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Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease in adolescents with obesity. Nonetheless, the guidelines for screening and managing this disease are contradictory. The purpose of this study is to non-invasively assess the prevalence, patient characteristics, and potential associated factors of MASLD in this demographic. Methods: This study used baseline data from an RCT in adolescents eligible for bariatric surgery. MASLD was determined by measuring the hepatorenal index (HRI) with ultrasonography, blood liver tests, and the fatty liver index (FLI). Results: A total of 56 adolescents enrolled in the analyses; the majority were female n = 44 (79%); the mean age was 15.75 (±1.01) years; the average body mass index (BMI) was 44.08 (±5.16) kg/m2. In 35 (62.5%) of the patients, the HRI was abnormal. This group had a higher waist/hip ratio, elevated liver biochemistry, and significantly lower leptin levels (mean difference = −46.35, 95% CI −76.72, −15.99) compared to the group with a normal HRI. In 32 (55.2%) of the patients, ALT levels were elevated and the FLI was abnormal in all (100%) participants. Linear regression analysis indicated associations between the HRI and typical anthropometric and metabolic measurements; and an inverse association between HRI and leptin B = −0.003 (95% CI −0.005, −0.00), independently of sex- and age-adjusted BMI. Conclusions: MASLD is highly prevalent in adolescents with severe obesity. However, the prevalence strongly depends on which tool is used, namely the HRI (62.5%), alanine transaminase levels (55.2%), and FLI (100%). Our findings suggest that leptin may be a valuable biomarker in supporting the diagnosis of MASLD. [ABSTRACT FROM AUTHOR]

Aβ peptides are known to bind neural plasma membranes in a process leading to the deposit of Aβ-enriched plaques. These extracellular structures are characteristic of Alzheimer's disease, the major cause of late-age dementia. The mechanisms of Aβ plaque formation and deposition are far from being understood. A vast number of studies in the literature describe the efforts to analyze those mechanisms using a variety of tools. The present review focuses on biophysical studies mostly carried out with model membranes or with computational tools. This review starts by describing basic physical aspects of lipid phases and commonly used model membranes (monolayers and bilayers). This is followed by a discussion of the biophysical techniques applied to these systems, mainly but not exclusively Langmuir monolayers, isothermal calorimetry, density-gradient ultracentrifugation, and molecular dynamics. The Methodological Section is followed by the core of the review, which includes a summary of important results obtained with each technique. The last section is devoted to an overall reflection and an effort to understand Aβ-bilayer binding. Concepts such as Aβ peptide membrane binding, adsorption, and insertion are defined and differentiated. The roles of membrane lipid order, nanodomain formation, and electrostatic forces in Aβ–membrane interaction are separately identified and discussed. [ABSTRACT FROM AUTHOR]

The standard of care for glioblastoma (GBM) involves surgery followed by adjuvant radio- and chemotherapy, but often within months, patients relapse, and this has been linked to glioma stem cells (GSCs), self-renewing cells with increased therapy resistance. The identification of the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) as key players in gliomagenesis inspired the development of inhibitors targeting these tyrosine kinases (TKIs). However, results from clinical trials testing TKIs have been disappointing, and while the role of GSCs in conventional therapy resistance has been extensively studied, less is known about resistance of GSCs to TKIs. In this study, we have used compartmentalised proteomics to analyse the adaptive response of GSCs to ponatinib, a TKI with activity against PDGFR. The analysis of differentially expressed proteins revealed that GSCs respond to ponatinib by broadly rewiring lipid metabolism, involving fatty acid beta-oxidation, cholesterol synthesis, and sphingolipid degradation. Inhibiting each of these metabolic pathways overcame ponatinib adaptation of GSCs, but interrogation of patient data revealed sphingolipid degradation as the most relevant pathway in GBM. Our data highlight that targeting lipid metabolism, and particularly sphingolipid degradation in combinatorial therapies, could improve the outcome of TKI therapies using ponatinib in GBM. [ABSTRACT FROM AUTHOR]

Simple Summary: Cholesterol and cholesterol derivatives accumulate in prostate cancer cells. Epidemiologic studies about diet and/or treatment with cholesterol-lowering drugs indicate that this metabolite plays a role in cancer progression, but they do not discriminate its possible role in cancer incidence. The goal of this study is so to determine whether cholesterol availability impacts tumor formation itself. Using a drosophila model specifically dedicated to the study of early epithelial tumorigenesis, we find that basal extrusion, a critical step of tumor formation, directly depends on cholesterol availability through dietary intake, and on cholesterol metabolization by the tumor cells. As we find that many genes related to cholesterol homeostasis and metabolism are ill-expressed in primary prostate cancer samples, this work indicates that cholesterol levels and metabolism could play a crucial role in the early phases of prostate cancer as well. Epidemiological studies point to cholesterol as a possible key factor for both prostate cancer incidence and progression. It could represent a targetable metabolite as the most aggressive tumors also appear to be sensitive to therapies designed to decrease hypercholesterolemia, such as statins. However, it remains unknown whether and how cholesterol, through its dietary uptake and its metabolism, could be important for early tumorigenesis. Oncogene clonal induction in the Drosophila melanogaster accessory gland allows us to reproduce tumorigenesis from initiation to early progression, where tumor cells undergo basal extrusion to form extra-epithelial tumors. Here we show that these tumors accumulate lipids, and especially esterified cholesterol, as in human late carcinogenesis. Interestingly, a high-cholesterol diet has a limited effect on accessory gland tumorigenesis. On the contrary, cell-specific downregulation of cholesterol uptake, intracellular transport, or metabolic response impairs the formation of such tumors. Furthermore, in this context, a high-cholesterol diet suppresses this impairment. Interestingly, expression data from primary prostate cancer tissues indicate an early signature of redirection from cholesterol de novo synthesis to uptake. Taken together, these results reveal that during early tumorigenesis, tumor cells strongly increase their uptake and use of dietary cholesterol to specifically promote the step of basal extrusion. Hence, these results suggest the mechanism by which a reduction in dietary cholesterol could lower the risk and slow down the progression of prostate cancer. [ABSTRACT FROM AUTHOR]

Background: A correlation between plasma lipids and timing of pubertal development has been hypothesized, though lipid influence remains unclear in central precocious puberty (CPP). Aim: To assess any possible alterations in the lipid profile and triglyceride glucose index (TyG) in children diagnosed with CPP. Patients and Methods: Retrospective single-center study conducted on children (aged 6.3 ± 2.1 years) evaluated for the suspicion of CPP. Results: Based on the results of the gonadotropin releasing hormone (GnRH) test, considering 5 IU/L as cut-off of the luteinizing hormone peak, CPP was confirmed in 43 patients (57.3%). Sixteen (37.2%) had a pathologic body mass index (BMI), with 9 (20.9%) being overweight and 7 (16.27%) obese. High total cholesterol was found in 3 patients with CPP (6.97%), high triglycerides were found in 11 patients with CPP (25.58%), high LDL cholesterol was found in 5 patients with CPP (11.62%), low HDL cholesterol was found in 12/43 patients with CPP (27.9%), a pathologic TyG was found in 13/43 patients with CPP (30.23%). No significant association was observed in the lipid profile for patients with or without CPP, except for HDL cholesterol, which was lower in the CPP group (47.1 ± 10.9; p = 0.033). However, the association between serum HDL cholesterol and CPP was not confirmed at the multivariate logistic regression analysis adjusted for patients' sex and age (p = 0.1; OR: 1.035; 95% CI: 0.993–1.078). Conclusion: The overall lipid profile of our pediatric patients diagnosed with CPP did not differ from patients having idiopathic precocious thelarche or normal variants of puberty development. [ABSTRACT FROM AUTHOR]

All over the world, birds' eggs are an important and valuable component of the human diet. This study aimed to compare the content of lipid components and their nutritional value as well as iron and zinc levels in chicken and quail eggs commonly available on the market. In egg lipids, unsaturated fatty acids were dominant, especially oleic acid, the content of which was about 40% of the total fatty acids (TFAs). Linoleic acid was the major polyunsaturated fatty acid. Compared to other products of animal origin, eggs were characterized by favorable values of lipid quality indices, especially the index of atherogenicity, thrombogenicity, and the hypocholesterolemic-to-hypercholesterolemic ratio. In the present study, no differences were found in the content of tested nutrients between eggs from different production methods (organic, free-range, barn, cages). Based on linear discriminant analysis, inter-breed differences were noticed. Cluster analysis showed that eggs enriched in n3 PUFAs (according to the producers' declarations) differed from other groups of chicken eggs. However, in eggs from one producer only, the amount of EPA and DHA exceeds 80 mg per 100 g, entitling the use of the nutrition claim on the package. Quail eggs differed from chicken eggs in FA profile and cholesterol and iron levels. [ABSTRACT FROM AUTHOR]

Cholesterol has for decades ruled the history of atherosclerotic cardiovascular diseases (CVDs), and the present view of the etiology of the disease is based on the transport of cholesterol by plasma lipoproteins. The new knowledge of the lipoprotein-specific transport of lipid oxidation products (LOPs) has introduced another direction to the research of CVD, revealing strong associations between lipoprotein transport functions, atherogenic LOP, and CVD. The aim of this review is to present the evidence of the lipoprotein-specific transport of LOP and to evaluate the potential consequences of the proposed role of the LOP transport as a risk factor. The associations of cholesterol and lipoprotein LOP with the known risk factors of CVD are mostly parallel, and because of the common transport and cellular intake mechanisms it is difficult to ascertain the independent effects of either cholesterol or LOP. While cholesterol is known to have important physiological functions, LOPs are merely regarded as metabolic residues and able to initiate and boost atherogenic processes. It is therefore likely that with the increased knowledge of the lipoprotein-specific transport of LOP, the role of cholesterol as a risk factor of CVD will be challenged. [ABSTRACT FROM AUTHOR]

An analysis of the membrane organization and intracellular trafficking of lipids often relies on multiphoton (MP) and super-resolution microscopy of fluorescent lipid probes. A disadvantage of particularly intrinsically fluorescent lipid probes, such as the cholesterol and ergosterol analogue, dehydroergosterol (DHE), is their low MP absorption cross-section, resulting in a low signal-to-noise ratio (SNR) in live-cell imaging. Stimulated emission depletion (STED) microscopy of membrane probes like Nile Red enables one to resolve membrane features beyond the diffraction limit but exposes the sample to a lot of excitation light and suffers from a low SNR and photobleaching. Here, dynamic mode decomposition (DMD) and its variant, higher-order DMD (HoDMD), are applied to efficiently reconstruct and denoise the MP and STED microscopy data of lipid probes, allowing for an improved visualization of the membranes in cells. HoDMD also allows us to decompose and reconstruct two-photon polarimetry images of TopFluor-cholesterol in model and cellular membranes. Finally, DMD is shown to not only reconstruct and denoise 3D-STED image stacks of Nile Red-labeled cells but also to predict unseen image frames, thereby allowing for interpolation images along the optical axis. This important feature of DMD can be used to reduce the number of image acquisitions, thereby minimizing the light exposure of biological samples without compromising image quality. Thus, DMD as a computational tool enables gentler live-cell imaging of fluorescent probes in cellular membranes by MP and STED microscopy. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is recognized as the most common cancer within the female population. In this context, cholesterol is recognized as a vital component for the proliferation and survival of cancer cells. These cells primarily acquire cholesterol through the receptor-mediated uptake from external sources, including low-density lipoprotein (LDL), utilizing the endocytosis pathway. Thus, this observational study aimed to test the effectiveness of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in cancer onset. Although PCSK9 correlated with lipid parameters (e.g., cholesterol, LDL) and with 17 β-estradiol, our results do not portend PCSK9 is a prognostic biomarker, at least, in the context of breast neoplastic events. Background and aim: The involvement of cholesterol in cancer development remains a topic of debate, and its association with breast cancer has yet to be consistently demonstrated. Considering that circulating cholesterol levels depend on several concomitant processes, we tested the liability of plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in the context of breast neoplastic events. Methods: Within a prospective randomized breast cancer prevention trial we measured baseline plasma levels of PCSK9. A total of 235 at-risk premenopausal women were randomized and followed up for 17 years. Participants enrolled in this placebo-controlled, phase II, double-blind trial were randomly assigned to receive either tamoxifen 5 mg/d or fenretinide 200 mg/d, both agents, or placebo for 2 years. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models, adjusted for randomization strata (5-year Gail risk ≥ 1.3% vs. intraepithelial neoplasia or small invasive breast cancer of favorable prognosis), age, and treatment allocation. PCSK9 associations with biomarkers linked to breast cancer risk were assessed on blood samples collected at baseline. Results: The plasmatic PCSK9 median and interquartile range were 207 ng/mL and 170–252 ng/mL, respectively. Over a median follow-up period of 17 years and 89 breast neoplastic events, disease-free survival curves showed a hazard ratio of 1.002 (95% CI: 0.999–1.005, p = 0.22) for women with PCSK9 plasma levels ≥ 207 ng/mL compared to women with levels below 207 ng/mL. No differences between randomization strata were observed. We found a negative correlation between PCSK9 and estradiol (r = −0.305), maintained even after partial adjustment for BMI and age (r = −0.287). Cholesterol (r = 0.266), LDL-C (r = 0.207), non-HDL-C (r = 0.246), remnant cholesterol (r = 0.233), and triglycerides (r = 0.233) also correlated with PCSK9. Conclusions: In premenopausal women at risk of early-stage breast cancer, PCSK9 did not appear to have a role as a prognostic biomarker of breast neoplastic events. Larger studies are warranted investigating patients in different settings. [ABSTRACT FROM AUTHOR]

Shrimp is a rich source of bioactive molecules that provide health benefits. However, the high cholesterol content in shrimp oil may pose a risk. We utilized the cholesterol elimination method to obtain cholesterol-free shrimp lipids (CLs) and investigated their anticancer potential, focusing on cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT). Our study focused on CSCs and EMT, as these factors are known to contribute to cancer metastasis. The results showed that treatment with CLs at doses ranging from 0 to 500 µg/mL significantly suppressed the cell migration ability of human lung cancer (H460 and H292) cells, indicating its potential to inhibit cancer metastasis. The CLs at such concentrations did not cause cytotoxicity to normal human keratinocytes. Additionally, CL treatment was found to significantly reduce the levels of Snail, Slug, and Vimentin, which are markers of EMT. Furthermore, we investigated the effect of CLs on CSC-like phenotypes and found that CLs could significantly suppress the formation of a three-dimensional (3D) tumor spheroid in lung cancer cells. Furthermore, CLs induced apoptosis in the CSC-rich population and significantly depleted the levels of CSC markers CD133, CD44, and Sox2. A mechanistic investigation demonstrated that exposing lung cancer cells to CLs downregulated the phosphorylation of Akt and mTOR, as well as c-Myc expression. Based on these findings, we believe that CLs may have beneficial effects on health as they potentially suppress EMT and CSCs, as well as the cancer-potentiating pathway of Akt/mTOR/c-Myc. [ABSTRACT FROM AUTHOR]

The amyloidogenic Aβ peptides are widely considered as a pathogenic agent in Alzheimer's disease. Aβ(1-42) would form aggregates of amyloid fibrils on the neuron plasma membranes, thus perturbing neuronal functionality. Conflicting data are available on the influence of bilayer order on Aβ(1-42) binding to membranes. In the present study, a biophysical approach was used in which isothermal calorimetry and surface pressure measurements were applied to explore the interaction of Aβ(1-42) in either monomeric, oligomeric, or fibrillar form with model membranes (bilayers or monolayers) in the liquid-ordered state that were either electrically neutral or negatively charged. In the latter case, this contained phosphatidic acid, cardiolipin, or ganglioside. The calorimetric studies showed that Aβ(1-42) fibrils, oligomers, and monomers could bind and/or be inserted into bilayers, irrespective of electric charge, in the liquid-ordered state, except that monomers could not interact with electrically neutral bilayers. The monolayer studies in the Langmuir balance demonstrated that Aβ(1-42) aggregation hindered peptide insertion into the monolayer, hindered insertion in the decreasing order of monomer > oligomer > fibril, and that lipid composition did not cause large differences in insertion, apart from a slight facilitation of monomer and oligomer insertion by gangliosides. [ABSTRACT FROM AUTHOR]

Apremilast, a phosphodiesterase-4 inhibitor, has shown promise to have a potential beneficial metabolic effect. We conducted a single-centre retrospective study on adult patients with moderate-to-severe psoriasis who underwent apremilast treatment over at least 12 and 52 weeks, respectively. Baseline characteristics, weight, lipid profile, and fasting glucose levels were collected at baseline and at 12, 24, and 52 weeks. Furthermore, we conducted a narrative review of the current scientific knowledge on the metabolic effects of apremilast in patients with psoriasis and psoriatic arthritis. We observed a significant reduction in average weight and body mass index (BMI) in patients treated with apremilast in both the initial and the subgroup analysis, a significant reduction in triglycerides levels at 24 and 52 weeks, and a significant increase in high-density lipoprotein (HDL) levels at 52 weeks, whereas there were no significant changes in total cholesterol or low-density lipoprotein (LDL) concentrations over the 52-week treatment period. These findings suggest a potential positive impact of apremilast on both weight management and lipid profile in individuals with moderate-to-severe psoriasis in the medium–long term. [ABSTRACT FROM AUTHOR]

The purpose of this review is to succinctly examine the methodologies used in lipid raft research in the brain and to highlight the drawbacks of some investigative approaches. Lipid rafts are biochemically and biophysically different from the bulk membrane. A specific lipid environment within membrane domains provides a harbor for distinct raftophilic proteins, all of which in concert create a specialized platform orchestrating various cellular processes. Studying lipid rafts has proved to be arduous due to their elusive nature, mobility, and constant dynamic reorganization to meet the cellular needs. Studying neuronal lipid rafts is particularly cumbersome due to the immensely complex regional molecular architecture of the central nervous system. Biochemical fractionation, performed with or without detergents, is still the most widely used method to isolate lipid rafts. However, the differences in solubilization when various detergents are used has exposed a dire need to find more reliable methods to study particular rafts. Biochemical methods need to be complemented with other approaches such as live-cell microscopy, imaging mass spectrometry, and the development of specific non-invasive fluorescent probes to obtain a more complete image of raft dynamics and to study the spatio-temporal expression of rafts in live cells. [ABSTRACT FROM AUTHOR]

RNA vaccines are applicable to the treatment of various infectious diseases via the inducement of robust immune responses against target antigens by expressing antigen proteins in the human body. The delivery of messenger RNA by lipid nanoparticles (LNPs) has become a versatile drug delivery system used in the administration of RNA vaccines. LNPs are widely considered to possess adjuvant activity that induces a strong immune response. However, the properties of LNPs that contribute to their adjuvant activity continue to require clarification. To characterize the relationships between the lipid composition, particle morphology, and adjuvant activity of LNPs, the nanostructures of LNPs and their antibody production were evaluated. To simply compare the adjuvant activity of LNPs, empty LNPs were subcutaneously injected with recombinant proteins. Consistent with previous research, the presence of ionizable lipids was one of the determinant factors. Adjuvant activity was induced when a tiny cholesterol assembly (cholesterol-induced phase, ChiP) was formed according to the amount of cholesterol present. Moreover, adjuvant activity was diminished when the content of cholesterol was excessive. Thus, it is plausible that an intermediate structure of cholesterol (not in a crystalline-like state) in an intra-particle space could be closely related to the immunogenicity of LNPs. [ABSTRACT FROM AUTHOR]

Dyslipidemia is a serious condition affecting an increasing number of people, and thus, preventive measures, including supplementation, are being developed. We aimed to compare the effect of linseed oil, its ethyl esters and fish oil supplementation on the serum lipid profiles of rats fed a high-fat diet. Wistar rats were divided into nine groups. Four of them were fed a high-fat diet for the whole experiment, four groups were fed a high-fat diet before the supplementation period and then the control one with supplements, and one was fed a control diet without supplements. The whole experiment lasted 12 weeks. A significant reduction in blood triglycerides, total cholesterol and the LDL fraction was noted in supplemented groups compared to the controls, especially in groups supplemented with ethyl esters of linseed oil and linseed oil compared to fish oil groups. The results were also more beneficial in groups where, in addition to supplementation, there was also a diet change from a high-fat diet to a control diet during the supplementation period. We may conclude that supplementation with omega-3 fatty acids, combined with a healthy diet, may be a good way of preventing or alleviating dyslipidemia. [ABSTRACT FROM AUTHOR]

Piezo1 is a mechanosensitive ion channel required for various biological processes, but its regulation remains poorly understood. Here, we used erythrocytes to address this question since they display Piezo1 clusters, a strong and dynamic cytoskeleton and three types of submicrometric lipid domains, respectively enriched in cholesterol, GM1 ganglioside/cholesterol and sphingomyelin/cholesterol. We revealed that Piezo1 clusters were present in both the rim and the dimple erythrocyte regions. Upon Piezo1 chemical activation by Yoda1, the Piezo1 cluster proportion mainly increased in the dimple area. This increase was accompanied by Ca2+ influx and a rise in echinocytes, in GM1/cholesterol-enriched domains in the dimple and in cholesterol-enriched domains in the rim. Conversely, the effects of Piezo1 activation were abrogated upon membrane cholesterol depletion. Furthermore, upon Piezo1-independent Ca2+ influx, the above changes were not observed. In healthy donors with a high echinocyte proportion, Ca2+ influx, lipid domains and Piezo1 fluorescence were high even at resting state, whereas the cytoskeleton membrane occupancy was lower. Accordingly, upon decreases in cytoskeleton membrane occupancy and stiffness in erythrocytes from patients with hereditary spherocytosis, Piezo1 fluorescence was increased. Altogether, we showed that Piezo1 was differentially controlled by lipid domains and the cytoskeleton and was favored by the stomatocyte–discocyte–echinocyte transformation. [ABSTRACT FROM AUTHOR]

Reduced sperm motility and/or count are among the major causes of reduced fertility in men, and sperm membranes play an important role in the spermatogenesis and fertilization processes. However, the impact of sperm lipid composition on male fertility remains under-investigated. The aim of the present study was to perform a lipidomic analysis of human sperm membranes: we performed an untargeted analysis of membrane lipid composition in fertile (N = 33) and infertile subjects (N = 29). In parallel, we evaluated their serum lipid levels. Twenty-one lipids were identified by their mass/charge ratio and post-source decay spectra. Sulfogalactosylglycerolipid (SGG, seminolipid) was the most abundant lipid component in the membranes. In addition, we observed a significant proportion of PUFAs. Important differences have emerged between the fertile and infertile groups, leading to the identification of a lipid cluster that was associated with semen parameters. Among these, cholesterol sulfate, SGG, and PUFAs represented the most important predictors of semen quality. No association was found between the serum and sperm lipids. Dietary PUFAs and SGG have acknowledged antioxidant functions and could, therefore, represent sensitive markers of sperm quality and testicular function. Altogether, these results underline the important role of sperm membrane lipids, which act independently of serum lipids levels and may rather represent an independent marker of reproductive function. [ABSTRACT FROM AUTHOR]

This clinical study examined the influence of SLCO1B1 c.521T>C (rs4149056) on plasma atorvastatin concentrations in pediatric hypercholesterolemia. The participants (8–21 years), including heterozygous (c.521T/C, n = 13), homozygous (c.521C/C, n = 2) and controls (c.521T/T, n = 13), completed a single-oral-dose pharmacokinetic study. Similar to in adults, the atorvastatin (AVA) area-under-concentration-time curve from 0 to 24 h (AUC0–24) was 1.7-fold and 2.8-fold higher in participants with c.521T/C and c.521C/C compared to the c.521T/T participants, respectively. The inter-individual variability in AVA exposure within these genotype groups ranged from 2.3 to 4.8-fold, indicating that additional factors contribute to the inter-individual variability in the AVA dose–exposure relationship. A multivariate model reinforced the SLCO1B1 c.521T>C variant as the central factor contributing to AVA systemic exposure in this pediatric cohort, accounting for ~65% of the variability in AVA AUC0–24. Furthermore, lower AVA lactone concentrations in participants with increased body mass index contributed to higher exposure within the c.521T/T and c.521T/C genotype groups. Collectively, these factors contributing to higher systemic exposure could increase the risk of toxicity and should be accounted for when individualizing the dosing of atorvastatin in eligible pediatric patients. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease and presents a major public health problem worldwide. It is characterized by a recurrent and/or chronic course of inflammatory skin lesions with intense pruritus. Its pathophysiologic features include barrier dysfunction, aberrant immune cell infiltration, and alterations in the microbiome that are associated with genetic and environmental factors. There is a complex crosstalk between these components, which is primarily mediated by cytokines. Epidermal barrier dysfunction is the hallmark of AD and is caused by the disruption of proteins and lipids responsible for establishing the skin barrier. To better define the role of cytokines in stratum corneum lipid abnormalities related to AD, we conducted a systematic review of biomedical literature in PubMed from its inception to 5 September 2023. Consistent with the dominant TH2 skewness seen in AD, type 2 cytokines were featured prominently as possessing a central role in epidermal lipid alterations in AD skin. The cytokines associated with TH1 and TH17 were also identified to affect barrier lipids. Considering the broad cytokine dysregulation observed in AD pathophysiology, understanding the role of each of these in lipid abnormalities and barrier dysfunction will help in developing therapeutics to best achieve barrier homeostasis in AD patients. [ABSTRACT FROM AUTHOR]

Hybrid lipid bilayers (HLBs) are rugged biomimetic cell membrane interfaces that can form on inorganic surfaces and be designed to contain biologically important components like cholesterol. In general, HLBs are formed by depositing phospholipids on top of a hydrophobic self-assembled monolayer (SAM) composed of one-tail amphiphiles, while recent findings have shown that two-tail amphiphiles such as inverse phosphocholine (CP) lipids can have advantageous properties to promote zwitterionic HLB formation. Herein, we explored the feasibility of fabricating cholesterol-enriched HLBs on CP SAM-functionalized TiO2 surfaces with the solvent exchange and vesicle fusion methods. All stages of the HLB fabrication process were tracked by quartz crystal microbalance-dissipation (QCM-D) measurements and revealed important differences in fabrication outcome depending on the chosen method. With the solvent exchange method, it was possible to fabricate HLBs with well-controlled cholesterol fractions up to ~65 mol% in the upper leaflet as confirmed by a methyl-β-cyclodextrin (MβCD) extraction assay. In marked contrast, the vesicle fusion method was only effective at forming HLBs from precursor vesicles containing up to ~35 mol% cholesterol, but this performance was still superior to past results on hydrophilic SiO2. We discuss the contributing factors to the different efficiencies of the two methods as well as the general utility of two-tail CP SAMs as favorable interfaces to incorporate cholesterol into HLBs. Accordingly, our findings support that the solvent exchange method is a versatile tool to fabricate cholesterol-enriched HLBs on CP SAM-functionalized TiO2 surfaces. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women. Cardiovascular diseases are common complications after chemotherapy due to the effect of the drug on lipid levels. This study aimed to explore the changes in lipid profiles in patients with breast cancer under chemotherapy. Methods: In this prospective study, 50 patients with breast cancer participated. Three biochemical–lipid hematological tests were performed: total cholesterol (TC), triglycerides (TGs), High-Density Lipoprotein (HDL-C), and Low-Density Lipoprotein (LDL-C) before initiation (pre-chemotherapy), at the start (first follow-up), and at the completion (second follow-up) of the first cycle of chemotherapy. Statistical significance was set at p < 0.05. Analyses were conducted using SPSS Statistical Software (version 22.0). Results: Mean TC values increased significantly at second follow-up. TGs values decreased significantly from first to second follow-up. HDL-C was significantly lower at first follow-up compared with pre-chemotherapy and was similar to the pre-chemotherapy levels at second follow-up. LDL-C values were significantly higher at second follow-up compared with pre-chemotherapy measurement. Significantly positive correlations of BMI with pre-chemotherapy LDL-C, first follow-up TC, first follow-up LDL-C, second follow-up TC, and second follow-up LDL-C were found. Conclusions: There is a statistically significant increase in the levels of TC and LDL-C in breast cancer patients during chemotherapy. This study was not registered. [ABSTRACT FROM AUTHOR]

Tightly regulated and highly adaptive lipid metabolic and transport pathways are critical to maintaining brain cellular lipid homeostasis and responding to lipid and inflammatory stress to preserve brain function and health. Deficits in the lipid handling genes APOE and GBA1 are the most significant genetic risk factors for Lewy body dementia and related dementia syndromes. Parkinson's disease patients who carry both APOE4 and GBA1 variants have accelerated cognitive decline compared to single variant carriers. To investigate functional interactions between brain ApoE and GBA1, in vivo GBA1 inhibition was tested in WT versus ApoE-deficient mice. The experiments demonstrated glycolipid stress caused by GBA1 inhibition in WT mice induced ApoE expression in several brain regions associated with movement and dementia disorders. The absence of ApoE in ApoE-KO mice amplified complement C1q elevations, reactive microgliosis and astrocytosis after glycolipid stress. Mechanistically, GBA1 inhibition triggered increases in cell surface and intracellular lipid transporters ABCA1 and NPC1, respectively. Interestingly, the absence of NPC1 in mice also triggered elevations of brain ApoE levels. These new data show that brain ApoE, GBA1 and NPC1 functions are interconnected in vivo, and that the removal or reduction of ApoE would likely be detrimental to brain function. These results provide important insights into brain ApoE adaptive responses to increased lipid loads. [ABSTRACT FROM AUTHOR]

Global rates of adolescent obesity have led the World Health Organization to consider the disease a pandemic that needs focus. In search of new anti-obesity agents, Crocus sativus, popularly known as saffron, is a nutraceutical agent, praised for its beneficial effects. The study aimed to investigate the possible effect of Kozanis saffron administration on weight management of obese prediabetic adolescents. Seventy-four obese prediabetic adolescents participated in a double-blind placebo-controlled trial of three arms, randomly assigned to receive either Kozanis saffron (n = 25, 60 mg/day), metformin (n = 25, 1000 mg/day) or a placebo (n = 24), for twelve weeks. Anthropometry, glycemic markers and lipid profiles were investigated at baseline and post-intervention. Saffron supplementation significantly reduced the weight z-score, BMI, BMI z-score and waist circumference (WC) of obese adolescents; however, this reduction was less significant compared to the effect of metformin. Metformin administration offered a significantly more profound improvement in anthropometry compared to saffron administration. Saffron administration also provided significant improvements in weight, weight z-scores, BMI values, BMI z-scores and WCs compared to the placebo. Saffron supplementation failed to change any glycemic marker, but provided a significant reduction in fasting triglyceride levels and also a significant increase in fasting HDL levels. Saffron Kozanis constitutes a promising nutraceutical option for adolescents and children with obesity and prediabetes in need of weight management. [ABSTRACT FROM AUTHOR]

The gut microbiome is a versatile system regulating numerous aspects of host metabolism. Among other traits, variations in the composition of gut microbial communities are related to blood lipid patterns and hyperlipidaemia, yet inconsistent association patterns exist. This study aims to assess the relationships between the composition of the gut microbiome and variations in lipid profiles among healthy adults. This study used data and samples from 23 adult participants of a previously conducted dietary intervention study. Circulating lipid measurements and whole-metagenome sequences of the gut microbiome were derived from 180 blood and faecal samples collected from eight visits distributed across an 11-week study. Lipid-related variables explained approximately 4.5% of the variation in gut microbiome compositions, with higher effects observed for total cholesterol and high-density lipoproteins. Species from the genera Odoribacter, Anaerostipes, and Parabacteroides correlated with increased serum lipid levels, whereas probiotic species like Akkermansia muciniphila were more abundant among participants with healthier blood lipid profiles. An inverse correlation with serum cholesterol was also observed for Massilistercora timonensis, a player in regulating lipid turnover. The observed correlation patterns add to the growing evidence supporting the role of the gut microbiome as an essential regulator of host lipid metabolism. [ABSTRACT FROM AUTHOR]

The milk fat globule membrane (MFGM) is a complex tri-layer membrane that wraps droplets of lipids in milk. In recent years, it has attracted widespread attention due to its excellent bioactive functions and nutritional value. MFGM contains a diverse array of bioactive lipids, including cholesterol, phospholipids, and sphingolipids, which play pivotal roles in mediating the bioactivity of the MFGM. We sequentially summarize the main lipid types in the MFGM in this comprehensive review and outline the characterization methods used to employ them. In this comprehensive review, we sequentially describe the types of major lipids found in the MFGM and outline the characterization methods employed to study them. Additionally, we compare the structural disparities among glycerophospholipids, sphingolipids, and gangliosides, while introducing the formation of lipid rafts facilitated by cholesterol. The focus of this review revolves around an extensive evaluation of the current research on lipid isolates from the MFGM, as well as products containing MFGM lipids, with respect to their impact on human health. Notably, we emphasize the clinical trials encompassing a large number of participants. The summarized bioactive functions of MFGM lipids encompass the regulation of human growth and development, influence on intestinal health, inhibition of cholesterol absorption, enhancement of exercise capacity, and anticancer effects. By offering a comprehensive overview, the aim of this review is to provide valuable insights into the diverse biologically active functions exhibited by lipids in the MFGM. [ABSTRACT FROM AUTHOR]

A specific feature of dyslipidemia in pregnancy is increased high-density lipoprotein (HDL) cholesterol concentration, which is probably associated with maternal endothelium protection. However, preeclampsia is most often associated with low HDL cholesterol, and the mechanisms behind this change are scarcely explored. We aimed to investigate changes in HDL metabolism in risky pregnancies and those complicated by late-onset preeclampsia. We analyze cholesterol synthesis (cholesterol precursors: desmosterol, 7-dehydrocholesterol, and lathosterol) and absorption markers (phytosterols: campesterol and β-sitosterol) within HDL particles (NCSHDL), the activities of principal modulators of HDL cholesterol's content, and major HDL functional proteins levels in mid and late pregnancy. On the basis of the pregnancy outcome, participants were classified into the risk group (RG) (70 women) and the preeclampsia group (PG) (20 women). HDL cholesterol was lower in PG in the second trimester compared to RG (p < 0.05) and followed by lower levels of cholesterol absorption markers (p < 0.001 for campesterolHDL and p < 0.05 for β-sitosterolHDL). Lowering of HDL cholesterol between trimesters in RG (p < 0.05) was accompanied by a decrease in HDL phytosterol content (p < 0.001), apolipoprotein A-I (apoA-I) concentration (p < 0.05), and paraoxonase 1 (PON1) (p < 0.001), lecithin–cholesterol acyltransferase (LCAT) (p < 0.05), and cholesterol ester transfer protein (CETP) activities (p < 0.05). These longitudinal changes were absent in PG. Development of late-onset preeclampsia is preceded by the appearance of lower HDL cholesterol and NCSHDL in the second trimester. We propose that reduced capacity for intestinal HDL synthesis, decreased LCAT activity, and impaired capacity for HDL-mediated cholesterol efflux could be the contributing mechanisms resulting in lower HDL cholesterol. [ABSTRACT FROM AUTHOR]

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder caused by pathogenic variants in CYP27A1, leading to a deficiency in sterol 27-hydroxylase. This defect results in the accumulation of cholestanol and bile alcohols in various tissues, including the brain, tendons and peripheral nerves. We conducted this review to evaluate lipid profile abnormalities in patients with CTX. A search was conducted in PubMed, Embase and the Virtual Health Library in January 2023 to evaluate studies reporting the lipid profiles of CTX patients, including the levels of cholestanol, cholesterol and other lipids. Elevated levels of cholestanol were consistently observed. Most patients presented normal or low serum cholesterol levels. A decrease in chenodeoxycholic acid (CDCA) leads to increased synthesis of cholesterol metabolites, such as bile alcohols 23S-pentol and 25-tetrol 3-glucuronide, which may serve as surrogate follow-up markers in patients with CTX. Lipid abnormalities in CTX have clinical implications. Cholestanol deposition in tissues contributes to clinical manifestations, including neurological symptoms and tendon xanthomas. Dyslipidemia and abnormal cholesterol metabolism may also contribute to the increased risk of atherosclerosis and cardiovascular complications observed in some CTX patients. [ABSTRACT FROM AUTHOR]

Holarrhena pubescens seeds are used in the treatment of various diseases, especially diabetes and associated complications, in different parts of the world. The present study was undertaken to determine the hypolipidemic and antihyperlipidemic effects of methanolic extract of H. pubescens seeds in rats. The extract was subjected to LC-MS analysis to determine the chemical constituents. The hypolipidemic action was studied by determining the effect of 28-day oral administration of seed extract on serum cholesterol, serum triglycerides, and serum HDL-cholesterol levels. The antihyperlipidemic action was studied in rats fed with a high-fat diet containing cholesterol and saturated fat, and the same lipid parameters were estimated during 28-day treatment. To elucidate its probable mechanism of action, in vitro studies on the inhibition of lipid accumulation in preadipocytes, DPP-IV inhibitory effect, and lipase enzyme inhibition were studied. The seed extract reduced serum levels of cholesterol and triglycerides in both normal rats and animals fed with a high-fat diet without a significant effect on HDL-cholesterol levels. The seed extract was highly effective in inhibiting lipase enzyme activity but showed a modest effect on the inhibition of lipid accumulation and DPP-IV. The results demonstrated that H. pubescens seed extract has hypolipidemic and antihyperlipidemic effects mediated probably through inhibition of lipase enzyme activity. [ABSTRACT FROM AUTHOR]

Beta-cyclodextrin (β-CD) is a cyclic oligosaccharide consisting of seven glucose units. β-CD is increasingly used in food research to reduce cholesterol due to its affinity for non-polar molecules such as cholesterol and as a natural additive. The purpose of this study was to evaluate the effect of curd washing in ewe's milk cheese on the reduction in cholesterol by β-CD from pasteurized ewe's milk Manchego cheese and the characteristics of its main components: milk, lipids, and flavor. An approximately 98.45% cholesterol reduction was observed in washed experimental cheeses that were treated by using β-CD. The remaining residual β-CD from the effect of curd washing was 0.15% in mature cheese, of the initial 1% β-CD treatment of the milk. The chemical properties (fat, moisture, and protein) did not change as a result of the curd washing with or without β-CD. The curd washing with or without β-CD on the levels of the various lipid fraction (fatty acids, triglycerides, and phospholipids) were comparable in treated and untreated cheeses. The effects of curd washing and the β-CD treatment did not significantly affect flavor components or short chain free fatty acids. The β-CD molecules were edible and nontoxic; as a result, they could be used safely in cholesterol removal processing in cheese manufacturing, improving the reduction in residual β-CD by curd washing by 85%. Therefore, the present study suggests that curd washing combined with β-CD is an effective process for cholesterol removal in Manchego cheese, preserving its desirable properties. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown etiology. Many metabolic alterations occur during ALS progress and can be used as a method of pre-diagnostic and early diagnosis. Dyslipidemia is one of the physiological changes observed in numerous ALS patients. The aim of this study is to analyze the possible relationship between the rate of disease progression (functional rating scale (ALS-FRS)) and the plasma lipid levels at the early stage of ALS. A systematic review was carried out in July 2022. The search equation was "Triglycerides AND amyotrophic lateral sclerosis" and its variants. Four meta-analyses were performed. Four studies were included in the meta-analysis. No significant differences were observed between the lipid levels (total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol) and the ALS-FRS score at the onset of the disease. Although the number of studies included in this research was low, the results of this meta-analytic study suggest that there is no clear relationship between the symptoms observed in ALS patients and the plasma lipid levels. An increase in research, as well as an expansion of the geographical area, would be of interest. [ABSTRACT FROM AUTHOR]

Background: Observational studies suggest that statins may affect amyotrophic lateral sclerosis (ALS). However, they are limited by confounding and reverse causality biases. Therefore, we aimed to investigate the potential causal associations between statins and ALS using a mendelian randomization (MR) approach. Methods: Two-sample MR and drug-target MR were performed. Exposure sources included GWAS summary statistics of statin use, low-density-lipoprotein cholesterol (LDL-C), HMGCR-mediated LDL-C and LDL-C response to statins. Results: Genetic predisposition to statin medication was associated with increased ALS risk (OR = 1.085, 95% CI = 1.025–1.148, p = 0.005). After removing SNPs significantly associated with statin use from the instrumental variables (IVs), LDL-C-related higher ALS risk was absent (before removing: OR = 1.075, 95% CI = 1.013–1.141, p = 0.017; after removing: OR = 1.036, 95% CI = 0.949–1.131, p = 0.432). HMGCR-mediated LDL-C (OR = 1.033, 95% CI = 0.823–1.296, p = 0.779) and blood LDL-C response to statins (OR = 0.998, 95% CI = 0.991–1.005, p = 0.538) had no association with ALS. Conclusions: Here, we show that statins may be a risky exposure that increases ALS risk independent of the lowering effect of LDL-C in peripheral circulation. This provides insights into ALS development and prevention. [ABSTRACT FROM AUTHOR]

Sesamol is a phenolic lignan isolated from Sesamum indicum seeds and sesame oil. Numerous studies have reported that sesamol exhibits lipid-lowering and anti-atherogenic properties. The lipid-lowering effects of sesamol are evidenced by its effects on serum lipid levels, which have been attributed to its potential for significantly influencing molecular processes involved in fatty acid synthesis and oxidation as well as cholesterol metabolism. In this review, we present a comprehensive summary of the reported hypolipidemic effects of sesamol, observed in several in vivo and in vitro studies. The effects of sesamol on serum lipid profiles are thoroughly addressed and evaluated. Studies highlighting the ability of sesamol to inhibit fatty acid synthesis, stimulate fatty acid oxidation, enhance cholesterol metabolism, and modulate macrophage cholesterol efflux are outlined. Additionally, the possible molecular pathways underlying the cholesterol-lowering effects of sesamol are presented. Findings reveal that the anti-hyperlipidemic effects of sesamol are achieved, at least in part, by targeting liver X receptor α (LXRα), sterol regulatory element binding protein-1 (SREBP-1), and fatty acid synthase (FAS) expression, as well as peroxisome proliferator-activated receptor α (PPARα) and AMP activated protein kinase (AMPK) signaling pathways. A detailed understanding of the molecular mechanisms underlying the anti-hyperlipidemic potential of sesamol is necessary to assess the possibility of utilizing sesamol as an alternative natural therapeutic agent with potent hypolipidemic and anti-atherogenic properties. Research into the optimal sesamol dosage that may bring about such favorable hypolipidemic effects should be further investigated, most importantly in humans, to ensure maximal therapeutic benefit. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory disease with a complex, multifactorial pathogenesis, which includes lipid metabolism alterations. miR-33a is a microRNA that plays a key role in cholesterol efflux and promotes atherosclerosis, yet its relationship with lipid markers in carotid atherosclerosis (CA) remains unclear. The objective is to evaluate possible associations between miR-33a expression and lipid biomarkers in patients with CA. This was a prospective study that included 61 patients (median age 66.0 years, 55.7% male) with evidence of CA. Lipid profile (total cholesterol, triglycerides [TG], high-density lipoprotein [HDL] and low-density lipoprotein [LDL] cholesterol) was analyzed. Extraction and quantification of miR-33a-5p/3p was performed according to protocol. Patients were further divided depending on the target LDL level (<1.8 mmol/L). Patients with CA had relatively favorable LDL levels with a median of 2.0 mmol/L. Both miR-33a-5p and miR-33a-3p levels were lower in patients with less than targeted LDL levels (37.4 and 38.3 vs. 41.8 and 42.5 respectively, p < 0.05). A significant positive correlation between expression levels of miR-33a-5p/3p and degree of carotid stenosis was found (r = 0.44 and r = 0.38 respectively, p < 0.05). In a univariate linear regression model miR-33a-3p/5p was positively associated with LDL cholesterol (p = 0.02). miR-33a up-regulation is associated with CA and may, in fact, be a key player by targeting cholesterol metabolism. A decrease in LDL cholesterol (<1.8 mmol/L) corresponded to lower levels of miR-33a, yet the direction and causality of this association remains unclear. [ABSTRACT FROM AUTHOR]

Background: Babesiosis, an intra-erythrocytic protozoan disease, is an emerging zoonotic parasitic disease worldwide. Cholesterol levels are correlated with severe infections, such as sepsis and COVID-19, and anecdotal reports suggest that high-density lipoprotein (HDL) cholesterol declines during acute babesiosis. Our aim was to describe the cholesterol levels in patients with acute babesiosis diagnosed in an endemic area in New York, hypothesizing that HDL levels correlate with the severity of infection. Methods: We reviewed the medical records of adult patients with babesiosis diagnosed by identification of Babesia parasites on a thin blood smear and confirmed by polymerase chain reaction from 2013 to 2018, who also had available a lipid profile drawn at the time of clinical presentation. Additional lipid profile levels were considered as "baseline" if they were drawn within 2 months before or after the infection as part of routine care. Results: A total of 39 patients with babesiosis had a lipid profile drawn on presentation. The patients were divided into two groups for comparison based on the treating physician's clinical decision: 33 patients who were admitted to the hospital and 8 patients who were evaluated as outpatients. A history of hypertension was more common in admitted patients (37% vs. 17%, p = 0.02). The median levels of low-density lipoprotein (LDL) and HDL were significantly reduced in admitted patients compared to non-admitted patients (46 vs. 76 mg/dL, p = 0.04; and 9 vs. 28.5 mg/dL, p = 0.03, respectively). In addition, LDL and HDL levels returned to baseline values following resolution of acute babesiosis. Conclusion: LDL and HDL levels are significantly reduced during acute babesiosis, suggesting that cholesterol depletion may predict disease severity. Pathogen and host factors may contribute to a reduction in serum cholesterol levels during acute babesiosis. [ABSTRACT FROM AUTHOR]

The aim of this research is to investigate the risk factors during pregnancy affect abnormal lipid profiles in women with early postpartum period. This was a single-center retrospective study including 869 women who delivered between December 2017 and May 2019. We collected total cholesterol levels, both at 24–28 GWs and 1 month before delivery. Lipid profiles such as total cholesterol, high-density lipoprotein (HDL), triglyceride (TG) and low-density lipoprotein (LDL) at 6 weeks after delivery were retrieved. Subjects were categorized into 3 groups such as normal, borderline and abnormal group according to the lipid profile levels. The risk factors associated with borderline to abnormal HDL level were body mass index (BMI) of pre-pregnancy (OR = 1.182, 95% CI: 1.116–1.252, p < 0.001), weight gain during pregnancy (OR = 1.085, 95% CI: 1.042–1.131, p < 0.001) and hypertension (HTN) (OR = 3.451, 95% CI: 1.224–9.727, p = 0.02). The risk factors associated with borderline or abnormal TG were BMI of pre-pregnancy, weight gain during pregnancy and weight reduction after delivery. HTN was associated with borderline to abnormal TG in postpartum (OR = 2.891, 95% CI: 1.168–7.156, p = 0.02), while GDM correlated purely with abnormal TG in postpartum (OR = 2.453, 95% CI: 1.068–5.630, p = 0.03). Abnormal lipid profiles in postpartum were significantly associated with BMI of pre-pregnancy, weight gain during pregnancy and weight reduction after delivery. In addition, pregnancy-related HTN was highly associated with abnormal HDL level, and GDM was associated with abnormal TG level in the early postpartum period. [ABSTRACT FROM AUTHOR]

Highlights: What are the main finding? Higher serum levels of total cholesterol and low-density lipoprotein cholesterol are associated with the severity of AP, while the persistent inflammation of AP is linked with decreased serum levels of cholesterol-related lipids. What is the implication of the main finding? Cholesterol-related lipids should be recommended both as risk factors and early predictors for studying the severity of AP. Cholesterol-lowering drugs may play a role in the treatment and prevention of AP with hypercholesterolemia. It is well known that hypercholesterolemia in the body has pro-inflammatory effects through the formation of inflammasomes and augmentation of TLR (Toll-like receptor) signaling, which gives rise to cardiovascular disease and neurodegenerative diseases. However, the interaction between cholesterol-related lipids and acute pancreatitis (AP) has not yet been summarized before. This hinders the consensus on the existence and clinical importance of cholesterol-associated AP. This review focuses on the possible interaction between AP and cholesterol-related lipids, which include total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein (Apo) A1, from the bench to the bedside. With a higher serum level of total cholesterol, LDL-C is associated with the severity of AP, while the persistent inflammation of AP is allied with a decrease in serum levels of cholesterol-related lipids. Therefore, an interaction between cholesterol-related lipids and AP is postulated. Cholesterol-related lipids should be recommended as risk factors and early predictors for measuring the severity of AP. Cholesterol-lowering drugs may play a role in the treatment and prevention of AP with hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is a hereditary disorder that causes severely elevated low-density lipoprotein (LDL-C) levels, which leads to an increased risk for premature cardiovascular disease. A variety of genetic variants can cause FH, namely variants in the genes for the LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and/or LDL-receptor adaptor protein 1 (LDLRAP1). Variants can exist in a heterozygous form (HeFH) or the more severe homozygous form (HoFH). If affected individuals are diagnosed early (through screening), they benefit tremendously from early initiation of lipid-lowering therapy, such as statins, and cardiovascular imaging to detect possible atherosclerosis. Over the last years, due to intensive research on the genetic basis of LDL-C metabolism, novel, promising therapies have been developed to reduce LDL-C levels and subsequently reduce cardiovascular risk. Results from studies on therapies focused on inhibiting PCSK9, a protein responsible for degradation of the LDLR, are impressive. As the effect of PCSK9 inhibitors (PCSK9-i) is dependent of residual LDLR activity, this medication is less potent in patients without functional LDLR (e.g., null/null variant). Novel therapies that are expected to become available in the near future focused on inhibition of another major regulatory protein in lipid metabolism (angiopoietin-like 3 (ANGPTL3)) might dramatically reduce the frequency of apheresis in children with HoFH, independently of their residual LDLR. At present, another independent risk factor for premature cardiovascular disease, elevated levels of lipoprotein(a) (Lp(a)), cannot be effectively treated with medication. Further understanding of the genetic basis of Lp(a) metabolism, however, offers a possibility for the development of novel therapies. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the vessel wall, leading to the formation of an atheroma and eventually to the development of vascular calcification (VC). Lipoproteins play a central role in the development of atherosclerosis and VC. Both low- and very low-density lipoproteins (LDL and VLDL) and lipoprotein (a) (Lp(a)) stimulate, while high-density lipoproteins (HDL) reduce VC. Apolipoproteins, the protein component of lipoproteins, influence the development of VC in multiple ways. Apolipoprotein AI (apoAI), the main protein component of HDL, has anti-calcific properties, while apoB and apoCIII, the main protein components of LDL and VLDL, respectively, promote VC. The role of lipoproteins in VC is also related to their metabolism and modifications. Oxidized LDL (OxLDL) are more pro-calcific than native LDL. Oxidation also converts HDL from anti- to pro-calcific. Additionally, enzymes such as autotaxin (ATX) and proprotein convertase subtilisin/kexin type 9 (PCSK9), involved in lipoprotein metabolism, have a stimulatory role in VC. In summary, a better understanding of the mechanisms by which lipoproteins and apolipoproteins contribute to VC will be crucial in the development of effective preventive and therapeutic strategies for VC and its associated cardiovascular disease. [ABSTRACT FROM AUTHOR]

Kidney cancer is among the top ten most common cancers to date. Within the kidney, renal cell carcinoma (RCC) is the most common solid lesion occurring. While various risk factors are suspected, including unhealthy lifestyle, age, and ethnicity, genetic mutations seem to be a key risk factor. In particular, mutations in the von Hippel–Lindau gene (Vhl) have attracted a lot of interest since this gene regulates the hypoxia inducible transcription factors HIF-1α and HIF-2α, which in turn drive the transcription of many genes that are important for renal cancer growth and progression, including genes involved in lipid metabolism and signaling. Recent data suggest that HIF-1/2 are themselves regulated by bioactive lipids which make the connection between lipids and renal cancer obvious. This review will summarize the effects and contributions of the different classes of bioactive lipids, including sphingolipids, glycosphingolipids, eicosanoids, free fatty acids, cannabinoids, and cholesterol to renal carcinoma progression. Novel pharmacological strategies interfering with lipid signaling to treat renal cancer will be highlighted. [ABSTRACT FROM AUTHOR]

Lipid membrane turnover and myelin repair play a central role in diseases and lesions of the central nervous system (CNS). The aim of the present study was to analyze lipid composition changes due to inflammatory conditions. We measured the fatty acid (FA) composition in erythrocytes (RBCs) and spinal cord tissue (gas chromatography) derived from mice affected by experimental allergic encephalomyelitis (EAE) in acute and remission phases; cholesterol membrane content (Filipin) and GM1 membrane assembly (CT-B) in EAE mouse RBCs, and in cultured neurons, oligodendroglial cells and macrophages exposed to inflammatory challenges. During the EAE acute phase, the RBC membrane showed a reduction in polyunsaturated FAs (PUFAs) and an increase in saturated FAs (SFAs) and the omega-6/omega-3 ratios, followed by a restoration to control levels in the remission phase in parallel with an increase in monounsaturated fatty acid residues. A decrease in PUFAs was also shown in the spinal cord. CT-B staining decreased and Filipin staining increased in RBCs during acute EAE, as well as in cultured macrophages, neurons and oligodendrocyte precursor cells exposed to inflammatory challenges. This regulation in lipid content suggests an increased cell membrane rigidity during the inflammatory phase of EAE and supports the investigation of peripheral cell membrane lipids as possible biomarkers for CNS lipid membrane concentration and assembly. [ABSTRACT FROM AUTHOR]

Resistance training is used as adjunctive therapy for type 2 diabetes (T2DM), and the aim of this study was to investigate the differences in the treatment effects of different intensities of resistance training in terms of glycemia, lipids, blood pressure, adaptations, and body measurements. A comprehensive search was conducted in the PubMed, EMBASE (Excerpta Medica dataBASE), EBSCO (Elton B. Stephens Company) host, Cochrane Library, WOS (Web of Science), and Scopus databases with a cut-off date of April 2022, and reference lists of relevant reviews were also consulted. The literature screening and data extraction were performed independently by two researchers. RoB2 (Risk of bias 2) tools were used for the literature quality assessment, the exercise intensity was categorized as medium-low intensity and high intensity, and the meta subgroup analysis was performed using R Version. A fixed or random effects model was selected for within-group analysis based on the heterogeneity test, and a random effects model was used for the analysis of differences between subgroups. A total of 36 randomized controlled trials were included, with a total of 1491 participants. It was found that resistance training significantly improved HbA1c (glycated hemoglobin), fasting blood glucose, TG (triglycerides), TC (total cholesterol), and LDL (low-density lipoprotein cholesterol) levels in patients with T2DM and caused a significant reduction in systolic blood pressure, percent of fat mass, and HOMA-IR (homeostatic model assessment for insulin resistance) indexes. The effects of high and medium-low intensity resistance training on T2DM patients were different in terms of HOMA-IR, maximal oxygen consumption, weight, waist-to-hip ratio, and body mass indexes. Only medium-low intensity resistance training resulted in a decrease in HOMA-IR. In addition to weight (MD = 4.25, 95% CI: [0.27, 8.22], I2 = 0%, p = 0.04; MD = −0.33, 95% CI: [−2.05, 1.39], I2 = 0%, p = 0.76; between groups p = 0.03) and HOMA-IR (MD = 0.11, 95% CI: [−0.40, −0.63], I2 = 0%, p = 0.85; MD = −1.09, 95% CI: [−1.83, −0.36], I2 = 87%, p = < 0.01; between groups p = 0.0085), other indicators did not reach statistical significance in the level of difference within the two subgroups of high intensity and medium-low intensity. The treatment effects (merger effect values) of high intensity resistance training were superior to those of medium-low intensity resistance training in terms of HbA1c, TG, TC, LDL levels and diastolic blood pressure, resting heart rate, waist circumference, fat mass, and percentage of fat mass. Therefore, high intensity resistance training can be considered to be a better option to assist in the treatment of T2DM and reduce the risk of diabetic complications compared to medium-low intensity resistance training. Only one study reported an adverse event (skeletal muscle injury) associated with resistance training. Although results reflecting the difference in treatment effect between intensity levels reached no statistical significance, the practical importance of the study cannot be ignored. [ABSTRACT FROM AUTHOR]

In the present review, we provide a comprehensive narrative overview of the current knowledge on the effects of total and specific types of nut consumption (excluding nut oil) on blood lipids and lipoproteins. We identified a total of 19 systematic reviews and meta-analyses of randomized controlled trials (RCTs) that were available in PubMed from the inception date to November 2022. A consistent beneficial effect of most nuts, namely total nuts and tree nuts, including walnuts, almonds, cashews, peanuts, and pistachios, has been reported across meta-analyses in decreasing total cholesterol (mean difference, MD, −0.09 to −0.28 mmol/L), LDL-cholesterol (MD, −0.09 to −0.26 mmol/L), and triglycerides (MD, −0.05 to −0.17 mmol/L). However, no effects on HDL-cholesterol have been uncovered. Preliminary evidence indicates that adding nuts into the regular diet reduces blood levels of apolipoprotein B and improves HDL function. There is also evidence that nuts dose-dependently improve lipids and lipoproteins. Sex, age, or nut processing are not effect modifiers, while a lower BMI and higher baseline lipid concentrations enhance blood lipid/lipoprotein responses. While research is still emerging, the evidence thus far indicates that nut-enriched diets are associated with a reduced number of total LDL particles and small, dense LDL particles. In conclusion, evidence from clinical trials has shown that the consumption of total and specific nuts improves blood lipid profiles by multiple mechanisms. Future directions in this field should include more lipoprotein particle, apolipoprotein B, and HDL function studies. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the high-density lipoprotein (HDL) capacity to efflux cellular cholesterol from lipid-loaded macrophages to find a reliable and low-cost biomarker with the purpose of better evaluating the risk of premature cardiovascular (CV) events in FH patients. This case-controlled study comprised 16 homozygous (HOFH) and 18 heterozygous (HEFH) FH patients, as well as 20 healthy subjects recruited as controls. Two main subfractions of HDL (HDL2 (d = 1.063–1.125 g/mL) and HDL3 (d = 1.125–1.210 g/mL)) were isolated from the patients' serum samples using sequential ultracentrifugation. After compositional characterization, the capacity of HDL to efflux cholesterol (CEC%) from lipid-laden macrophages was measured. The HDL2 and HDL3 subfractions showed some differences in lipid and protein composition between the studied groups. In addition, both HDL subfractions (p < 0.001) revealed significantly reduced CEC% in HOFH patients (HDL2: 2.5 ± 0.1 and HDL3: 3.2 ± 0.2) in comparison with the HEFH (HDL2: 3.2 ± 0.1% and HDL3: 4.1 ± 0.2%) and healthy (HDL2: 3.3 ± 0.2% and HDL3: 4.5 ± 0.3%) subjects. Additionally, multinomial logistic regression results indicated that the CEC% of both HDL2 (OR: 0.091; 95% CI: 0.018–0.452, p < 0.01) and HDL3 (OR: 0.118; 95% CI: 0.035–0.399, p < 0.01) subfractions are strongly and inversely associated with the homozygous form of FH. A decreased capacity of HDL particles to efflux cholesterol from macrophages might identify homozygous FH patients who are at elevated risk for premature CVDs. Prospective studies with a large sample size are warranted to evaluate this hypothesis. [ABSTRACT FROM AUTHOR]

The methoxylated flavone xanthomicrol represents an uncommon active phenolic compound identified in herbs/plants with a long application in traditional medicine. It was isolated from a sample of Achillea erba-rotta subsp. moschata (musk yar-row) flowering tops. Xanthomicrol promising biological properties include antioxidant, anti-inflammatory, antimicrobial, and anticancer activities. This study mainly focused on the evaluation of the xanthomicrol impact on lipid metabolism in cancer HeLa cells, together with the investigation of the treatment-induced changes in cell growth, morphology, and apoptosis. At the dose range of 5–100 μM, xanthomicrol (24 h of incubation) significantly reduced viability and modulated lipid profile in cancer Hela cells. It induced marked changes in the phospholipid/cholesterol ratio, significant decreases in the levels of oleic and palmitic acids, and a marked increase of stearic acid, involving an inhibitory effect on de novo lipogenesis and desaturation in cancer cells. Moreover, marked cell morphological alterations, signs of apoptosis, and cell cycle arrest at the G2/M phase were observed in cancer treated cells. The bioactivity profile of xanthomicrol was compared to that of the anticancer methoxylated flavones eupatilin and artemetin, and structure–activity relationships were underlined. [ABSTRACT FROM AUTHOR]

It is assumed that the human brain is especially susceptible to oxidative stress, based on specific traits such as a higher rate of mitochondrial free radical production, a high content in peroxidizable fatty acids, and a low antioxidant defense. However, it is also evident that human neurons, although they are post-mitotic cells, survive throughout an entire lifetime. Therefore, to reduce or avoid the impact of oxidative stress on neuron functionality and survival, they must have evolved several adaptive mechanisms to cope with the deleterious effects of oxidative stress. Several of these antioxidant features are derived from lipid adaptations. At least six lipid adaptations against oxidative challenge in the healthy human brain can be discerned. In this work, we explore the idea that neurons and, by extension, the human brain is endowed with an important arsenal of non-pro-oxidant and antioxidant measures to preserve neuronal function, refuting part of the initial premise. [ABSTRACT FROM AUTHOR]

The plasma membrane of eukaryotic cells is composed of a large number of lipid species that are laterally segregated into functional domains as well as asymmetrically distributed between the outer and inner leaflets. Additionally, the spatial distribution and organization of these lipids dramatically change in response to various cellular states, such as cell division, differentiation, and apoptosis. Division of one cell into two daughter cells is one of the most fundamental requirements for the sustenance of growth in all living organisms. The successful completion of cytokinesis, the final stage of cell division, is critically dependent on the spatial distribution and organization of specific lipids. In this review, we discuss the properties of various lipid species associated with cytokinesis and the mechanisms involved in their polarization, including forward trafficking, endocytic recycling, local synthesis, and cortical flow models. The differences in lipid species requirements and distribution in mitotic vs. male meiotic cells will be discussed. We will concentrate on sphingolipids and phosphatidylinositols because their transbilayer organization and movement may be linked via the cytoskeleton and thus critically regulate various steps of cytokinesis. [ABSTRACT FROM AUTHOR]

Sustained-release formulations of decoquinate were evaluated for the long-term prophylaxis of malaria. In the initial experiment, mice were protected from liver-stage Plasmodium infection by intramuscular administration of a lipids-based formulation at a dose of decoquinate 200 mg/kg. The mice that were inoculated with Plasmodium berghei sporozoites 34 days after the administration of a one-time drug dose were continuously monitored for 60 days and shown to be free of Plasmodium parasites. The optimized formulation for the sustained release of decoquinate was prepared by hot melt extrusion, constructed by lipids including cholesterol and mono or diglycerides, and had a drug load of 20 to 40% and particle size of 30 to 50 μm. Decoquinate of the lipids-based formulation was slowly released in vitro at a constant rate for the duration of two months, and was examined and continuously exposed at a therapeutic level in the blood for as long as 4 to 6 months. Further evaluation showed that the lipids-based formulation at doses of decoquinate 100 to 150 mg/kg could protect mice from Plasmodium infection for a period of 120 days. It is the first time that cholesterol has been used for a controlled drug delivery system of decoquinate. The results may provide useful information, not only for preparing a formulation of long-acting decoquinate but also in general for developing a controlled drug release system. The one-time administration of pharmaceutical agents in such a slow-release system may serve patients with no concerns about compliance. [ABSTRACT FROM AUTHOR]

Background: Our aim was to systematically investigate the effect of upadacitinib, an oral JAK-1 selective inhibitor, on lipid profile and cardiovascular disease risk. Methods: PubMed, PubMed Central and ClinicalTrials.gov databases were searched for relevant randomized controlled trials (RCTs) up to 31 July 2022. We performed a qualitative synthesis of published RCTs to investigate the associations of upadacitinib with lipoprotein changes, along with a quantitative synthesis of MACE and mean lipoprotein changes where there were available data. Results: Nineteen RCTs were eligible for the present systematic review, which included 10,656 patients with a mean age of 51 years and a follow-up period of 12–52 weeks. Increases in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were noted upon upadacitinib administration (3–48 mg/day) in 15 studies, while the LDL-C:HDL-C ratio remained unchanged. The pooled analyses of three placebo-controlled RCTs (n = 2577) demonstrated that upadacitinib at 15 mg increased the LDL-C by 15.18 mg/dL (95% CI: 7.77–22.59) and HDL-C by 7.89 mg/dL (95% CI: 7.08–8.69). According to the pooled analysis of 15 placebo-controlled RCTs (n = 7695), upadacitinib had no effect on MACE (risk ratio, RR: 0.62; 95% CI: 0.24–1.60). A sub-analysis focusing on upadacitinib at 15 mg (12 studies, n = 5395) demonstrated similar results (RR: 0.67; 95% CI: 0.19–2.36). Conclusions: Treatment with upadacitinib increases both LDL-C and HDL-C levels. Nevertheless, upadacitinib had no significant effect on the cardiovascular disease risk during a ≤52-week follow-up. [ABSTRACT FROM AUTHOR]

Dyslipidaemia is a major cause of morbidity and mortality. The aims of this study are to determine the prevalence of dyslipidaemia subtypes, the proportions of lipid-lowering therapy (LLT) use, and the achievement of low-density lipoprotein cholesterol (LDL-C) treatment targets for high-risk (HR) and very high-risk (VHR) Malaysians. This cross-sectional study involves 5279 participants across 11 states in Malaysia. The data were obtained through a standardised questionnaire, anthropometric measurements, venous glucose and lipid profile. The participants with existing cardiovascular disease (CVD) or diabetes with at least one of the other major risk factors (smoking, hypertension or dyslipidaemia) were grouped into the VHR category. Other participants were risk-categorised using the Framingham General CVD Risk Score (FRS-CVD). The prevalence of elevated LDL-C, LLT use and LDL-C target were set according to respective risk categories. Pearson's chi-squared test was used to test the difference in the proportions. The mean ± standard deviation (SD) age was 41.1 ± 14.8 years, and 62.2% (3283/5279) of the group were females. Within the participant group, 51.5% were found to have elevated total cholesterol, 28.8% had low HDL-C, and 33.8% had high triglyceride. As for elevated LDL-C, 9.8% were in VHR, 8.6% in HR, 5.8% in MR and 34.9% in LR categories. Among the VHR group, 75.8% were not on LLT, and only 15.9% achieved the LDL-C target. As for the HR category, 87.7% were not on LLT, and only 16.1% achieved the LDL-C target. Dyslipidaemia is highly prevalent among Malaysians. The majority of VHR and HR participants were not on LLT and did not achieve LDL-C treatment targets. Proactive programs are warranted to combat dyslipidaemia-associated CVD events in these groups. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most malignant primary brain tumor. Despite increasing research on GBM treatment, the overall survival rate has not significantly improved over the last two decades. Although recent studies have focused on aberrant metabolism in GBM, there have been few advances in clinical application. Thus, it is important to understand the systemic metabolism to eradicate GBM. Together with the Warburg effect, lipid metabolism has emerged as necessary for GBM progression. GBM cells utilize lipid metabolism to acquire energy, membrane components, and signaling molecules for proliferation, survival, and response to the tumor microenvironment. In this review, we discuss fundamental cholesterol, fatty acid, and sphingolipid metabolism in the brain and the distinct metabolic alterations in GBM. In addition, we summarize various studies on the regulation of factors involved in lipid metabolism in GBM therapy. Focusing on the rewiring of lipid metabolism will be an alternative and effective therapeutic strategy for GBM treatment. [ABSTRACT FROM AUTHOR]