Cholesteryl Ester Research Articles

Repetitive transcranial magnetic stimulation elicits weight loss and improved insulin sensitivity in type 2 diabetic rats.

Type 2 diabetes (T2D) accounts for the majority of diabetes incidences and remains a widespread global chronic disorder. Apart from early lifestyle changes, intervention options for T2D are mainly pharmaceutical. Repetitive transcranial magnetic stimulation (rTMS) has been approved by the FDA as a therapeutic intervention option for major depressive disorders, with further studies also indicating its role in energy metabolism and appetite. Considering its safe and non-invasive properties, we evaluated the effects of rTMS on systemic metabolism using T2D rats. We observed that rTMS improved glucose tolerance and insulin sensitivity in T2D rats after a 10-day exposure. Improved systemic insulin sensitivity was maintained after a 21-day treatment period, accompanied by modest yet significant weight loss. Circulating serum lipid levels, including those of cholesteryl ester, tryglyceride and ceramides, were also reduced following rTMS application. RNA-seq analyses further revealed a changed expression profile of hepatic genes that are related to sterol production and fatty acid metabolism. Altered expression of hypothalamic genes that are related to appetite regulation, neural activity and ether lipid metabolism were also implicated. In summary, our data report a positive impact of rTMS on systemic insulin sensitivity and weight management of T2D rats. The underlying mechanisms via which rTMS regulates systemic metabolic parameters partially involve lipid utilization in the periphery as well as central regulation of energy intake and lipid metabolism.

Metabolomics Approach to Identify Biomarkers of Acute and Subacute Mastitis in Milk Samples: A Pilot Case-Control Study.

Background and aims: Mastitis is one of the main complications during breastfeeding and contributes to the cessation of breastfeeding. However, the etiopathogenesis and diagnosis of mastitis are complex and not yet well defined. We aimed to identify metabolic and lipidic changes in human milk during acute and subacute mastitis in order to detect potential biomarkers of mastitis. Methods: We conducted a pilot case-control study including 14 breastfeeding women with acute mastitis, 32 with subacute mastitis symptoms, and 19 without any mastitis symptoms (control). Milk samples were collected and analyzed by proton nuclear magnetic resonance (H-NMR) for metabolomics analysis. To assess the association between the significant metabolites and lipids and the development of acute and subacute mastitis, multi-adjusted logistic regression models were developed. Results: The NMR-based metabolomics approach was able to identify and quantify a total of 40 metabolites in breast milk samples. After adjusting for confounding variables, acute mastitis was significantly associated with acetate (OR 3.9 IC 1.4-10.8), total cholesterol (OR 14 CI 3.2-62), esterified cholesterol (OR 3.3 CI 1.9-5.8), and sphingomyelin (OR 2.6 CI 1.2-5.8). The other metabolites presented weak association (OR < 2.5). Subacute mastitis was significantly associated with glutamine, lysophosphatidylcholine, phosphatidylcholine, plasmalogen, and total polyunsaturated fatty acids, but only cholesterol showed a strong association (OR > 2.5) with an OR of 2.6 (IC 1.1-6.6). Conclusions: Metabolic alteration in breast milk occurs during a process of both acute and subacute mastitis. Acetate, esterified cholesterol, lysophostidylcholine, and polyunsaturated fatty acids increased in both acute and subacute mastitis. However, according to the multi-adjusted regression logistic models, the candidate biomarkers for acute and subacute mastitis are cholesterol, lysophosphatidylcoholine, phosphatidylcholine, plasmalogen, and polyunsaturated fatty acids.

Cholesteryl Phenolipids as Potential Biomembrane Antioxidants

The lipophilization of polyphenols (phenolipids) may increase their affinity for membranes, leading to better antioxidant protection. Cholesteryl esters of caffeic, dihydrocaffeic, homoprotocatechuic and protocatechuic acids were synthetized in a one-step procedure with good to excellent yields of ~50–95%. After evaluation of their radical scavenging capacity by the DPPH method and establishing the anodic peak potential by cyclic voltammetry, their antioxidant capacity against AAPH-induced oxidative stress in soybean PC liposomes was determined. Their interaction with the liposomal membrane was studied with the aid of three fluorescence probes located at different depths in the membrane. The cholesteryl esters showed a better or similar radical scavenging capacity to that of α-tocopherol and a lower anodic peak potential than the corresponding parental phenolic acids. Cholesteryl esters were able to protect liposomes to a similar or greater extent than α-tocopherol. However, despite their antiradical capacity and being able to penetrate and orientate in the membrane in a parallel position to phospholipids, the antioxidant efficiency of cholesteryl esters was deeply dependent on the phenolipid polyphenolic moiety structure. When incorporated during liposome preparation, cholesteryl protocatechuate and caffeate showed more than double the activity of α-tocopherol. Thus, cholesteryl phenolipids may protect biomembranes against oxidative stress to a greater extent than α-tocopherol.

Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis

BackgroundElevated concentrations of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia.MethodsDrug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (μg/mL) on plasma lipids, cardiovascular disease outcomes, autopsy confirmed Lewy body dementia (LBD), as well as Parkinson’s dementia.ResultsMR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on coronary heart disease (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm, any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96). Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson’s dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4 + participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81 × 10− 4.ConclusionsThese results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect expected in APOE-ε4 carriers.

Longitudinal lipidomic profiles of left ventricular mass and hypertrophy in American Indians.

Left ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well-studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking. Using LC-MS, we repeatedly measured 1,542 lipids from 1,755 unique American Indians attending two exams (mean~5-year apart). Cross-sectional associations of individual lipid species with LVM index (LVMI) were examined by generalized estimating equation (GEE), followed by replication in an independent bi-racial cohort (65% white, 35% black). Baseline plasma lipids associated with LVH risk beyond traditional risk factors were identified by Cox frailty model in American Indians. Longitudinal associations between changes in lipids and changes in LVMI were examined by GEE, adjusting for baseline lipids, baseline LVMI, and covariates. Multiple lipid species (e.g., glycerophospholipids, sphingomyelins, acylcarnitines) were significantly associated with LVMI or the risk of LVH in American Indians. Some lipids were confirmed in black and white individuals. Moreover, some LVH-related lipids were inversely associated with risk of coronary heart disease (CHD). Longitudinal changes in several lipid species (e.g., glycerophospholipids, sphingomyelins, cholesterol esters) were significantly associated with changes in LVMI. These findings provide insights into the role of lipid metabolism in LV remodeling and the risk of LVH or CHD.

Inhibiting the Cholesterol Storage Enzyme ACAT1/SOAT1 in Myelin Debris-Treated Microglial Cell Lines Activates the Gene Expression of Cholesterol Efflux Transporter ABCA1

Aging is the major risk factor for Alzheimer’s disease (AD). In the aged brain, myelin debris accumulates and is cleared by microglia. Phagocytosed myelin debris increases neutral lipid droplet content in microglia. Neutral lipids include cholesteryl esters (CE) and triacylglycerol (TAG). To examine the effects of myelin debris on neutral lipid content in microglia, we added myelin debris to human HMC3 and mouse N9 cells. The results obtained when using 3H-oleate as a precursor in intact cells reveal that myelin debris significantly increases the biosynthesis of CE but not TAG. Mass analyses have shown that myelin debris increases both CE and TAG. The increase in CE biosynthesis was abolished using inhibitors of the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1). ACAT1 inhibitors are promising drug candidates for AD treatment. In myelin debris-loaded microglia, treatment with two different ACAT1 inhibitors, K604 and F12511, increased the mRNA and protein content of ATP-binding cassette subfamily A1 (ABCA1), a protein that is located at the plasma membrane and which controls cellular cholesterol disposal. The effect of the ACAT1 inhibitor on ABCA1 was abolished by preincubating cells with the liver X receptor (LXR) antagonist GSK2033. We conclude that ACAT1 inhibitors prevent the accumulation of cholesterol and CE in myelin debris-treated microglia by activating ABCA1 gene expression via the LXR pathway.

Serum lipidome reveals lipid metabolic dysregulation in severe fever with thrombocytopenia syndrome

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is a rapidly progressing infectious disease with a high fatality rate caused by a novel bunyavirus (SFTSV). The role of lipids in viral infections is well-documented; however, the specific alterations in lipid metabolism during SFTSV infection remain elusive. This study aims to elucidate the lipid metabolic dysregulations in the early stages of SFTS patients.MethodsThis study prospectively collected peripheral blood sera from 11 critical SFTS patients, 37 mild SFTS patients, and 23 healthy controls during the early stages of infection for lipidomics analysis. A systematic bioinformatics analysis was conducted from three aspects integrating lipid differential expressions, lipid differential correlations, and lipid-clinical indices correlations to reveal the serum lipid metabolic dysregulation in SFTSV-infected individuals.ResultsOur findings reveal significant lipid metabolic dysregulation in SFTS patients. Specifically, compared to healthy controls, SFTS patients exhibited three distinct modes of lipid differential expression: increased levels of lipids including phosphatidylserine (PS), hexosylceramide (HexCer), and triglycerides (TG); decreased levels of lipids including lysophosphatidylcholine (LPC), acylcarnitine (AcCa), and cholesterol esters (ChE); and lipids showing “dual changes” including phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Finally, based on lipid metabolic pathways and literature analysis, we systematically elucidated the potential mechanisms underlying lipid metabolic dysregulation in the early stage of SFTSV infection.ConclusionsOur study presents the first global serum lipidome profile and reveals the lipid metabolic dysregulation patterns in the early stage of SFTSV infection. These findings provide a new basis for the diagnosis, treatment, and further investigation of the disease.

Unveiling Lipidomic Alterations in Metabolic Syndrome: A Study of Plasma, Liver, and Adipose Tissues in a Dietary-Induced Rat Model

Metabolic syndrome (MetS) is a complex condition characterized by fat accumulation, dyslipidemia, impaired glucose control and hypertension. In this study, rats were fed a high-fat high-fructose (HFF) diet in order to develop MetS. After ten weeks, the dietary-induced MetS was confirmed by higher body fat percentage, lower HDL-cholesterol and increased blood pressure in the HFF-fed rats compared to the normal-fed control animals. However, the effect of MetS development on the lipidomic signature of the dietary-challenged rats remains to be investigated. To reveal the contribution of specific lipids to the development of MetS, the lipid profiling of rat tissues particularly susceptible to MetS was performed using untargeted UHPLC-QTOF-MS/MS lipidomic analysis. A total of 37 lipid species (mainly phospholipids, triglycerides, sphingolipids, cholesterol esters, and diglycerides) in plasma, 43 lipid species in liver, and 11 lipid species in adipose tissue were identified as dysregulated between the control and MetS groups. Changes in the lipid signature of selected tissues additionally revealed systemic changes in the dietary-induced rat model of MetS.

Limited Alleviation of Lysosomal Acid Lipase Deficiency by Deletion of Matrix Metalloproteinase 12.

Lysosomal acid lipase (LAL) is the only known enzyme that degrades cholesteryl esters and triglycerides at an acidic pH. In LAL deficiency (LAL-D), dysregulated expression of matrix metalloproteinase 12 (MMP-12) has been described. The overexpression of MMP-12 in myeloid lineage cells causes an immune cell dysfunction resembling that of Lal knockout (Lal KO) mice. Both models develop progressive lymphocyte dysfunction and expansion of myeloid-derived suppressor (CD11b+ Gr-1+) cells. To study whether MMP-12 might be a detrimental contributor to the pathology of LAL-D, we have generated Lal/Mmp12 double knockout (DKO) mice. The phenotype of Lal/Mmp12 DKO mice closely resembled that of Lal KO mice, while the weight and morphology of the thymus were improved in Lal/Mmp12 DKO mice. Cytological examination of blood smears showed a mildly reversed lymphoid-to-myeloid shift in DKO mice. Despite significant decreases in CD11b+ Ly6G+ cells in the peripheral blood, bone marrow, and spleen of Lal/Mmp12 DKO mice, the hematopoietic bone marrow progenitor compartment and markers for neutrophil chemotaxis were unchanged. Since the overall severity of LAL-D remains unaffected by the deletion of Mmp12, we conclude that MMP-12 does not represent a viable target for treating the inflammatory pathology in LAL-D.

Mobile Phase Contaminants Affect Neutral Lipid Analysis in LC-MS-Based Lipidomics Studies.

Lipidomics is a well-established field, enabled by modern liquid chromatography mass spectrometry (LC-MS) technology, rapidly generating large amounts of data. Lipid extracts derived from biological samples are complex, and most spectral features in LC-MS lipidomics data sets remain unidentified. In-depth analyses of commercial triacylglycerol, diacylglycerol, and cholesterol ester standards revealed the expected ammoniated and sodiated ions as well as five additional unidentified higher mass peaks with relatively high intensities. The identities and origin of these unknown peaks were investigated by modifying the chromatographic mobile-phase components and LC-MS source parameters. Tandem MS (MS/MS) of each unknown adduct peak yielded no lipid structural information, producing only an intense ion of the adducted species. The unknown adducts were identified as low-mass contaminants originating from methanol and isopropanol in the mobile phase. Each contaminant was determined to be an alkylated amine species using their monoisotopic masses to calculate molecular formulas. Analysis of bovine liver extract identified 33 neutral lipids with an additional 73 alkyl amine adducts. Analysis of LC-MS-grade methanol and isopropanol from different vendors revealed substantial alkylated amine contamination in one out of three different brands that were tested. Substituting solvents for ones with lower levels of alkyl amine contamination increased lipid annotations by 36.5% or 27.4%, depending on the vendor, and resulted in >2.5-fold increases in peak area for neutral lipid species without affecting polar lipid analysis. These findings demonstrate the importance of solvent selection and disclosure for lipidomics protocols and highlight some of the major challenges when comparing data between experiments.

6826 Mevalonate Treatment Worsened Hypocholesterolemia During Prolonged Sepsis Without Affecting Adrenal And Muscle Function

Abstract Disclosure: L. De Bruyn: None. S. Derde: None. F. Van Beek: None. S. Vander Perre: None. I. Derese: None. L. Pauwels: None. G. Van den Berghe: None. L. Langouche: None. Introduction: Sepsis is hallmarked by an immediate and sustained reduction in total-, HDL- and LDL-cholesterol (-C), associated with illness severity and a potential contributor to the development of adrenal failure and muscle weakness. The underlying mechanisms that might be involved in sepsis-induced hypocholesterolemia are multifactorial and partly understood. We hypothesized that treatment with the cholesterol precursor mevalonate might improve cholesterol availability, thereby improving adrenal gland and skeletal muscle function. Our hypothesis was tested in a validated and clinically relevant mouse model of prolonged sepsis. Methods: In a catheterized mouse model of cecal ligation and puncture-induced, fluid resuscitated and antibiotics treated polymicrobial abdominal sepsis (5 d), septic mice received continuous infusion with either mevalonate (78 mg/d) or placebo solution, whereas healthy mice served as controls (N=50). Plasma total-C (HDL- + LDL-C), CORT and total bile acids were measured, in addition to ex vivo muscle force and adrenocortical cholesterol ester content. Gene expression markers of inflammation (Tnf-α, Il-6) were measured in the adrenal gland, as well as hepatic mRNA expression of cholesterol synthesis enzymes (Hmgcs1, Hmgcr, Fdft1). Metabolites of the mevalonate pathway (mevalonic acid, squalene, lanosterol, desmosterol and (7-dehydro) cholesterol) were quantified in the liver with LC-MS. Results: The sepsis-induced reduction in plasma total-C was further decreased in mevalonate-treated septic mice (26±3 mg/dL) as compared with placebo (53±3 mg/dL) and healthy controls (108±3 mg/dL) (p&amp;lt;0.0001). Metabolites of the mevalonate pathway were all increased in the liver after mevalonate treatment (p&amp;lt;0.01), whereas hepatic cholesterol content was decreased as compared with placebo (p&amp;lt;0.05). Also, gene expression markers of cholesterol synthesis enzymes were further decreased in the liver of mevalonate-treated septic mice as compared with placebo (p&amp;lt;0.05). In the context of the unexpected further reduction in plasma total-C, no additional effect on plasma CORT, total bile acids, and sepsis-induced loss of muscle force and depletion in adrenocortical cholesterol ester content was observed. In addition, the sepsis-induced rise in markers of adrenal inflammation (Tnf-α, Il-6) was not further affected by mevalonate treatment. Conclusion: Mevalonate treatment further reduced the sepsis-induced hypocholesterolemia in prolonged septic mice, potentially due to increased feedback inhibition on hepatic cholesterol biosynthesis, but without further affecting adrenal and muscle function. Other therapies such as substitution with bovine serum HDL-C are currently investigated to improve altered cholesterol availability during sepsis. Presentation: 6/2/2024

Age-dependent changes in visceral adiposity are associated with decreased plasma levels of DHEA-S in sigma-1 receptor knockout male mice

The sigma-1 receptor (S1R) is involved in intracellular lipid synthesis and transport. Recent studies have shown that its genetic inactivation impairs adipogenic differentiation in vitro. This study investigated the role of S1R in adipose tissue physiology and metabolic health using adult and old WT and S1R KO mice.Visceral fat mass was increased in adult, but not old S1R-KO male mice compared to that of WT mice, despite having similar body weights, food intake, and energy expenditure. The average adipocyte size was 64 % larger in adult KO mice than in adult WT mice. Adult S1R-KO mice showed reduced plasma dehydroepiandrosterone sulfate (DHEA-S) and elevated fasting plasma leptin concentrations. Lipidomic analysis revealed alterations in plasma metabolite concentrations, particularly reduced levels of sphingomyelins, ceramides, phosphatidylcholines, lysophosphatidylcholines, and cholesteryl esters in adult mice. Decreased expression of Pparγ, Adipoq, and Atgl was detected in visceral white adipose tissue (vWAT) isolated from adult KO mice. Additionally, Fabp4 and Adipoq expression levels were significantly lower in KO adipose-derived stromal cells than in WT adipose-derived stromal cells. A fivefold increase in the mitochondrial fatty acid oxidation rate and a 43 % increase in electron transfer coupling capacity were detected in adult S1R-KO vWAT.In summary, our investigation revealed an age-dependent association between increased visceral adiposity and decreased plasma levels of DHEA-S in S1R-deficient male mice. These findings underscore the potential role of S1R in regulating metabolic processes in adipose tissue and suggest that DHEA-S is a potential mediator of adiposity changes in the absence of S1R.

Effects of the organochlorine pesticide metabolite p,p’-DDE on the gastrointestinal lipidome in fish: A novel toxicity pathway for a legacy pollutant

Though phased out from use in the United States, environmental contamination by organochlorine pesticides (OCPs) remains a widespread issue, especially around intensive agricultural regions. OCPs, such as dichlorodiphenyltrichloroethane (DDT) and its primary metabolite, dichlorodiphenyldichloroethylene (DDE), have been detected in soils, sediments, surface waters, and biota decades after their discontinued use. As OCPs are persistent and can bioaccumulate in fats, these compounds can transfer and magnify across food webs. Freshwater predatory fish and birds can accumulate high OCP concentrations, leading to a myriad of deleterious impacts on organismal health. Studies have found evidence of reproductive disruption in predatory fish, such as the largemouth bass (LMB; Micropterus salmoides), associated with DDT and DDE exposure. DDE can act through estrogenic pathways and induce the expression of estrogenic signals in male animals; however, the molecular mechanism of disruption is unclear. Recently, metabolomics research has revealed corollary relationships between lipid signals and organic pollutant toxicity. Here, a two-month feeding experiment on LMB was conducted to assess the interactions of DDE (as p,p'-DDE) in food with gut and liver lipid signaling. Targeted lipidomic analysis revealed global alterations in the abundance of tissue lipids, especially cholesteryl esters and phospholipids, in LMB exposed to low levels of p,p'-DDE. Results from these studies indicate that p,p'-DDE may act through disruption of normal lipid homeostasis to cause toxicity in freshwater fish.

Integrating lipidomics and metabolomics to reveal biomarkers of fat deposition in chicken meat

Local chicken breeds in China are highly regarded for their superior meat flavor. This study utilized lipidomics and non-targeted metabolomics to identify biomarkers influencing intramuscular fat (IMF) deposition in the breast muscle of 42- and 180-day-old Jingyuan chickens. Results revealed that IMF content was higher in the breast muscle of 180-day-old Jingyuan chickens compared to 42-day-old chickens (P < 0.01). We identified 248 differentially expressed lipids (DELs) and 1042 differentially expressed metabolites (DEMs). The breast muscle of 180-day-old chickens contained higher levels of TG, fatty acid (FA) and cholesteryl ester (CE), with C16:1 and C18:1 being particularly abundant. Integration of non-targeted metabolomic analyses emphasized glycerolipid metabolism and vitamin digestion and absorption as the main pathways distinguishing between 42- and 180-day-old chickens. Additionally, the differential metabolites LysoPS 18:1, LysoPC 20:3, LysoPC 18:2, LysoPI 20:3, and Pantothenic acid contributed to enhanced meat flavor in Jingyuan chickens.

Cardiometabolic effects of sacubitril/valsartan in a rat model of heart failure with preserved ejection fraction

The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF

The influence of feed additive “Activo” on the content of total lipids and their classes profile in liver and skeletal muscles of pigs

With an increase in meat consumption the requirements for its quality also rise. As pork is the second most popular meat in the world, producers of this product are trying to improve its quality. The purpose of our research was to determine the effect of the feed additive “Activo”, containing essential oils of cinnamon, rosemary and oregano, and chili pepper extract, on the total lipids content and their individual class profile in liver and skeletal muscles of pigs. The study was conducted on pigs of the large white breed, weighing 70 kg, divided on two groups, according to the piglets-analogues principle, which then were divided into control and experimental groups. Pigs of both groups received standard feed (SF) intended for this age group. Pigs of the experimental group received the feed additive “Activo” in an amount of 0.1 kg/t of feed in addition to SF. The duration period of experiment was 40 days. Samples of liver, longissimus dorsi, and latissimus dorsi muscle tissues were used as material for the study. The total lipid content was determined using gravimetric method, and individual lipid profile using thin-layer chromatography on silica gel plates. The study has shown that the total lipid content in the liver, long and broad back muscles of pigs of the experimental group was 1.66 and 1.95 (P≤0.001) and 1.26 (P≤0.05) times higher, respectively, than in animals of the control group. The relative cholesterol esters content in the liver lipids of the experimental group pigs was 1.9 (P≤0.001) times higher than in the control group. Instead, in the latissimus dorsi muscle, a lower content of triacylglycerols and a higher content of unesterified fatty acids (P≤0.05), esterified cholesterol (P≤0.05), and especially phospholipids (P≤0.001) were admitted. It was determined significant decrease of unesterified cholesterol content in the latissimus dorsi muscle (P≤0.001) and increase of phospholipids content (P≤0.001) under the effect of the researched feed additive.

Exploring the Influence of Cheese Consumption on Blood Metabolites: Implications for Disease Pathogenesis, with a Focus on Essential Hypertension

This study examines the causal effects of cheese consumption on blood metabolites and essential hypertension using Mendelian Randomization (MR). GWAS data from the Open GWAS project and FinnGen Biobank were analyzed, focusing on cheese intake, 249 metabolic traits, and hypertension. Instrumental variables were selected based on strict criteria, and causal relationships were assessed using IVW, weighted-median, and MR-Egger methods. Cheese consumption significantly influenced 118 metabolic traits, including amino acids, cholesterol esters, and triglycerides. Notably, it was linked to a reduction in hypertension risk (OR = 0.652, P < 0.0001). Mediation analysis identified 50 metabolic traits as intermediaries, accounting for 0.88% to 8.25% of the total effect. These findings suggest that moderate cheese intake may benefit cardiovascular health by lowering hypertension risk, emphasizing the importance of cheese type and dietary context in health recommendations.

Synthesis, Molecular Modeling and Biological Evaluation of Novel Trifluoromethyl Benzamides as Promising CETP Inhibitors.

Hyperlipidemia is considered a major risk factor for the progress of atherosclerosis. Cholesteryl ester transfer protein (CETP) facilitates the relocation of cholesterol esters from HDL to LDL. CETP inhibition produces higher HDL and lower LDL levels. Synthesis of nine benzylamino benzamides 8a-8f and 9a-9c was performed. In vitro biological study displayed potential CETP inhibitory activity, where compound 9c had the best activity with an IC50 of 1.03 μM. Induced-fit docking demonstrated that 8a-8f and 9a-9c accommodated the CETP active site and hydrophobic interaction predominated ligand/ CETP complex formation. Pharmacophore mapping showed that this scaffold endorsed CETP inhibitors features and consequently elaborated the high CETP binding affinity.

ACAT1/SOAT1 maintains adipogenic ability in preadipocytes by regulating cholesterol homeostasis

Maintaining cholesterol homeostasis is critical for preserving adipocyte function during the progression of obesity. Despite this, the regulatory role of cholesterol esterification in governing adipocyte expandability has been understudied. Acyl-coenzyme A (CoA):cholesterol acyltransferase / Sterol O-acyltransferase 1 (ACAT1/SOAT1) is the dominant enzyme to synthesize cholesteryl ester in most tissues. Our previous study demonstrated that knockdown of either ACAT1 or ACAT2 impaired adipogenesis. However, the underlying mechanism of how ACAT1 mediates adipogenesis remains unclear. Here, we reported that ACAT1 is the dominant isoform in white adipose tissue of both humans and mice and knocking out ACAT1 reduced fat mass in mice. Furthermore, ACAT1-deficiency inhibited the early stage of adipogenesis via attenuating PPARγ pathway. Mechanistically, ACAT1 deficiency inhibited SREBP2-mediated cholesterol uptake and thus reduced intracellular and plasma membrane cholesterol level during adipogenesis. While replenishing cholesterol could rescue adipogenic master gene – Pparγ’s transcription in ACAT1 deficient cells during adipogenesis. Finally, overexpression of catalytically functional ACAT1, not the catalytic-dead ACAT1, rescued cholesterol level and efficiently rescued the transcription of PPARγ, as well as the adipogenesis in ACAT1-deficient preadipocytes. In summary, our study revealed the indispensable role of ACAT1 in adipogenesis via regulating intracellular cholesterol homeostasis.

7524 Cholesterol ester storage disease

7524 Cholesterol ester storage disease