Elevated Cholesterol Research Articles

Osteocytes/Osteoblasts Produce SAA3 to Regulate Hepatic Metabolism of Cholesterol.

Hypercholesterolaemia is a systemic metabolic disease, but the role of organs other than liver in cholesterol metabolism is unappreciated. The phenotypic characterization of the Tsc1Dmp1 mice reveal that genetic depletion of tuberous sclerosis complex 1 (TSC1) in osteocytes/osteoblasts (Dmp1-Cre) triggers progressive increase in serum cholesterol level. The resulting cholesterol metabolic dysregulation is shown to be associated with upregulation and elevation of serum amyloid A3 (SAA3), a lipid metabolism related factor, in the bone and serum respectively. SAA3, elicited from the bone, bound to toll-like receptor 4 (TLR4) on hepatocytes to phosphorylate c-Jun, and caused impeded conversion of cholesterol to bile acids via suppression on cholesterol 7 α-hydroxylase (Cyp7a1) expression. Ablation of Saa3 in Tsc1Dmp1 mice prevented the CYP7A1 reduction in liver and cholesterol elevation in serum. These results expand the understanding of bone function and hepatic regulation of cholesterol metabolism and uncover a potential therapeutic use of pharmacological modulation of SAA3 in hypercholesterolaemia.

Low Dietary Betaine Intake Is Associated with Increased Blood Cholesterol in Mexican Subjects

Background: Betaine, an osmolyte derivative of the metabolite choline and the amino acid glycine, acts as a methyl donor in the conversion of homocysteine to methionine and is involved in the maintenance of adequate lipid metabolism. There is growing evidence for the role of betaine in the development of various lipid-related diseases, including dyslipidemia and cardiovascular risk. This study aimed to analyze associations between betaine intake and blood lipid profiles in Mexican subjects. Methods: A total of 212 adults were randomly recruited in the city of Tijuana, Baja California, Mexico. Betaine intake was estimated using Nutritionist Pro software. Body composition and metabolic measurements were obtained by conventional methods. In the total sample, the average intake of betaine was 14.32 mg/d. Individuals were categorized into three groups according to tertiles of betaine consumption: tertile/group 1 (<4.16 mg/d), tertile/group 2 (4.16–12.02 mg/d), and tertile/group 3 (>12.02 mg/d). Results: Compared to group 3, subjects within group 1 had higher serum levels of total cholesterol (p = 0.001), LDL-c (p = 0.026), and non-HDL-c (p = 0.021). In addition, significant negative Pearson correlations were found between betaine intake and the serum levels of total cholesterol (r = −0.432, 95% CI, −0.684, −0.185, p = 0.001), LDL-c (r = −0.370, 95% CI, −0.606, −0.134, p = 0.002), and non-HDL-c (r = −0.351, 95%CI, −0.604, −0.098, p = 0.007). Conclusions: Our results show that a low intake of betaine is associated with elevated blood cholesterol levels in Mexican subjects. On this basis, betaine consumption could be used as an additional dietary measure for cardiovascular care. However, additional studies are required to confirm our results in other Mexican regions as well as in other populations worldwide.

Remnant cholesterol and the risk of carotid plaque in hypertension: results from a community-based screening among old adults in Hangzhou, China

Elevated remnant cholesterol (RC) is considered a risk factor for atherosclerotic cardiovascular disease, but the evidence on this association applies to the Chinese population with hypertension is limited. We aimed to explore the association between RC levels and carotid plaque in old adults with hypertension. 8523 hypertensive patients aged ≥ 60 years with serum lipids and carotid ultrasonography data were included in this community-based screening. Fasting RC was calculated as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDLC). The associations of RC levels with carotid plaque risk were evaluated using Logistic regression and restricted cubic spline models. Carotid plaque was screened in 4821 (56.56%) subjects. After multivariable-adjusted, RC was significantly related to carotid plaque [Odd ratio (OR)] = 1.043 per 0.1 mmol/L increase, 95% confidence interval (CI): 1.030–1.056). The highest versus the lowest quartile of RC was 1.928 (1.673–2.223) for carotid plaque. A nonlinear association was found between serum RC levels and the risk of carotid plaque (P for nonlinearity < 0.001). Moreover, an RC > 0.78 mmol/L differentiated patients at a higher risk of carotid plaque compared to those at lower concentrations, regardless of whether LDLC was on target at 2.59 mmol/L. In old adults with hypertension, elevated RC was positively associated with carotid plaque, independent of LDLC and other conventional risk factors.

Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications

Diabetic vascular complications are prevalent and severe among diabetic patients, profoundly affecting both their quality of life and long-term prospects. These complications can be classified into macrovascular and microvascular complications. Under the impact of risk factors such as elevated blood glucose, blood pressure, and cholesterol lipids, the vascular endothelium undergoes endothelial dysfunction, characterized by increased inflammation and oxidative stress, decreased NO biosynthesis, endothelial-mesenchymal transition, senescence, and even cell death. These processes will ultimately lead to macrovascular and microvascular diseases, with macrovascular diseases mainly characterized by atherosclerosis (AS) and microvascular diseases mainly characterized by thickening of the basement membrane. It further indicates a primary contributor to the elevated morbidity and mortality observed in individuals with diabetes. In this review, we will delve into the intricate mechanisms that drive endothelial dysfunction during diabetes progression and its associated vascular complications. Furthermore, we will outline various pharmacotherapies targeting diabetic endothelial dysfunction in the hope of accelerating effective therapeutic drug discovery for early control of diabetes and its vascular complications.

Headache to a Patient with the Coexistence of Chiari I Malformations and Primary Empty Sella Syndrome: A Case Report la Syndrome: A Case Report

Background: Chiari I malformations (CM-I) and Primary Empty Sella syndrome (PESS) are rare disorders of structural defects within a skull. Headache is the most common presenting symptom in both conditions. However, CM-I and ESS comorbidity in patients with severe headaches is yet to be reported. Case description: The patient was a 38-year-old woman with a one-year history of headaches at various localisations (occipital and bilateral frontal) preceded by mood agitation. Physical examination was significant for obesity. Magnetic resonance imaging (MRI) revealed a 6.4 mm cerebellar tonsil descent through the foramen magnum and hypointense (CSF-filled) flattened sella. The lipid panel showed elevated cholesterols (total) and low-density lipoprotein (LDL) levels.  She was medically managed, with no report of symptoms relapses at one-month and two-month follow-ups. Conclusion: This is the first report on comorbid CM-I and PESS in adults presenting with cephalalgia. PESS and CM-I co-occurrence may present with mixed headache localisation; careful history-taking and imaging are mandatory for diagnosis confirmation. Future extensive studies are warranted to analyse the pathophysiological interplay between these two rare disorders.

Lipid Profiles Impact on the Oncologic Outcome of Upper Tract Urothelial Carcinoma.

The prognosis of upper tract urothelial carcinoma (UTUC) varies, with T3/T4 UTUC having less than 50% 5-year survival post-radical nephroureterectomy (RNU). Lipid profiles including cholesterol (CHOL), low-density lipoprotein (LDL), and triglycerides (TGs), and high-density lipoprotein (HDL) have shown correlations with oncologic outcomes in various cancers. We aimed to investigate the prognostic significance of the lipid profiles in UTUC patients who had received RNU. In this retrospective study, a total of 217 UTUC patients who underwent RNU were analyzed. Prognostic factors for overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) were assessed using Cox proportional hazards regression model and competing risk analysis. The median follow-up duration was 2.36 years. Fifty-one (23.50%) of the patients experienced tumor progression, 16 (7.37%) died from UTUC, and 41 (18.89%) died from all causes during the follow-up period. Multivariate analysis revealed that elevated CHOL, low HDL, and elevated TG were linked to worse OS (P = 0.0188, 0.0002, and 0.0001, respectively). Higher CHOL, LDL, and TG, as well as lower HDL significantly affected PFS (P < 0.001 for all), and elevated CHOL and TG were associated with poorer CSS (P = 0.0033 and 0.0179). A competing risk model indicated that elevated LDL increased the risk of cancer progression (P = 0.407), with CHOL increasing the risk of UTUC-specific mortality (P = 0.0162). Limitations include retrospective design, limited, single-time sampling and relatively small sample size. Lipid profiles were identified as prognostic indicators for UTUC patients post-RNU. It highlights the potential importance of lipid management in improving tumor-related outcomes.

Cholesterol Interference in the Assessment of Vitamin D Status: a Canadian Health Measures Survey Biobank Project

BackgroundMatrix effects are a known problem with immunoassays measuring serum 25-hydroxyvitamin D (25(OH)D). ObjectiveTo determine if the inverse association between serum 25(OH)D and serum cholesterol concentrations is a function of assay method: Diasorin Liaison 25(OH) Vitamin D Total Assay (Liaison Total Assay), an immunoassay, vs. liquid chromatography tandem mass spectrometry (LC-MS/MS). Methods/Design: Canadian Health Measures Survey data and biobank serum (white males 20-79 years, n=392) were evaluated for bias in serum 25(OH)D using Bland-Altman plots. Differences in serum 25(OH)D (Liaison Total Assay - LC-MS/MS) were compared among non-high density cholesterol (non-HDL-cholesterol) <4.2 (n=295) vs. ≥4.2 (n=97) mmol/L and total cholesterol groups <5.2 (n=256) vs. ≥5.2 (n=136) mmol/L, and associations tested between 25(OH)D and non-HDL-cholesterol or total cholesterol concentrations, using regression. ResultsSerum 25(OH)D measured using Liaison Total Assay ranged from 10.7 to 137.0 nmol/L and 14.4 to 137.9 nmol/L by LC-MS/MS. Liaison Total Assay - LC-MS/MS showed a negative bias of 5.5 (95% limits of agreement -23.8, 12.7) nmol/L. Differences in 25(OH)D were -4.0±9.0 (±SD) nmol/L if non-HDL-cholesterol was <4.2 mmol/L and -10.2±8.7 nmol/L if ≥4.2 mmol/L (P<0.0001). Differences in 25(OH)D if total cholesterol was <5.2 mmol/L were -3.4±8.6 nmol/L and -9.6±9.3 nmol/L if ≥5.2 mmol/L (P<0.0001). Serum non-HDL-cholesterol (beta -3.17, P=0.0014) and total cholesterol (beta -2.77, P=0.0046) inversely associated with Liaison Total Assay 25(OH)D (adjusted for age, fasting and body mass index), but not with LC-MS/MS measured 25(OH)D. Interference by these lipoproteins was not eliminated by standardization of the Liaison Total Assay. Similar associations were observed with triglycerides as for the lipoproteins. ConclusionTotal cholesterol inversely associates with 25(OH)D, which is likely due to elevated non-HDL-cholesterol lipoprotein or triglyceride interference with the Liaison Total Assay. This is important as elevated cholesterol is common and an underestimation in vitamin D status could be an unnecessary cause for concern.

Growth performance, health status, gut microbiome, and expression of immune and growth-related genes of rainbow trout (Oncorhynchus mykiss) fed diets with pea protein replacement of fish meal

The need for fish meal constrains fish farming and significantly impacts sustainability of the aquaculture industry. Hence, it is important to investigate the use of plant-based protein sources in fish diets. The present study was conducted to determine the effects of different levels of fish meal (FM) replacement by pea protein (PP) in a 60-day feeding experiment in rainbow trout, Oncorhynchus mykiss. Effects on growth performance, body composition, hematology, serum biochemistry and immunology, and immune (TNF-α, IL1-ß and Il-8) and growth-related (GH and IGFI) gene expression were investigated. Five experimental diets (45% protein and 20% lipid) differed in replacement level of FM by PP at rates of 0% (control (PP0)), 25% (PP25), 50%(PP50), 75%(PP75) and 100%(PP100). Fish were fed with experimental diets in triplicate twice daily. The best growth performance was obtained in PP0 and PP25 groups. While fat ratios of fish fillets significantly differed (p < 0.05), there was no significant effects on protein ratios (p < 0.05). There was no significant change in the hematological values of fish, except those fed the PP100 diets, which displayed a reduction in eyrthocyte counts, hemoglobin content and hematocrit. As PP supplementation increased fish showed elevated serum glucose, total protein, cholesterol and myeloperoxidase activity and decreased glutamic pyruvic transaminase and alkaline phosphatase activity. Fish fed diets with between 25 and 75% replacement showed a decline in lactic acid bacteria in the gut. Significant increases in expression were observed in the liver of the PP25 fish relative to the 0% control for all immune and growth-related genes except for IL1-ß. These data suggest that up to 25% of FM can be replaced by PP without any adverse effects on rainbow trout.

Association of indoor solid fuel pollution with risk factors for cardiovascular disease among Chinese adults: A nationally multi-center study

Few studies have comprehensively assessed the associations of household air pollution (HAP) from solid fuel burning with cardiovascular risk factors (eg, hypertension, diabetes, dyslipidemia, and obesity). Moreover, whether these associations with cardiovascular disease (CVD) risk factors varied by residential environment characteristics remains unclear. Using two waves data (2011 and 2015) of 13,953 participants aged at least 45 years from 125 cities in the China Health and Retirement Longitudinal Study, we explored how solid fuel exposure is associated with CVD risk factors among Chinese adults. Blood pressure (BP), fasting blood glucose (FBG), lipid profiles, C-reactive protein, and body mass index (BMI) were measured using standard methods. Multivariate logistic regression and generalized linear models explored the associations of solid fuel use for heating and cooking with CVD risk factors. Stratified analyses examined whether the associations varied by sociodemographics and living environmental characteristics. Compared with clean fuels, solid fuel used for heating and cooking was associated with a higher risk of hypertension, diabetes, and dyslipidemia, respectively. Solid fuel was related to elevated systolic BP (adjusted β 1.369 mmHg, 0.481-2.258), diastolic BP (0.704 mmHg, 0.183-1.225), FBG (0.309 mmol/l, 0.218-0.399), total cholesterol (0.055 mmol/l, 0.012-0.099), and low-density lipoprotein (0.100 mmol/l, 0.061-0.139), while inversely with BMI (-0.437 kg/m2, -0.599--0.275). Women, who live in a house with poor cleanliness (according to the overall tidiness and whether have tap water in the house) had a stronger association for hypertension or dyslipidemia. Our findings provide implications for policymakers to implement interventions to improve cardiovascular health by reducing HAP.

Exploring the Role of Non-HDL Cholesterol in Acute Coronary Syndrome: A Case-Control Study

Objectives: This case-control study aimed to investigate the association between non-high-density lipoprotein (non-HDL) cholesterol levels and acute coronary syndrome (ACS) among individuals not recently treated with statins. Methodology: A total of 100 participants with ACS, who had not received recent statin therapy, were selected from the Coronary Care Unit (CCU) at Al-Kadhimiyah Hospital in Baghdad, Iraq. Controls, matching the eligibility criteria of cases except for ACS symptoms, were randomly chosen from the same hospital. Both groups met criteria including age over 40, and a history of diabetes mellitus, hypertension, smoking, and obesity. Statistical significance was set at p &lt; 0.05. Results: The study found a significant independent association between elevated non-HDL cholesterol levels and ACS, with an average non-HDL level of 154.2 mg/dl (normal: 130 mg/dl) among ACS cases (p &lt; 0.001), compared to 120 mg/dl in controls. Elevated non-HDL levels were also correlated with increased BMI (p = 0.01, r = 0.3) and various lipid markers (p &lt; 0.05), except HDL. Conclusion: Elevated non-HDL cholesterol levels upon admission may serve as a potential indicator of ACS risk. These findings underscore the importance of non-HDL cholesterol assessment in ACS risk stratification and management.

Subtherapeutic Kitasamycin Promoted Fat Accumulation in the Longissimus Dorsi Muscle in Growing-Finishing Pigs.

Kitasamycin (KM), a broad-spectrum macrolide antibiotic, has implications for growth performance and residue in animals and humans. This study aimed to explore the effects of different KM doses on intramuscular fat accumulation, cecal microflora, and short-chain fatty acids (SCFAs) using a growing-finishing pig model. Forty-two pigs were divided into three groups: control, subtherapeutic KM (50 mg/kg, KM50), and therapeutic KM (200 mg/kg, KM200) diets over 8 weeks. KM50 led to increased back fat thickness, fat content in the longissimus dorsi muscle (LM), and elevated plasma total cholesterol (TC) levels (p < 0.05), supported by upregulated lipid synthesis gene expression (Acc1, Fas, Scd1) (p < 0.05) in the LM. KM50 altered cecal microflora, reducing Lactobacillus spp. and Bifidobacterium spp. abundance, while increasing SCFA concentrations (acetic acid, propionic acid, total SCFAs) (p < 0.05). KM200 had minimal effects on intestinal weight and density, with increased apparent digestibility of nutrients. These findings highlight the dose-dependent impact of KM on intramuscular fat deposition. Subtherapeutic KM induced ectopic fat deposition, emphasizing potential risks in disease treatment for humans and animals.

Phenome-wide causal associations between osteoarthritis and other complex traits through the latent causal variable analysis

BackgroundIndividuals with osteoarthritis present with comorbidities, and the potential causal associations remain incompletely elucidated. The present study undertook a large-scale investigation about the causality between osteoarthritis and variable traits, using the summary-level data of genome-wide association studies (GWAS).MethodsThe present study included the summary-level GWS data of knee osteoarthritis, hip osteoarthritis, hip or knee osteoarthritis, hand osteoarthritis, and other 1355 traits. Genetic correlation analysis was conducted between osteoarthritis and other traits through cross-trait bivariate linkage disequilibrium score regression. Subsequently, latent causal variable analysis was performed to explore the causal association when there was a significant genetic correlation. Genetic correlation and latent causal variable analysis were conducted on the Complex Traits Genomics Virtual Lab platform (https://vl.genoma.io/).ResultsWe found 133 unique phenotypes showing causal relationships with osteoarthritis. Our results confirmed several well-established risk factors of osteoarthritis, such as obesity, weight, BMI, and meniscus derangement. Additionally, our findings suggested putative causal links between osteoarthritis and multiple factors. Socioeconomic determinants such as occupational exposure to dust and diesel exhaust, extended work hours exceeding 40 per week, and unemployment status were implicated. Furthermore, our analysis revealed causal associations with cardiovascular and metabolic disorders, including heart failure, deep venous thrombosis, type 2 diabetes mellitus, and elevated cholesterol levels. Soft tissue and musculoskeletal disorders, such as hallux valgus, internal derangement of the knee, and spondylitis, were also identified to be causally related to osteoarthritis. The study also identified the putative causal associations of osteoarthritis with digestive and respiratory diseases, such as Barrett’s esophagus, esophagitis, and asthma, as well as psychiatric conditions including panic attacks and manic or hyperactive episodes. Additionally, we observed osteoarthritis causally related to pharmacological treatments, such as the use of antihypertensive medications, anti-asthmatic drugs, and antidepressants.ConclusionOur study uncovered a wide range of traits causally associated with osteoarthritis. Further studies are needed to validate and illustrate the detailed mechanism of those causal associations.

Abstract 1258: A cholesterol metabolite can modulate neutrophil-derived extracellular vesicles to promote breast cancer cell epithelial to mesenchymal transition (EMT) and stemness

Abstract Breast cancer is the second leading cause of cancer-related death in women, with mortality most often due to metastatic recurrence. Elevated cholesterol is associated with poor prognosis, with several potential mechanisms proposed. Work in murine models found that many of the pro-metastatic actions of cholesterol required the enzymatic conversion of cholesterol to 27-hydroxycholesterol (27HC), which functions as a ligand for both the estrogen receptors (ERs) and liver X receptors (LXRs). Importantly, we have found that 27HC promotes metastasis, in part through its actions on neutrophils. When examining mechanisms, we have made the observation that 27HC resulted in increased secretion of small extracellular vesicles (sEVs) from neutrophils. These 27HC-neutrophil-sEVs independently promote metastatic colonization. Since we have found that breast cancer cell lines can take up neutrophil-derived sEVs, we hypothesized that 27HC results in altered cargo within sEVs which leads to functional changes within cancer cells, the ultimate consequence of which being their increased metastatic potential. Using a non-biased small RNA-seq approach we have found that sEVs from 27HC-treated neutrophils had an altered miRNA signature. Bioinformatic analysis revealed several downregulated miRNAs from the let-7 subgroup. Let-7 miRs are known to target several genes associated with the WNT/β-catenin pathway, a pathway strongly implicated in epithelial to mesenchymal transition (EMT) and cancer cell stemness. Strikingly, breast cancer cells treated with sEVs from neutrophils treated with 27HC lost their adherent properties and adopted a mesenchymal and stem-like phenotype. In order to elucidate the mechanism by which these sEVs promote EMT and stemness, we performed comprehensive transcriptomics through time. Weighted gene co-expression network analysis (WGCNA) confirmed these phenotypic shifts, and implicated the WNT/β-catenin pathway, providing support to our hypothesis that the loss of let-7 miRs is the upstream mediator. Collectively, our data suggests that 27HC increases metastasis in part through its effects on neutrophils, by shifting sEVs cargo towards a loss of protective microRNA, resulting in increased EMT and stemness, and thus the ability of cancer cells to migrate, invade and metastasize. Funding: National Cancer Institute (ERN: R01CA234025) Department of Defense (ERN: BCRP Era of Hope Award), and Beckman Institute for Advanced Science and Technology (NK) Citation Format: Natalia J. Krawczynska, Yu Wang, Anasuya Das Gupta, Jenny Drnevich, Julie Ostrander, Erik R. Nelson. A cholesterol metabolite can modulate neutrophil-derived extracellular vesicles to promote breast cancer cell epithelial to mesenchymal transition (EMT) and stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1258.

Abstract 174: Cholesterol efflux protein ABCA1 skews macrophages towards an anti-tumor phenotype and consequently impacts breast cancer progression

Abstract With a lifetime risk of approximately 1 in 8, breast cancer maintains in its position as the most prevalent form of cancer and ranks second in terms of cancer-related fatalities in women. The primary cause of mortality is often attributed to the recurrence of metastatic breast cancer. While immune therapy shows some effectiveness, many patients do not exhibit meaningful responses, likely due to immune-suppressive factors present within the tumor microenvironment. These factors include myeloid cells such as Macrophages(MΦ), therefore, there is a strong need to devise strategies to shift (MΦ) from a pro-tumor to an anti-tumor phenotype. Our previous research has uncovered the susceptibility of MΦs to disruptions in cholesterol metabolic balance. Considering these findings, coupled with epidemiological evidence linking elevated plasma cholesterol to unfavorable prognosis, the impact of cholesterol homeostasis in tumor associated MΦs on breast cancer becomes evident. An in-depth computational screen helped us identify ABCA1—a cholesterol efflux protein with elevated mRNA expression associated with increased survival. Beyond cholesterol efflux, ABCA1 also facilitates the movement of cholesterol from the inner membrane layer to the outer layer. Previous work has shown that cholesterol within the inner membrane layer can directly interact with and activate various receptors on the membrane's surface, initiating downstream signaling events. Consequently, the activities of ABCA1 in cholesterol efflux and translocation likely hold substantial regulatory implications. Underscoring the clinical significance of ABCA1 are our findings that heightened ABCA1 expression within breast tumors correlates with augmented levels of cytotoxic T cells, T cell effector enzymes (Prf-1 and Gzmb), and improved survival rates. Crucially, our in vitro investigations indicate that ABCA1 modulates multiple functions of MΦs to adopt an anti-cancer phenotype, encompassing: (1) the ability to infiltrate tumor spheroids, (2) angiogenesis, (3) efferocytosis—an immune-suppressive phagocytic process devoid of antigen presentation, and (4) the expansion, migration, and activity of cytotoxic T cells. ABCA1 transports cholesterol from macrophages to a lipid poor ApoA1 protein and facilitates the formation of nascent HDL via reverse cholesterol transport. We leveraged this mechanism to therapeutically target ABCA1 using ApoA1 mimetics 5A and 4F. Our data so far indicates that these ApoA1 phenocopy ABCA1 overexpression in MΦs. Together, our data provides compelling evidence for the involvement of ABCA1 in the pathophysiology of breast tumors. The anticipated outcomes of this research will establish the basis for the future utilization of ABCA1 and its downstream effects for therapeutic purposes. Citation Format: Shruti V. Bendre, Natalia Krawczynska, Shaunak Bhogale, Erin Weisser, Simon Han, Basel Hajyousif, Avni Singh, Rajendra K C, Yu Wang, Claire P. Schane, Adam T. Nelczyk, Anasuya DasGupta, Hashni E. Gamage, Kevin T. VanBortle, Emad Tajkhorshid, Saurabh Sinha, Wohnwa Cho, Erik R. Nelson. Cholesterol efflux protein ABCA1 skews macrophages towards an anti-tumor phenotype and consequently impacts breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 174.

Association of lipoprotein lipase (LPL) gene variants with hyperlipidemic acute pancreatitis in southeastern Chinese population.

The study aims to explore the relationship between lipoprotein lipase (LPL) variants and hyperlipidemic acute pancreatitis (HLAP) in the southeastern Chinese population. In total, 80 participants were involved in this study (54 patients with HLAP and 26 controls). All coding regions and intron-exon boundaries of the LPL gene were sequenced. The correlations between variants and phenotypes were also analysed. The rate of rare LPL variants in the HLAP group is 14.81% (8 of 54), higher than in controls. Among the detected four variants (rs3735959, rs371282890, rs761886494 and rs761265900), the most common variant was rs371282890. Further analysis demonstrated that subjects with rs371282890 "GC" genotype had a 2.843-fold higher risk for HLAP (odds ratio [OR]: 2.843, 95% confidence interval [CI]: 1.119-7.225, p = 0.028) than subjects with the "CC" genotype. After adjusting for sex, the association remained significant (adjusted OR: 3.083, 95% CI: 1.208-7.869, p = 0.018). Subjects with rs371282890 "GC" genotype also exhibited significantly elevated total cholesterol, triglyceride and non-high-density lipoprotein cholesterol levels in all the participants and the HLAP group (p < 0.05). Detecting rare variants in LPL might be valuable for identifying higher-risk patients with HLAP and guiding future individualised therapeutic strategies.

Assessing Serum Vaspin Dynamics in Dairy Cows during Late Pregnancy and Early Lactation in Relation to Negative Energy Balance

The periparturient period, which spans late pregnancy to early lactation in dairy cows, is a crucial phase characterized by complex metabolic and endocrine adjustments necessary for sustained milk production. This research focused on the relationship between serum vaspin, inflammatory cytokines (IL-1, TNF), and markers of negative energy balance (NEB) in 100 primiparous and multiparous Holstein dairy cows. The results demonstrated that one month post-calving, both groups had a significant decrease in serum vaspin levels but increased NEFA levels, indicating possible consequences for lipid metabolism and energy balance. Multiparous cows showed significant elevations in cholesterol, IL-1, and TNF concentrations after calving, indicating increased inflammatory responses. Primiparous cows, on the other hand, responded differently, indicating the role of parity in metabolic adjustments. The study acknowledges limitations such as sample size and its observational nature. Future research should investigate the long-term effects of these metabolic changes on herd health and lactational performance, using advanced technologies to gain a molecular understanding. Despite limitations, this study provides valuable insights into how adipokines, inflammatory markers, and energy balance interact during the periparturient period, offering the potential for improved dairy cow management and productivity while ensuring animal welfare.

Elevated blood remnant cholesterol and triglycerides are causally related to the risks of cardiometabolic multimorbidity

The connection between triglyceride-rich lipoproteins and cardiometabolic multimorbidity, characterized by the concurrence of at least two of type 2 diabetes, ischemic heart disease, and stroke, has not been definitively established. We aim to examine the prospective associations between serum remnant cholesterol, triglycerides, and the risks of progression from first cardiometabolic disease to multimorbidity via multistate modeling in the UK Biobank. We also evaluate the causality of these associations via Mendelian randomization using 13 biologically relevant SNPs as the genetic instruments. Here we show that elevated remnant cholesterol and triglycerides are significantly associated with gradually higher risks of cardiometabolic multimorbidity, particularly the progression of ischemic heart disease to the multimorbidity of ischemic heart disease and type 2 diabetes. These results advocate for effective management of remnant cholesterol and triglycerides as a potential strategy in mitigating the risks of cardiometabolic multimorbidity.

Cholesterol depletion induces mesenchymal properties in oral squamous cell carcinoma cell line.

Cholesterol in cell membranes is crucial for cell signaling, adhesion, and migration. Membranes feature cholesterol-rich caveolae with caveolin proteins, playing roles in epithelial-mesenchymal transition and cancer progression. Despite elevated cholesterol levels in tumors, its precise function and the effects of its depletion in oral squamous cell carcinoma remain unclear. The aim of this study was to evaluate the influence of cholesterol depletion in oral squamous cell carcinoma cell line and epithelial-mesenchymal transition process. Cholesterol depletion was induced on SCC-9 cells by methyl-β-cyclodextrin and cell viability, proliferation, apoptosis, and colony formation capacities were evaluated. Gene and protein expressions were evaluated by reverse transcription polymerase chain reaction (RT-qPCR) and Western Blot, respectively, and cell sublocalization was assessed by immunofluorescence. Cholesterol depletion resulted in alteration of oral squamous cell carcinoma cell morphology at different concentrations of methyl-β-cyclodextrin, as well as decreased cell proliferation and viability rates. Analysis of CAV1 transcript expression revealed increased gene expression in the treated SCC-9 during the 24 h period, at different concentrations of methyl-β-cyclodextrin: 5 , 7.5, 10, and 15 mM, in relation to parental SCC-9. CAV1 protein expression was increased, with subsequent dose-dependent decrease. A statistically significant difference was observed in samples treated with 5 mM of methyl-β-cyclodextrin (p = 0.02, Kruskal-Wallis test). The immunofluorescence assay showed lower cytoplasmic and membrane labeling intensity in the treated samples for CAV1. These findings indicate the modulation of cholesterol as a possible mechanism underlying the regulation of these molecules and activation of epithelial-mesenchymal transition in oral squamous cell carcinoma.

Cholesterol-regulated cellular stiffness may enhance evasion of NK cell-mediated cytotoxicity in gastric cancer stem cells.

Gastric cancer has a high rate of recurrence, and as such, immunotherapy strategies are being investigated as a potential therapeutic strategy. Although the involvement of immune checkpoints in immunotherapy is well studied, biomechanical cues, such as target cell stiffness, have not yet been subject to the same level of investigation. Changes in the cholesterol content of the cell membrane directly influence tumor cell stiffness. Here, we investigated the effect of cholesterol on NK cell-mediated killing of gastric cancer stem-like cells. We report that surviving tumor cells with stem-like properties elevated cholesterol metabolism to evade NK cell cytotoxicity. Inhibition of cholesterol metabolism enhances NK cell-mediated killing of gastric cancer stem-like cells, highlighting a potential avenue for improving immunotherapy efficacy. This study suggests a possible effect of cancer cell stiffness on immune evasion and offers insights into enhancing immunotherapeutic strategies against tumors.

Chemical characterization, safety profile and antileiomyoma effects of Tetrapleura tetraptera Taubert (Fabaceae) fruit ethanol extract in Sprague Dawley rats

BackgroundTetrapleura tetraptera Taubert (Fabaceae) fruits are employed by herbal practitioners in the management of uterine leiomyoma, but its usage in this regard and level of safety in chronic administration has not been sufficiently established. This study evaluated the toxicity effects of T. tetraptera ethanol fruit extract and explored its antileiomyoma effect in female Sprague Dawley (SD) rats.MethodsSub-chronic toxicity test of the extract was done, with biochemical and hematological changes as well as histopathology of organs assessed. Leiomyoma formation was induced in SD rats with monosodium glutamate (MSG) and the extract given at 100, 200 and 400 mg/kg doses, following both the preventive and curative methods. Total serum cholesterol, protein and estradiol were determined, as well as histopathology assessment of the uterus. Phytochemical profiling of the extract was evaluated by analytical high-performance liquid chromatography (HPLC).ResultsNo significant alterations were seen in the biochemical and hematological indices in the toxicity test. The vital organs showed no changes at 200 mg/kg, but at 800 mg/kg it appeared to induce multiplication of glandular epithelium and stromal fibrosis in the uterus, and induced perivascular inflammation around the vessels of the heart. Total serum cholesterol and estradiol were significantly elevated (P ≤ 0.05) on treating normal female rats with 800 mg/kg MSG. Preventive and curative treatment of MSG-treated animals with the extract significantly decreased the elevated serum cholesterol (P ≤ 0.01) and estradiol (P ≤ 0.05). Histological studies of the uterus showed an amelioration of the proliferating fibroid cells with administration of the extract, which was more evident in the curative treatment. Result of HPLC analysis of the extract revealed rich composition in bioactive compounds such as umbelliferone, ferulic acid, aridanin, echinocystic acid, naringenin and hentriacontane.ConclusionThe ethanol fruit extract of T. tetraptera is relatively safe in Sprague Dawley rats in low doses and has antifibroid potential as seen in its significant reduction in the elevated total cholesterol and estradiol content as well as its ability to decrease uterine leiomyoma proliferation, which may be due to its array of phytochemical constituents.