Conventional Medications in the Management of Type 2 Diabetes Mellitus Concurrent With Sudden Deafness.

Objective: The aim of this study is to investigate the effectiveness of combining hyperbaric oxygen therapy (HBOT) with conventional pharmacological interventions in the management of type 2 diabetes mellitus concurrent with sudden deafness. Methods: A cohort of 96 patients diagnosed with sudden deafness was enrolled and subsequently randomized into 2 groups: a treatment group (n = 50) and a control group (n = 46). The control group received standard conventional treatment aimed at enhancing microcirculation and nutritional support for nerves, while the treatment group underwent conventional symptomatic treatment coupled with HBOT. The evaluation encompassed the monitoring of blood glucose and blood lipid levels, clinical efficacy, and absolute hearing threshold improvement in both groups. Results: Following the intervention, noteworthy reductions in blood glucose and blood lipid levels were observed in both groups compared to their respective pretreatment values. Furthermore, posttreatment values in the treatment group exhibited a statistically significant decrease in comparison to those in the control group (P < .05). On assessing clinical efficacy posttreatment, the treatment group demonstrated a significantly higher efficacy than the control group (P < .05). In addition, the absolute hearing thresholds in both groups exhibited a significant decrease posttreatment compared to baseline values. Notably, the treatment group displayed a statistically significant reduction in absolute hearing thresholds compared to the control group posttreatment (P < .05). Conclusion: The combined therapeutic approach utilizing hyperbaric oxygen exhibits effectiveness in mitigating auditory impairment among individuals manifesting sudden deafness concomitant with type 2 diabetes mellitus. Furthermore, this treatment approach is associated with a concurrent reduction in blood glucose and blood lipid levels.

Glycemic Index, Glycemic Load and Dyslipidemia in Adolescents from Chiapas, Mexico.

Cardiovascular disease risk throughout the life course is increased by abnormal blood lipid levels in youth. The dietary glycemic index (GI) and glycemic load (GL) during adolescence might be related to abnormal blood lipids. This study aimed to analyze the association between dietary GI, GL and dyslipidemia in adolescents from two marginalized regions of Chiapas, Mexico. A cross-sectional study was conducted with 213 adolescents. Food intake was assessed using 24 h recalls. The association between dyslipidemia and dietary GI or GL was tested by using logistic regression models. Low HDL-c was the most prevalent risk factor (47.4%), followed by hypertriglyceridemia (25.4%). In this population, overall dietary GI was not associated with dyslipidemia. A high dietary GL was associated with 2.39 higher odds of low HDL-c (95% CI: 1.21-4.74) when compared to low GL. Female adolescents with high dietary GL had 3.20 higher odds of hypertriglyceridemia (95% CI: 1.03-9.88), whereas no association was found for males. No associations were observed between overall dietary GL and total cholesterol or LDL-c. In adolescents from urban and rural communities in Chiapas, a high dietary GL was associated with a detrimental effect on HDL-c. In female adolescents, high GL was associated with hypertriglyceridemia.

Epoxygenase Cyp2c44 regulates hepatic lipid metabolism and insulin signaling by controlling FATP2 localization and activation of the DAG/PKCδ axis.

Cytochrome P450 epoxygenase Cyp2c44, a murine epoxyeicosatrienoic acid (EET) producing enzyme, promotes insulin sensitivity and Cyp2c44(-/-) mice show hepatic insulin resistance. Because insulin resistance leads to hepatic lipid accumulation and hyperlipidemia, we hypothesized that Cyp2c44 regulates hepatic lipid metabolism. Standard chow diet (SD) fed male Cyp2c44(-/-) mice had significantly decreased EET levels and increased hepatic and plasma lipid levels compared to wild-type mice. We showed increased hepatic plasma membrane localization of the FA transporter 2 (FATP2) and total unsaturated fatty acids and diacylglycerol levels. Cyp2c44(-/-) mice had impaired glucose tolerance and increased hepatic plasma membraneassociated PKCδ and phosphorylated IRS-1, two negative regulators of insulin signaling. Surprisingly, SD and high fat diet fed (HFD) Cyp2c44(-/-) mice had similar glucose tolerance and hepatic plasma membrane PKCδ levels, suggesting that SD-fed Cyp2c44(-/-) mice have reached their maximal glucose intolerance. Inhibition of PKCδ resulted in decreased IRS-1 serine phosphorylation and improved insulin-mediated signaling in Cyp2c44(-/-) hepatocytes. Finally, Cyp2c44(-/-) HFD-fed mice treated with the analog EET-A showed decreased hepatic plasma membrane FATP2 and PCKDδ levels with improved glucose tolerance and insulin signaling. In conclusion, loss of Cyp2c44 with concomitant decreased EET levels leads to increased hepatic FATP2 plasma membrane localization, diacylglycerol accumulation, and PKCδ-mediated attenuation of insulin signaling. Thus, Cyp2c44 acts as a regulator of lipid metabolism by linking it to insulin signaling.

Cross-Sectional Associations between Prenatal Per- and Poly-Fluoroalkyl Substances and Bioactive Lipids in Three Environmental Influences on Child Health Outcomes (ECHO) Cohorts.

Prenatal per- and poly-fluoroalkyl substances (PFAS) exposure may influence gestational outcomes through bioactive lipids─metabolic and inflammation pathway indicators. We estimated associations between prenatal PFAS exposure and bioactive lipids, measuring 12 serum PFAS and 50 plasma bioactive lipids in 414 pregnant women (median 17.4 weeks' gestation) from three Environmental influences on Child Health Outcomes Program cohorts. Pairwise association estimates across cohorts were obtained through linear mixed models and meta-analysis, adjusting the former for false discovery rates. Associations between the PFAS mixture and bioactive lipids were estimated using quantile g-computation. Pairwise analyses revealed bioactive lipid levels associated with PFDeA, PFNA, PFOA, and PFUdA (p < 0.05) across three enzymatic pathways (cyclooxygenase, cytochrome p450, lipoxygenase) in at least one combined cohort analysis, and PFOA and PFUdA (q < 0.2) in one linear mixed model. The strongest signature revealed doubling in PFOA corresponding with PGD2 (cyclooxygenase pathway; +24.3%, 95% CI: 7.3-43.9%) in the combined cohort. Mixture analysis revealed nine positive associations across all pathways with the PFAS mixture, the strongest signature indicating a quartile increase in the PFAS mixture associated with PGD2 (+34%, 95% CI: 8-66%), primarily driven by PFOS. Bioactive lipids emerged as prenatal PFAS exposure biomarkers, deepening insights into PFAS' influence on pregnancy outcomes.

Relationship between Plasma Lipid Profile and Cognitive Status in Early Alzheimer Disease.

Alzheimer disease (AD) is a heterogeneous and complex disease in which different pathophysiological mechanisms are involved. This heterogenicity can be reflected in different atrophy patterns or clinical manifestations. Regarding biochemical pathways involved in early AD, lipid metabolism plays an important role; therefore, lipid levels have been evaluated as potential AD diagnosis biomarkers, and their levels could be related to different AD clinical manifestations. Therefore, the aim of this work is to study AD lipid profiles from early AD patients and evaluate their clinical significance. For this purpose, untargeted plasma lipidomic analysis was carried out in early AD patients (n = 31) diagnosed with cerebrospinal fluid (CSF) biomarkers. Cluster analysis was carried out to define early AD subgroups according to the lipid levels. Then, the clinical significance of each lipid profile subgroup was studied, analyzing differences for other variables (cognitive status, CSF biomarkers, medication, comorbidities, age, and gender). The cluster analysis revealed two different groups of AD patients. Cluster 1 showed higher levels of plasma lipids and better cognitive status than Cluster 2. However, no differences were found for the other variables (age, gender, medication, comorbidities, cholesterol, and triglycerides levels) between both groups. Plasma lipid levels could differentiate two early AD subgroups, which showed different cognitive statuses. However, further research with a large cohort and longitudinal study evaluating the clinical evolution of these patients is required. In general, it would involve a relevant advance in the knowledge of AD pathological mechanisms, potential treatments, and precision medicine.

Lipidomic studies revealing serological markers associated with the occurrence of retinopathy in type 2 diabetes

PurposeThe duration of type 2 diabetes mellitus (T2DM) and blood glucose levels have a significant impact on the development of T2DM complications. However, currently known risk factors are not good predictors of the onset or progression of diabetic retinopathy (DR). Therefore, we aimed to investigate the differences in the serum lipid composition in patients with T2DM, without and with DR, and search for potential serological indicators associated with the development of DR.MethodsA total of 622 patients with T2DM hospitalized in the Department of Endocrinology of the First Affiliated Hospital of Xi’an JiaoTong University were selected as the discovery set. One-to-one case–control matching was performed according to the traditional risk factors for DR (i.e., age, duration of diabetes, HbA1c level, and hypertension). All cases with comorbid chronic kidney disease were excluded to eliminate confounding factors. A total of 42 pairs were successfully matched. T2DM patients with DR (DR group) were the case group, and T2DM patients without DR (NDR group) served as control subjects. Ultra-performance liquid chromatography–mass spectrometry (LC–MS/MS) was used for untargeted lipidomics analysis on serum, and a partial least squares discriminant analysis (PLS-DA) model was established to screen differential lipid molecules based on variable importance in the projection (VIP) > 1. An additional 531 T2DM patients were selected as the validation set. Next, 1:1 propensity score matching (PSM) was performed for the traditional risk factors for DR, and a combined 95 pairings in the NDR and DR groups were successfully matched. The screened differential lipid molecules were validated by multiple reaction monitoring (MRM) quantification based on mass spectrometry.ResultsThe discovery set showed no differences in traditional risk factors associated with the development of DR (i.e., age, disease duration, HbA1c, blood pressure, and glomerular filtration rate). In the DR group compared with the NDR group, the levels of three ceramides (Cer) and seven sphingomyelins (SM) were significantly lower, and one phosphatidylcholine (PC), two lysophosphatidylcholines (LPC), and two SMs were significantly higher. Furthermore, evaluation of these 15 differential lipid molecules in the validation sample set showed that three Cer and SM(d18:1/24:1) molecules were substantially lower in the DR group. After excluding other confounding factors (e.g., sex, BMI, lipid-lowering drug therapy, and lipid levels), multifactorial logistic regression analysis revealed that a lower abundance of two ceramides, i.e., Cer(d18:0/22:0) and Cer(d18:0/24:0), was an independent risk factor for the occurrence of DR in T2DM patients.ConclusionDisturbances in lipid metabolism are closely associated with the occurrence of DR in patients with T2DM, especially in ceramides. Our study revealed for the first time that Cer(d18:0/22:0) and Cer(d18:0/24:0) might be potential serological markers for the diagnosis of DR occurrence in T2DM patients, providing new ideas for the early diagnosis of DR.

Cardiovascular and physiological risk factors in women at mid-life and beyond.

Cardiovascular disease (CVD) is the leading cause of death in women. After menopause, sex-specific and gender-specific factors may play an important role in increasing CVD risk, with changes in sex hormones, body fat distribution, lipid and metabolic profile, and structural and functional vascular modifications. Premature and early-onset menopause are detrimental to cardiovascular health due to the early cessation of the protective effect of endogenous estrogen. An independent association of menopause with an increased risk of CVD has been documented in early menopause (<45 years). Sex-related differences are relevant in pharmacokinetics and pharmacodynamics; different enzyme formations, drug compatibility, efficacy, and side effects vary for different sexes. Despite some progress in sex and gender research in CVD, disparities remain. Menopausal hormone therapy (MHT) is available at mid-life for symptoms of menopause and may impact cardiovascular risk. Taken early, MHT may reduce CVD morbimortality. However, this is balanced against the risk of increased thrombosis. This paper reviews physiologic changes that contribute to cardiovascular risk in postmenopausal women and discusses clinical implications. Specifically, it explores the atheroprotective effects of estrogen and MHT and the associations between menopause with lipid levels, hypertension, body composition, and diabetes for women at mid-life and beyond.

Use of a mixture design to optimize dietary macronutrients for large turbot (Scophthalmus maximus Linnaeus, 1758)

Aim of study: Studies on the dietary needs of turbot fish (Scophthalmus maximus Linnaeus, 1758) have largely focused on the juvenile stage; however, there are not many on the larger (300–500 g) species. The purpose of this experiment was to determine the ideal dietary levels of protein, fat, and carbohydrate for large turbot. Area of study: Demre, Antalya, Türkiye. Material and methods: A three-component mixture design model was created to adjust the quantities of dietary protein between 45.6% and 63.4%, carbohydrates between 4.9% and 30.5%, and fat between 5.6% and 17.7%. The components of the model were fish meal (FM), fish oil (FO), and wheat flour (W). Fish initially weighing 301.6±0.1 g on average were fed 14 different diets for 10 weeks. The ideal dietary macronutrient levels were estimated by examining the prediction profiler at the highest desirability based on the variables that were selected to maximize final weight, daily growth coefficient, protein efficiency ratio, nitrogen and energy retentions, and minimize feed conversion ratio, nitrogen and carbon losses. Main results: The optimal diet formulation yielded the highest desirability of 0.87 for all selected responses and resulted in dietary inclusion levels of FM, W and FO as 63.6%, 20.8%, and 9.4%, respectively. The proposed optimal nutrient concentrations for large turbot (growing from 300 to 500 g) are 54% protein, approximately 17% lipid, and 15.8% carbohydrate on dry matter basis. Research highlights: The mixture design successfully allowed us to estimate the optimum levels of dietary protein, lipid and carbohydrate for large turbot.