Aging is associated with significant alterations in systemic metabolism across species. We employed targeted metabolomics to investigate the effects of losartan, an angiotensin II receptor blocker, on the serum metabolome of aged mice and pre-frail older men. Losartan treatment resulted in a shift in serum metabolome aging signature to a more youthful state. This rejuvenation effect appears to be contingent on the presence of functional angiotensin II receptors, with receptor knockout mice showing no rejuvenation effect with treatment. Additionally, we observed a similar rejuvenation effect of losartan in the cardiac proteome of aged mice, with the most pronounced changes occurring in proteins involved in oxidative phosphorylation. While our study did not encompass a full lifespan analysis, in alignment with previous reports of lifespan extension in other models, we noted a statistically significant improvement in survival among geriatric mice treated with losartan. In parallel, we analyzed serum metabolomics data from pre-frail older men from a phase 2 randomized placebo-controlled trial of losartan, which indicated a dose-dependent metabolic rejuvenation effect. Correlation network analysis revealed divergent aging effects between species, with mice exhibiting broad decreases in metabolite concentrations and humans showing increases, particularly across lipid species. Principal component analysis further highlighted a global shift in metabolite levels, potentially linked to changes in lipoprotein metabolism, plasma volume, and amino acid metabolism with age. In summary, our results suggest that losartan can partially reverse age-related metabolomic changes in both male mice and humans, with distinct species-specific responses.

Lipoprotein metabolic regulation plays a vital role in human health and disease, with its abnormalities closely associated with the onset and progression of various disorders. In cases of lymphadenopathy, this study aimed to develop a linear model based on multimodal ultrasound parameters and lipoprotein metabolic regulation, predicting changes in intraluminal and perilymphatic tissue stiffness during cervical lymphadenopathy to provide clinical guidance for assessing lymph node characteristics. All patients underwent multimodal ultrasound examinations including conventional 2D ultrasound, colour Doppler ultrasound, and elastography. The linear model developed based on these factors demonstrated high predictive power, indicating that changes in lipoprotein metabolism are closely linked to the pathophysiological processes of lymph nodes. In lymphadenopathy, lipoprotein metabolic regulation affects local inflammatory responses and extracellular matrix remodelling, thereby influencing lymph node stiffness and function. Additionally, lipoprotein regulation indirectly impacts lymph node hardness by modulating angiogenesis and extracellular matrix remodelling.

Calves experience a significant decrease in dietary lipid intake with weaning. However, changes in lipoprotein metabolism during this period has not been described. Therefore, to evaluate changes in lipoprotein metabolism by weaning and age, differences in lipoprotein lipid concentrations and proportions were compared before and after weaning and between calves and adult cows. Blood samples were collected from 27 Holstein calves before (4 weeks old) and after weaning (13 weeks old). Blood samples were also collected from 10 adult cows (5 dry and 5 lactating cows). As the results, total lipid concentrations (triglycerides + total cholesterol + phospholipids) in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were higher for pre-weaning calves than those in post-weaning calves. However, there were no differences in lipid proportions contained in each fraction. Lipid concentrations were higher in adult cows than in calves for all fractions: very low-density lipoprotein (VLDL), LDL and HDL. The proportion of total cholesterol and phospholipids in the LDL fraction was higher in calves compared to adult cows and the proportion of lipids in the HDL fraction was higher in adult cows compared to calves. These results showed that weaning caused litte changes in lipid concentrations in each lipoprotein fraction, but that adult cows showed higher lipid concentration in VLDL, LDL, and HDL. In addition, more lipids were contained in HDL for adult cows than in calves.

Serum il-18 and rs187238 single nucleotide polymorphism are associated with high-density lipoprotein changes in covid-19 outpatients

Alzheimer’s disease (AD) is the most common form of dementia in the elderly and has been associated with changes in lipoprotein metabolism. We performed quantitative lipoprotein analysis in a local cohort of cognitively impaired elderly and control subjects using standardized nuclear magnetic resonance (NMR) spectroscopy. A commercially available quantitative NMR-based assay covering 112 lipoprotein main and subtype variables was used to investigate blood serum samples from a moderate cohort size of 161 persons (71 female, 90 male), including measures of quality control. Additionally, clinical metadata and cerebrospinal fluid AD biomarkers were collected and used for analysis. High-density lipoprotein (HDL) HDL-4 subfraction levels were mostly high in female individuals with mild cognitive impairment (MCI), followed by AD. Low-density lipoprotein (LDL) LDL-2 cholesterol was slightly elevated in male AD patients. HDL-2 apolipoprotein Apo-A1, HDL-2 phospholipids, and HDL-3 triglycerides were highly abundant in AD and MCI women compared to men. When considering clinical biomarkers (Aβ, tau), very low-density lipoprotein (VLDL) VLDL-1 and intermediate-density lipoprotein (IDL) triglycerides were substantially higher in AD compared to MCI. In addition, triglyceride levels correlated positively with dementia. Different lipoprotein serum patterns were identified for AD, MCI, and control subjects. Interestingly, HDL-4 and LDL-2 cholesterol parameters revealed strong gender-specific changes in the context of AD-driven dementia. As gender-based comparisons were based on smaller sub-groups with a low n-number, several statistical findings did not meet the significance threshold for multiple comparisons testing. Still, our finding suggests that serum HDL-4 parameters and various triglycerides correlate positively with AD pathology which could be a read-out of extended lipids traveling through the blood-brain barrier, supporting amyloid plaque formation processes. Thereof, we see herein a proof of concept that this quantitative NMR-based lipoprotein assay can generate important and highly interesting data for refined AD diagnosis and patient stratification, especially when larger cohorts are available.

BackgroundTamoxifen, which is one of the selective estrogen receptor modulators (SERMs), can bring out life-threatening complication, e.g. hypertriglyceridemia-induced acute pancreatitis, although it is rare. We precisely report changes in lipoprotein metabolism before and after tamoxifen discontinuation because there have been few reports of it.Case presentation47-year-old premenopausal woman with dyslipidemia, type 2 diabetes, nonalcoholic fatty liver disease and chronic kidney disease was prescribed tamoxifen as adjuvant therapy after operation of breast cancer. She experienced severe tamoxifen-induced hypertriglyceridemia several months after dosing tamoxifen. Before cessation of tamoxifen, lipoprotein fraction test revealed marked stagnation of VLDL and IDL metabolisms, resulting in severe hypertriglyceridemia (serum triglyceride level was 1881 mg/dL). Seven days after tamoxifen withdrawal, lipoprotein fraction test showed that the metabolisms of endogenous lipoproteins were changed drastically.ConclusionsFrom these results, we confirmed that tamoxifen certainly changes lipoprotein metabolism through suppression of post-heparin lipolytic activity. It is very important to evaluate the balance between benefit and risk before dosing tamoxifen and survey lipid profiles constantly during treatment to avoid life-threatening complication when prescription of tamoxifen is planned.

DMPA injectable contraceptives can cause changes in lipoprotein metabolism. Long term use of DMPA increases triglyceride levels, total cholesterol and LDL and decreases HDL levels. So, it can be concluded that DMPA can cause changes in lipid metabolism which can increase the risk of cardiovascular disease. Changes in fat metabolism occur due to the influence of the hormonal progesterone, which causes disruption of the balance of the lipid profile in the body. The purpose of this study was to determine the effect of using Depo Medroxy Progeserone Acetate injection on the lipid profile of three months injection family planning acceptors based on the duration of use.This research is an analytic observational study with a cross sectional approach, the population in this study were all DMPA family planning acceptors in the work area of ​​the Banjar Sengon Community Health Center, the sampling technique used was total sampling with a sample size of 30. Examination of the lipid profile was carried out by taking blood samples and then measuring them. lipid profile using the enzymatic colorimetric method (cholesterol oxidase method / CHOD PAP). The measurement results obtained were then analyzed using the Independent T test. The results of the T test analysis showed that the P value for cholesterol levels was 0.016 (P <0.05); The p value for triglyceride levels was 0.004 (P <0.05); The p value for HDL levels was 0.046 (P <0.05); The p value for LDL levels was 0.004 (P <0.05).From these data it can be concluded that there is a significant difference in the average levels of cholesterol, triglycerides, HDL, LDL between respondents with a duration of use <3 years and> 3 years. Respondents are expected to carry out routine lipid profile checks to detect early detection of possible abnormalities in lipid profiles that can lead to the risk of heart defects and stroke.

Injectable DMPA contraception can cause changes in lipoprotein metabolism. Changes in fat metabolism occur because of the hormonal influence of progesterone, causing disruption of the balance of lipid profiles in the body. The change in serum lipid profile (trgliseride, total cholesterol, HDL and LDL) in long-term use of DMPA is a risk factor for atherosclerosis and cardiovascular disease. The purpose of this study was to look at the description of the lipid profile at 3 months injection acceptors. The design of the study was descriptive. The population in this study was 76, the number of samples that met the inclusion and exclusion criteria in this study was 30. Examination of the lipid profile was carried out with an enzymatic colorimetric (cholesterol oxidase method / CHOD PAP). The results of lipid profile examination showed that 13.33% had high cholesterol levels, 3.33% had high triglyceride levels, 13.33% had high HDL levels, 20% had high LDL levels and 3.33% have very high LDL levels. The conclusion of this study was long term use of DMPA injection contraception could cause changes in the lipid profile, so it is recommended for acceptors who want to use contraception in the long term to use MKJP as an option so as not to affect the fat profile in the body.

Pregnancy is accompanied by significant physiological changes, which can impact the health and development of the fetus and mother. Pregnancy-induced changes in plasma lipoproteins are well documented, with modest to no impact observed on the generic measure of high density lipoprotein (HDL) cholesterol. However, the impact of pregnancy on the concentration and composition of HDL subspecies has not been examined in depth. In this prospective study, we collected plasma from 24 nonpregnant and 19 pregnant women in their second trimester. Using nuclear magnetic resonance (NMR), we quantified 11 different lipoprotein subspecies from plasma by size, including three in the HDL class. We observed an increase in the number of larger HDL particles in pregnant women, which were confirmed by tracking phospholipids across lipoproteins using high-resolution gel-filtration chromatography. Using liquid chromatography-mass spectrometry (LC-MS), we identified 87 lipid-associated proteins across size-speciated fractions. We report drastic shifts in multiple protein clusters across different HDL size fractions in pregnant females compared with nonpregnant controls that have major implications on HDL function. These findings significantly elevate our understanding of how changes in lipoprotein metabolism during pregnancy could impact the health of both the fetus and the mother.

Epidemiological studies have reported positive associations between serum perfluorooctanoic acid (PFOA) and total and non-high-density lipoprotein cholesterol (non-HDL-C) although the magnitude of effect of PFOA on cholesterol lacks consistency. The objectives of this study were to evaluate the effect of PFOA on plasma cholesterol and triglyceride metabolism at various plasma PFOA concentrations relevant to humans, and to elucidate the mechanisms using APOE*3-Leiden.CETP mice, a model with a human-like lipoprotein metabolism. APOE*3-Leiden.CETP mice were fed a Western-type diet with PFOA (10, 300, 30 000 ng/g/d) for 4–6 weeks. PFOA exposure did not alter plasma lipids in the 10 and 300 ng/g/d dietary PFOA dose groups. At 30 000 ng/g/d, PFOA decreased plasma triglycerides (TG), total cholesterol (TC), and non-HDL-C, whereas HDL-C was increased. The plasma lipid alterations could be explained by decreased very low-density lipoprotein (VLDL) production and increased VLDL clearance by the liver through increased lipoprotein lipase activity. The concomitant increase in HDL-C was mediated by decreased cholesteryl ester transfer activity and changes in gene expression of proteins involved in HDL metabolism. Hepatic gene expression and pathway analysis confirmed the changes in lipoprotein metabolism that were mediated for a major part through activation of the peroxisome proliferator-activated receptor (PPAR)α. Our data confirmed the findings from a phase 1 clinical trial in humans that demonstrated high serum or plasma PFOA levels resulted in lower cholesterol levels. The study findings do not show an increase in cholesterol at environmental or occupational levels of PFOA exposure, thereby indicating these findings are associative rather than causal.

Objective: Although Sodium glucose cotransporter 2 (SGLT2) inhibition in humans sometimes leads to increased levels of low density lipoprotein (LDL) cholesterol, this therapy is associated with marked reduction in cardiovascular disease. In this study, we aimed to determine how SGLT2 inhibition alters circulating lipoproteins. Approach and Results: We used a mouse model in which plasma lipoprotein profiles were humanized by expression of human cholesteryl ester transfer protein and human apolipoprotein B100 to determine how SGLT2 inhibition alters lipoprotein profiles. The mice were fed a high fat diet and then were made partially insulin deficient using streptozotocin. SGLT2 was inhibited using a specific anti-sense oligonucleotide or canagliflozin, a clinically available oral SGLT2 inhibitor. Inhibition of SGLT2 increased circulating levels of LDL cholesterol and reduced plasma triglyceride levels. SGLT2 inhibition was associated with increased lipoprotein lipase activity in the post heparin plasma and decreased postprandial lipemia. The changes in lipoprotein metabolism were more significant in mice treated with SGLT2 ASO compared to canagliflozin. Conclusions: Our studies in mice recapitulate many of the changes in circulating lipids found with SGLT2 inhibition therapy in humans and suggest that the increased LDL cholesterol found with this therapy is due to greater lipolysis of triglyceride-rich lipoproteins. This change in lipoprotein physiology is likely, in part, to explain the reduced cardiovascular disease found with SGLT2 inhibition.

Zur Prävention und Therapie metabolisch-vaskulärer Erkrankungen wurde jahrelang ein fett- und kalorienarmes Ernährungsmuster mit konkreten Vorgaben zu isolierten Nährstoffen propagiert wie bspw. dem Cholesterin oder den gesättigten Fettsäuren. Dieser Beitrag soll zeigen, dass lebensmittel- bzw. essmusterbasierte Empfehlungen ohne spezifische Angaben zu Nährstoffrelationen oder Kalorien sinnvoller sind.

Cardiovascular disease is the number one cause of death globally. Poor diet constitutes a key factor in the initiation and progression of cardiovascular disease and has become the leading risk factor for disability and death worldwide. Therefore, addressing suboptimal nutrition is of key prognostic relevance in primary and secondary prevention of metabolic vascular syndrome.Metabolic vascular syndrome is a multidimensional network of acquired cardiometabolic risk factors closely related to insulin resistance (IR) and concomitant hyperinsulinemia. IR, being the underlying cause of metabolic vascular syndrome and certain types of cancer, should attract the attention of every clinician. As changes in lipoprotein metabolism are one of the earliest indicators of metabolic dysfunction, a relevant biomarker for identifying individuals with IR is the TAG/HDL-C ratio.IR - and concomitant metabolic vascular risk - can be effectively treated by lifestyle intervention. If IR is present, dietary carbohydrate restriction has consistently been shown to be superior to dietary fat restriction in reversing metabolic dysfunction. The beneficial effects of carbohydrate restricted diets on metabolic vascular risk are independent of BMI - diet quality therefore confers patient benefit beyond weight reduction.The effect of single nutrients on isolated lipid surrogate markers such as LDL-C does not capture their global effect on metabolic vascular risk.Targeting IR with a low glycemic load, real food diet will reduce overall energy density and will improve all risk factors of metabolic vascular syndrome. In particular, replacing refined carbohydrates with healthy fats in the context of a Mediterranean style-, low carbohydrate and calorie-unrestricted dietary pattern has been shown to significantly reduce burden of metabolic vascular disease.

Breaking up sedentary time, physical activity and lipoprotein metabolism.

Low normal thyroid function as a determinant of increased large very low density lipoprotein particles

Subclinical hypothyroidism may adversely affect the development of cardiovascular disease (CVD). Less is known about the role of low-normal thyroid function, that is higher thyroid-stimulating hormone and/or lower free thyroxine levels within the euthyroid reference range, in the development of cardio-metabolic disorders. This review is focused on the relationship of low-normal thyroid function with CVD, plasma lipids and lipoprotein function, as well as with metabolic syndrome (MetS), chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD). This narrative review, which includes results from previously published systematic reviews and meta-analyses, is based on clinical and basic research papers, obtained via MEDLINE and PubMed up to November 2014. Low-normal thyroid function could adversely affect the development of (subclinical) atherosclerotic manifestations. It is likely that low-normal thyroid function relates to modest increases in plasma total cholesterol, LDL cholesterol and triglycerides, and may convey pro-atherogenic changes in lipoprotein metabolism and in HDL function. Most available data support the concept that low-normal thyroid function is associated with MetS, insulin resistance and CKD, but not with high blood pressure. Inconsistent effects of low-normal thyroid function on NAFLD have been reported so far. Observational studies suggest that low-normal thyroid function may be implicated in the pathogenesis of CVD. Low-normal thyroid function could also play a role in the development of MetS, insulin resistance and CKD, but the relationship with NAFLD is uncertain. The extent to which low-normal thyroid function prospectively predicts cardio-metabolic disorders has been insufficiently established so far.

131-POS

Alterations in lipid pattern and increased risk for obstetric/neonatal complications have been observed in patients with polycystic ovary syndrome (PCOS). Pregnancy leads to physiologic changes in lipoprotein metabolism, and alterations in lipid profile have been related with adverse pregnancy outcomes. Based on these considerations, the aim of the present prospective controlled clinical study was to test the hypothesis that the changes in the lipid profile in patients with PCOS during pregnancy are characteristic and potentially related to the increased risk of obstetric/neonatal complications. One hundred and fifty nonobese PCOS women and 150 age- and body mass index (BMI)-matched healthy controls were enrolled. Serum lipids, glucose, insulin, and androgens levels were serially assayed in all subjects before and throughout pregnancy. Serum low-density lipoprotein (LDL) and triglyceride (TG) concentrations were significantly (P<0.05) higher in PCOS group than in healthy controls at each assessment. Throughout pregnancy, serum LDL and TG levels increased significantly (P<0.05) in both groups, although the change from pre-pregnancy values was significantly (P<0.05) greater in PCOS patients than in healthy controls. A significant (P<0.05) relationship was observed between serum LDL and TG changes and changes in both insulin sensitivity indexes and androgen levels in PCOS patients alone. After adjusting for maternal age, pre-pregnancy BMI and lipid levels, body weight gain, and insulin-resistance markers, serum TG concentrations during pregnancy were directly and independently associated with obstetric complications in both groups, whereas serum LDL levels only in PCOS patients. We can conclude that nonobese PCOS patients had specific changes in lipid profile during pregnancy, and that the lipid pattern typical of PCOS may account for the more frequent adverse pregnancy outcomes. PCOS-related hormonal and metabolic features, such as insulin resistance and high androgen levels, may mediate this phenomenon.

Editorial for ‘Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis’

Metabolic profiling in combination with pathway-based analyses and computational modelling are becoming increasingly important in clinical and preclinical research. Modelling multi-factorial, progressive diseases requires the integration of molecular data at the metabolome, proteome and transcriptome levels. Also the dynamic interaction of organs and tissues needs to be considered. The processes involved cover time scales that are several orders of magnitude different. We report applications of a computational approach to bridge the scales and different levels of biological detail. Analysis of dynamic adaptations in parameter trajectories (ADAPTs) aims to investigate phenotype transitions during disease development and after a therapeutic intervention. ADAPT is based on a time-dependent evolution of model parameters to describe the dynamics of metabolic adaptations. The progression of metabolic adaptations is predicted by identifying necessary dynamic changes in the model parameters to describe the transition between experimental data obtained during different stages. To get a better understanding of the concept, the ADAPT approach is illustrated in a theoretical study. Its application in research on progressive changes in lipoprotein metabolism is also discussed.