Plasma Cholesterol Concentrations Research Articles

Abstract C027: The role of Liver Receptor Homolog 1 (LRH-1) in regulating cancer progression by modulating the immune response

Abstract Breast cancer is a significant global health concern, being the second most common type of cancer and the second leading cause of cancer-related deaths among women in the U.S. Metastatic breast cancer is responsible for most of these deaths, and current FDA-approved immunotherapies are effective only for a small subset of patients with PD-L1-positive tumors. Thus, there is a critical need for new therapeutic targets to enhance the immune response against breast cancer. Elevated plasma cholesterol concentrations are associated with poor breast cancer outcomes. Our previous studies indicated that myeloid immune cells are highly sensitive to changes in cholesterol levels and other proteins involved in regulating cholesterol homeostasis. However, the role of Liver Receptor Homolog 1 (LRH-1), a key regulator of cholesterol homeostasis, in myeloid cells is not well understood. Notably, higher expression of LRH-1 mRNA in breast tumors is associated with longer time to recurrence and improved overall survival. Therefore, we aimed to investigate the role of LRH-1 in myeloid immune cells and its impact on breast cancer progression. Initial analysis indicated that LRH-1 is expressed in myeloid cells, with particularly high levels observed in neutrophils. Therefore, we examined how LRH-1 regulates neutrophil functions important to cancer biology, including migration, NETosis, and phagocytosis, as well as its influence through neutrophils on T cells. We found that LRH-1 inhibited neutrophil migration toward cancer cells. Since tumor infiltrating neutrophils are generally associated with poor prognosis, LRH-1 reducing neutrophil migration could indicate a decreased ability of these immune-suppressive cells to infiltrate tumors. Importantly, neutrophils treated with an LRH-1 agonist showed reduced NETosis, while antagonist led to increased NETosis. LRH-1 agonist treatment also significantly reduced neutrophil phagocytosis, whereas an antagonist had no notable effect. Furthermore, T cells exhibited increased expansion when co-cultured with neutrophils treated with an LRH-1 agonist, and reduced proliferation with neutrophils pretreated with an LRH-1 antagonist or inverse agonist, particularly in CD4+ helper T cells and later divisions. Since neutrophils were previously implicated in invoking recurrence from dormant lesions, we evaluated LRH-1 in this context. The treatment of mice harboring dormant D2.0R lesions with an LRH-1 inverse agonist resulted in sooner recurrence and metastatic outgrowth compared to vehicle treated mice. In summary, our findings suggest that LRH-1 plays a crucial role in regulating various neutrophil functions, including migration, NETosis, phagocytosis, and T cell expansion. The ultimate consequence of these regulations are control of dormant mammary cancer lesions. These results highlight LRH-1 as a potential therapeutic target for cancer treatment or prevention of metastatic recurrence. Funding: National Cancer Institute (ERN: R01CA234025) Department of Defense (ERN: BCRP Era of Hope Award) Citation Format: Yu Wang, Bryan Duong, Natalia Krawczynska, Shruti V. Bendre, Claire P. Schane, Erin Weisser, Lara Kockaya, Yifan Fei, Anasuya Das Gupta, Hashni E. Vidana Gamage, Adam T. Nelczyk, Dhanya Pradeep, Erik R. Nelson. The role of Liver Receptor Homolog 1 (LRH-1) in regulating cancer progression by modulating the immune response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C027.

Dynamics of Blood Taurine Concentration and its Correlation with Nutritional and Physiological Status during the Fattening Period of Japanese Black Cattle.

Taurine, biosynthesized from methionine or cysteine in the liver, plays a crucial regulatory role in bile acid conjugation, antioxidant effects, and glucose and cholesterol metabolism. This may influence the metabolic changes associated with fat accumulation in beef cattle. However, the physiological role of taurine in this species has not been fully elucidated. In this study, we explored the physiological role of taurine in Japanese Black steers (Bos taurus) in different phases during the fattening period. To examine the correlation among plasma taurine concentrations, various physiological parameters, and genes related to taurine synthesis in the liver, we used biopsied liver tissues, blood samples, and rumen fluids collected from 21 steers at three different stages, i.e., early (T1; 13 months of age), middle (T2; 20 months of age), and late (T3; 28 months of age) phases. Additionally, to investigate the regulatory mechanisms underlying the expression profile of taurine synthesis genes, primary bovine hepatocytes obtained from 4-week-old Holstein calves were treated with palmitate, oleate, acetate, propionate, or β-hydroxybutyrate (BHBA). Plasma taurine and cholesterol concentrations significantly (P < 0.001) increased in the T2 phase, which is potentially attributable to increased energy intake and assimilation induced by increased intake of concentrated feed. Cysteine sulfinic acid decarboxylase (CSAD) expression significantly increased (P < 0.01) in T2 than in other phases. The expression levels of cysteine dioxygenase type 1 (CDO1) and cholesterol 7 alpha-hydroxylase (CYP7A1) were significantly higher (P < 0.001) in T2 than in T3; moreover, the CDO1/glutamate-cysteine ligase catalytic subunit (GCLC) ratio was higher (P < 0.05) in T2 than in T1. Plasma taurine concentrations were positively correlated with plasma methionine (r = 0.51; P < 0.05) and total cholesterol (r = 0.56; P < 0.05) concentrations at T2. Relative CDO1 mRNA expression was upregulated in cultured bovine hepatocytes treated with oleate and propionate, whereas it was downregulated upon acetate treatment. These findings indicate that the increase in plasma taurine concentrations in the T2 phase is associated with changes in lipid and methionine metabolism in Japanese Black steers.

Abstract 4138473: Detailed Lipoprotein Profiling in Assessing Coronary Calcium Score Progression and Atherosclerotic Risk

Background: Coronary calcium scoring (CCS) evaluates atherosclerotic burden and cardiovascular risk, correlating with coronary artery disease (CAD) severity. Advances in Nuclear Magnetic Resonance ( 1 H-NMR) spectroscopy for lipoprotein fraction analysis highlight precise atherogenic lipid parameter estimation. Enhanced lipid testing, including sub-fractionation assays, improves risk assessment and identifies new biochemical markers for CAD burden. Hypothesis: Specific lipid fractions and subfractions are significantly associated with CCS progression, serving as biochemical markers of CAD progression. Aim: To evaluate the association between lipid fractions and subfractions with CCS progression, aiming to improve CAD risk stratification. Methods: This study used data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). CCS progression was any positive change in CCS values over 5 years. High-field 1 H-NMR spectroscopy assessed lipoprotein fractions and subfractions, including plasma concentration, particle size, cholesterol, and triglyceride content. Descriptive and inferential statistics compared baseline characteristics. Multivariable binary logistic regression models, both unadjusted and propensity score-adjusted, assessed associations between plasma levels of lipoprotein fractions and CCS progression. Statistical significance was set at p &lt;0.05. Results/Data: In this study of 2,986 participants, 1,008 (33.8%) experienced CCS progression over 5 years. Significant associations were found between plasma lipoprotein fractions and CCS progression. Large, medium, and very small TRLP (89-37 and 29-24 nm) were linked to increased CCS risk, while small TRLP (36-30 nm) had an inverse association. Small cLDLP (20.4-19 nm) were directly associated with CCS progression, while medium and large cLDLP (23-20.5 nm) were inversely associated. Small cHDLP (7.4-8.0 nm) increased CCS risk, whereas medium to large cHDLP (8.1-13.0 nm) had an inverse association. Specific HDL subspecies (H7P to H3P, 12.0-8.7 nm) were inversely associated with CCS progression, while H2P and H1P (7.8-7.4 nm) increased CCS risk. TRLZ (30-100 nm) levels were positively associated with CCS progression, whereas LDLZ (19-22.5 nm) and HDLZ (7.1-13 nm) were inversely associated. Conclusion(s): Plasma levels of specific lipoprotein fractions and subfractions are associated with CCS progression, providing insights into the complexity of lipoprotein characteristics in CAD.

TOMM40 regulates hepatocellular and plasma lipid metabolism via an LXR-dependent pathway

The gene encoding TOMM40 (Transporter of Outer Mitochondrial Membrane 40) is adjacent to that encoding APOE, which has a central role in lipid and lipoprotein metabolism. Human genetic variants near APOE and TOMM40 are strongly associated with plasma lipid levels, but a specific role for TOMM40 in lipid metabolism has not been established. We show here that suppression of TOMM40 in human hepatoma cells upregulates expression of APOE and LDLR in part via activation of LXRB (NR1H2) by oxysterols, with consequent increased uptake of VLDL and LDL. This is in part due to disruption of mitochondria-endoplasmic reticulum contact sites, with resulting accrual of reactive oxygen species and non-enzymatically derived oxysterols. With TOMM40 knockdown, cellular triglyceride and lipid droplet content are increased, effects attributable in part to receptor-mediated VLDL uptake, since lipid staining is significantly reduced by concomitant suppression of either LDLR or APOE. In contrast, cellular cholesterol content is reduced due to LXRB-mediated upregulation of the ABCA1 transporter as well as increased production and secretion of oxysterol-derived cholic acid. Consistent with the findings in hepatoma cells, in vivo knockdown of TOMM40 in mice results in significant reductions of plasma triglyceride and cholesterol concentrations, reduced hepatic cholesterol and increased triglyceride content, and accumulation of lipid droplets leading to development of steatosis. These findings demonstrate a role for TOMM40 in regulating hepatic lipid and plasma lipoprotein levels and identify mechanisms linking mitochondrial function with lipid metabolism.

Effect of a Bacillus subtilis-based direct-fed microbial, on milk yield, milk components, feed intake and plasma hormones and metabolites in lactating Holstein cows

To investigate the effects of a Bacillus-based direct-fed microbial on milk production and related factors, a study was conducted on Holstein cows (n = 28) starting at 90 ± 11 DIM. The cows were divided into two dietary groups: a control group (CON) that received a total mixed ration (TMR), and a Bacillus-fed group (DFM) that received the same TMR along with a Bacillus subtilis product containing two strains (747 and 1781) in equal amounts. The study lasted for 25 wk and included both primiparous and multiparous cows. The cows were housed in a free-stall barn and were provided with ad libitum TMR, which was fed twice a day. Their daily meals and dry matter intake (DMI) were recorded during wk 1–4 and wk 19–25 using electronic feeders. Milk samples were collected weekly during morning and evening milkings and analyzed for milk fat, protein, lactose, and milk urea nitrogen (MUN). Blood samples were also collected weekly and analyzed for plasma glucose, insulin, cholesterol, insulin-like growth factor 1 (IGF1), and progesterone concentrations. Additionally, rumen fluid samples were collected and evaluated for various species of bacteria. One of the key findings was that daily 4 % fat-corrected milk production (FCM) was influenced by the interaction between treatment (DFM vs. CON) and parity (primiparous vs. multiparous), with multiparous DFM cows producing 11 % more FCM compared to CON. The DFM cows also had a higher milk fat percentage (4.41 % vs. 4.02 %) and MUN concentrations were 1.0 mg/dL higher in the DFM group. In terms of blood metabolites and hormones, multiparous DFM cows had lower plasma cholesterol, glucose, and insulin concentrations compared to CON multiparous cows. However, there were no significant differences between the groups in terms of plasma IGF1 concentrations, insulin-to-glucose ratios, and luteal phase plasma progesterone concentrations. The analysis of rumen fluid samples revealed that the abundance of Ruminococcus albus and Fibrobacter succinogenes group I was greater in the DFM cows compared to CON cows. Furthermore, during the periods when feed intake was measured, the DFM cows had a 9 % reduction in feed intake and a 14 % improvement in feed efficiency (FCM per DMI) compared to CON cows. In conclusion, the two-strain Bacillus product used in this study (Certillus) showed potential as an effective direct-fed microbial. It was found to increase feed efficiency and milk production by altering the composition of ruminal microbiota and metabolism in the cows.

Effects of phytosterol supplementation on lipid profiles and apolipoproteins: A meta-analysis of randomized controlled trials.

The use of phytosterols and phytostanols (PS) as food supplements to control plasma cholesterol concentrations has recently received attention as its efficacy has been endorsed by scientific authorities and leading guidelines. However, the effects of phytosterols on lipid profiles and atherosclerosis remain incomplete and controversial. This study aims to investigate the effects of PS supplementation on lipid profiles and apolipoproteins in adults based on a systematic review of the literature and a meta-analysis of randomized controlled trials (RCTs). A comprehensive search was conducted for RCTs published in PubMed, Embase, Cochrane Library, and Web of Science as of May 2024. Random effects model was utilized to determine the mean differences and 95% confidence interval for changes in circulating lipid profiles and apolipoproteins. Twenty-eight RCTs with a total of 1777 participants (895 cases and 882 controls) are included in the qualitative synthesis. PS supplementation significantly reduced total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and apolipoprotein B (Apo-B) levels, as well as Apo-B/apolipoprotein A1 ratios, but increased high-density lipoprotein cholesterol levels. PS supplementation dose is associated with TC, LDL-c, and Apo-B levels in a dose-response manner. Our findings suggest that dietary phytosterols can effectively promote the reduction of TC, LDL-c, and Apo-B, along with increased high-density lipoprotein cholesterol in adults.

Effect of Using Prickly Pear Seed Cake (Opuntia ficus indica L.) on Growth Performance, Digestibility, Physiological and Histometric Parameters in Rabbits

Prickly pear (Opuntia ficus indica L.) could be used in rabbit nutrition in compliance with circular economy principles, global warming issues, and reduction of production costs. This study aims to evaluate the effects of dietary incorporation of prickly pear seed cake (PPSC) on growth, physiological, and histometric parameters in rabbits. A total of 105 rabbits were divided into three experimental groups (n = 35) and fed different diets: a commercial feed (C group), the same feed with alfalfa replaced by PPSC at 10% (10PP group), and at 20% (20PP group). They were group-housed in cages with 5 animals per cage from weaning until slaughtering. While body weights and weight gains were similar in all groups, the coefficients of nutrient digestibility of dry matter, fibers, and ashes, as well as the characteristics of intestinal villi, were improved in the 10PP group compared to the others (p &lt; 0.05). The 20PP group showed a reduction in perirenal and interscapular fat (p &lt; 0.05), as well as lower plasma concentrations of triglycerides and cholesterol compared to the C group (p &lt; 0.001). In conclusion, PPSC can be incorporated into the diets of growing rabbits up to 20% as a partial substitute for alfalfa without the impairment of growth performance. Additionally, the inclusion of PPSC enhanced nutrient digestibility and increased the intestinal absorption surface area.

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.

Neonatal undernutrition induced by litter size expansion alters testicular parameters in adult Wistar rats.

Several models of maternal undernutrition reveal impairment of testicular development and compromise spermatogenesis in male offspring. The expansion of the litter size model, valuable for studying the impact of undernutrition on early development, has not yet been used to evaluate the consequences of early undernutrition in the adult male reproductive system. For this purpose, pups were raised in either normal litter (ten pups/dam) or large litter (LL; sixteen pups/dam). On postnatal day 90, sexual behaviour was evaluated or blood, adipose and reproductive tissues were collected for biochemical, histological and morphological analysis. Adult LL animals were lighter and thinner than controls. They showed increased food intake, but decrease of retroperitoneal white adipose tissue weight, glycaemia after oral glucose overload and plasma concentration of cholesterol. Reproductive organ weights were not altered by undernutrition, but histopathological analysis revealed an increased number of abnormal seminiferous tubules and number of immature spermatids in the tubular lumen of LL animals. These animals also showed reduction in total spermatic reserve and daily sperm production in the testes. Undernutrition decreased the number of Sertoli cells, and testosterone production was increased in the LL group. Mitochondrial activity of spermatozoa remained unchanged between experimental groups, suggesting no significant impact on the energy-related processes associated with sperm function. All animals from both experimental groups were considered sexually competent, with no significant difference in the parameters of sexual behaviour. We conclude that neonatal undernutrition induces histological and physiological testicular changes, without altering sperm quality and sexual behaviour of animals.

Effect of feeding two types of concentrates in morning and evening meals and two types of fat supplement on diurnal patterns of plasma parameters in lactation dairy cows

The diurnal patterns of feed intake and TMR composition influence blood parameters in dairy cows; however, the effect of feeding TMR with different compositions in the morning and evening meals is not well characterized. In a completely random design, forty Holstein cows (110 ± 30 days postpartum) were randomly assigned to four treatment groups, with 10 cows per treatment. The treatments were as follows: a base diet containing 50 % cereal starch from barley grain and 50 % cereal starch from corn grain in the morning and evening meal + either prilled fatty acids supplement (EqP) or calcium salts of fatty acids supplement (EqCS); a base diet containing 25 % cereal starch from barley grain, 75 % cereal starch from corn grain in the morning meal, and 75 % cereal starch from barley grain and 25 % cereal starch from corn grain in the evening meal + either prilled fatty acids supplement (DiP) or calcium salts of fatty acids supplement (DiCS). Dry matter intake was affected by treatments (P ˂ 0.01). The highest intake was observed for EqP, EqCS, DiP,and DiCS. 3.5 % fat-corrected milk and milk fat percentage was significantly higher for EqP than other treatments (P ˂ 0.01), but other milk components were not significantly different among treatments (P ˃ 0.05). A significant difference was observed for glucose, cholesterol, TG, AST, and insulin concentration among treatments (P ˂ 0.01). The concentrations of all plasma parameters (glucose, cholesterol, TG, BUN, AST, insulin, and NEFA) significantly changed over 24-h period (P ˂ 0.01). Plasma concentrations of glucose, cholesterol, TG, BUN, AST, insulin, and NEFA displayed a treatment-by-time interaction (P ˂ 0.01). In general, changes in the cereal starch ratio (corn and barley) in TMR in each meal during a day affect the 24-h concentration of plasma parameters, but there was no strong evidence of leverage for cows’ metabolism.

Sexual dimorphism in physiological responses of turbot (Scophthalmus maximus L) under acute hypoxia and reoxygenation

Dissolved oxygen (DO) is a crucial factor throughout fish life cycle. In this study, the hematology, hepatic antioxidant levels, histomorphology of the liver and gill were determined in both female and male turbot under acute hypoxia to evaluated the underlying mechanisms and potential sexual dimorphism difference. Results showed that acute hypoxia stress treatment for 3 h significantly increased plasma cortisol, glucose, hemoglobin (HGB), cholesterol (CHO), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and hepatic malondialdehyde (MDA) contents, red blood cell count (RBC) number, hepatic superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), alanine-aminotransferase (ALT) and aspartate-aminotransferase (AST) activity in both male and female turbot. Male obtained higher plasma CHO, TG and LDL contents, GSH-Px and SOD activity than female under hypoxia. Meanwhile, hypoxia increased gill respiratory frequency, secondary lamellar length, secondary lamellar width, perimeter, lamellar surface area and gill surface area and decreased interlamellar distance. Acute hypoxia induced clubbing, hyperplasia, hypertrophy of gill filaments and hepatic vacuolization in both male and female turbot. The aforementioned parameters were recovered to normal levels after reoxygenation for 12 h. In conclusion, sex dimorphism difference of turbot hematological (RBC, HGB) and biochemical (glucose, CAT, GSH-Px, MDA) parameters were observed under hypoxia stress, while male demonstrated more hypoxia tolerance than female. These results help understand turbot hypoxia tolerance mechanisms and provide more data for management in captivity.

A mixed animal and plant protein source replacing fishmeal affects bile acid metabolism and apoptosis in largemouth bass (Micropterus salmoides).

Chicken meal, shrimp meal, blood meal, and soybean protein concentrate (SPC) are common alternatives to fishmeal. This study used them to prepare three diets with different levels of fishmeal (FM48, FM40, FM32) for largemouth bass (Micropterus salmoides). The results found no significant difference in the growth performance of largemouth bass fed different diets. Mixed protein increased the total cholesterol (T-CHO) content in plasma, and reduced the total superoxide dismutase (T-SOD) activity in plasma and liver. Targeted metabolomics analysis found that the low fishmeal diets affected the cholesterol and bile acid metabolism of largemouth bass. Mixed protein inhibited cyp7a1 and enhanced hmgcr and pparγ mRNA levels, as well as enhanced the expression levels of FXR in the liver. The fish fed FM32 diet showed inhibited fxr, rxrα and cyp7a1 mRNA levels in the intestine. The results of TUNEL fluorescence staining showed that mixed protein induced apoptosis in largemouth bass. The caspase 3 and caspase 9 mRNA levels in the fish fed FM40 and FM32 diet significantly increased, as well as the expression levels of CASPASE 3. The experiment also found that it could induce oxidative stress and endoplasmic reticulum stress. In conclusion, replacement of fishmeal with mixed animal and plant protein diets did not affect the growth performance, but the health and bile acid metabolism of largemouth bass was affected when the fishmeal level was reduced to 32 %.

Effect of seminal plasma cholesterol and triacylglycerides concentrations and sperm morphology on semen freezability in domestic cats (Felis silvestris catus)

There is scarce information about the effect of sperm morphology and seminal plasma composition on cat semen freezability. Thus, this study aims to assess the effect of cat sperm morphology and seminal plasma cholesterol (CHOL) and triacylglyceride (TAG) concentrations on sperm post-thaw survival. Ejaculates (n = 49) were evaluated, and seminal plasma was separated and frozen until CHOL and TAG concentrations were measured. The sperm pellet was diluted in a tris-based egg yolk extender, frozen (n = 38), or processed for sperm ultrastructure study (n = 11). Abnormalities recorded were abnormal head shape and size, detached heads, knobbed or ruffled acrosomes, eccentric mid-piece insertion, proximal and distal cytoplasmic droplets, folded and coiled tails, and Dag defect. Ultramicroscopic evaluation detected several sperm abnormalities in fresh semen and some sperm damage in frozen semen. Seminal plasma lipids components were positively correlated with post-thaw motility and acrosome integrity. Higher freezability indices for motility and acrosome integrity were observed in frozen-thawed semen with high seminal plasma CHOL and TAG concentrations. No freezability differences were observed between teratozoospermic and normozoospermic ejaculates. Our results showed that even when seminal plasma was removed before cryopreservation, sperm survival after thawing was significantly higher in samples with high seminal plasma CHOL and TAG concentrations, indicating a rapid adherence to these compounds to the sperm plasma membrane, protecting sperm cells from temperature changes. Nevertheless, there were no differences in sperm freezability by sperm morphology.

Exploring Plasma Coenzyme Q10 Status in Paediatric Dyslipidaemia.

Coenzyme Q10 (CoQ) is a ubiquitous lipid with different biological functions. In blood, there is a close relationship between CoQ status and cholesterol, which strongly supports the study of both molecules simultaneously. The objective of this study was to evaluate plasma CoQ, lipoprotein concentrations and CoQ/Chol ratio in a cohort of paediatric patients with different types of dyslipidaemias. A total of 60 paediatric patients were recruited (age range: 7 months-18 years), including 52 with different types of hypercholesterolemia, 2 with isolated hypertriglyceridemia and 6 with hypobetalipoproteinemia. Plasma CoQ was analysed by HPLC with electrochemical detection, and lipoprotein and cholesterol concentrations by standard automated methods. The lowest CoQ values were detected in patients with hypobetalipoproteinemia and in two cases of liver cirrhosis. Mean CoQ values were significantly higher in hypercholesterolemic patients compared to controls (average values 1.07 µmol/L and 0.63 µmol/L) while the CoQ/cholesterol ratio did not show differences (170 vs. 163, respectively). Mean CoQ values were significantly lower in the group of patients with hypobetalipoproteinemia compared to controls (mean CoQ values of 0.22 µmol/L vs. 0.63 µmol/L, respectively), while those of CoQ/cholesterol did not show differences. Pearson's correlation test showed a positive correlation between the CoQ and cholesterol values (r = 0.565, p < 0.001) and between the CoQ and the LDL cholesterol values (r = 0.610, p < 0.001). Our results suggest that it is advisable to analyse plasma CoQ and cholesterol concentrations in patients with hypobetalipoproteinemia and hypercholesterolemia associated with liver damage.

Biochemical and histological changes in two nonalcoholic fatty liver disease models of different severity

Background. One of the priority areas of modern medicine, which unites the interests of various specialists (therapists, cardiologists, gastroenterologists, endocrinologists), is the study of the pathogenesis and clinical manifestations of nonalcoholic fatty liver disease (NAFLD), which is widespread and of unconditional social significance. The search for adequate experimental models of NAFLD that reflect the severity of liver damage is of paramount importance for studying its etiology and pathogenesis.The aim of the study. To compare biochemical and histological changes in experimental models of NAFLD of varying severity.Materials and methods. Two NAFLD model versions were used: a light one – nonalcoholic steatosis (NAS) and a severe variant – non-alcoholic steatohepatitis (NASH). The following biochemical parameters were measured: enzyme activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (AP), plasma glucose concentration, total protein (TP), total bilirubin (TBil) and its conjugate fraction (CB), plasma concentrations of homocysteine (HC), total cholesterol (TC), triacylglycerides (TG), catalase (Cat), superoxide dismutase (SOD) and malondialdehyde (MDA).Results. When used in a model of steatohepatitis, liver function was impaired to a significantly greater extent than in the model of steatosis; this difference was manifested in a statistically significant increase in ALT, AST, AP, TC, Tbil, MDA (p &lt; 0.001) and a decrease in Cat, SOD (p &lt; 0.05). This is confirmed by the development of more pronounced symptoms of disorders of pigment and lipid metabolism, cytolytic and cholestatic syndromes, significant activation of lipid peroxidation and depression of the antioxidant system when modeling non-alcoholic steatohepatitis. Various degrees of severity of morphological changes in the experimental groups were revealed.Conclusion. The study showed the priority of determining biochemical markers, including the levels of ALT, AST, OBIL, TG, MDA and SOD to optimize laboratory methods for diagnosing the severity of liver dystrophy.The practical originality of the results lies in the optimization of the methodology for laboratory diagnosis of the severity of the pathological process in NAFLD.

Inclusion of cocoa bran in the diet of lambs and its effect on reproductive parameters.

The objective of the study was to evaluate the effect of the inclusion of cocoa bran in the diet of lambs and its effect on reproductive parameters. For this, 40 lambs were randomly assigned to four treatments, and including 0, 10, 20 and 30% levels of cocoa bran in the concentrate. Blood was collected to measure cholesterol and testosterone and semen for physical and morphological evaluation; testicular biometry and morphometry were also evaluated. There was significant difference (P < 0.05) in body weight and tubulosomatic index between the lambs in the control treatment and those in the 30% cocoa bran treatment. There was no difference in testicular biometry, physical and morphological parameters of fresh semen, testicular morphometry, and volumetric ratio between lambs in all the treatments (P < 0.05). In addition, there was no difference in plasma cholesterol or testosterone concentration (P > 0.05). Thus, it is possible to include up to 30% of cocoa bran in diet without affecting the reproductive parameters of lambs.

Time profiles of energy balance in dairy cows in association with metabolic status, inflammatory status, and disease

The early lactation period in dairy cows is characterized by complex interactions among energy balance (EB), disease, and alterations in metabolic and inflammatory status. The objective of this study was to cluster cows based on EB time profiles in early lactation and investigate the association between EB clusters and inflammatory status, metabolic status, oxidative stress, and disease. Holstein-Friesian dairy cows (n = 153) were selected and monitored for disease treatments during wk 1 to 6 in lactation. Weekly EB was calculated based on energy intake and energy requirements for maintenance and milk yield in wk 1 to 6 in lactation. Weekly plasma samples were analyzed for metabolic variables in wk 1 to 6, and inflammatory and oxidative stress variables in wk 1, 2, and 4 in lactation. Liver activity index (LAI) was computed from plasma albumin, cholesterol, and retino-binding protein concentration. First, cows were clustered based on time profiles of EB, resulting in 4 clusters (SP: stable positive; MN: mild negative; IN: intermediate negative; SN: severe negative). Cows in the SN cluster had higher plasma nonesterified fatty acids and β-hydroxybutyrate concentrations, compared with cows in the SP cluster, with the MN and IN cluster being intermediate. Cows in the SN cluster had a higher milk yield, lower dry matter intake in wk 1, lower insulin concentration compared with cows in the SP cluster, and lower glucose and IGF-1 concentration compared with cows in the SP and MN clusters. Energy balance clusters were not related with plasma haptoglobin, cholesterol, albumin, paraoxonase, and liver activity index (LAI). Second, cows were grouped based on health status [IHP: cows with treatment for inflammatory health problem (endometritis, fever, clinical mastitis, vaginal discharge or retained placenta); OHP: cows with no IHP but treatment for other health problem (milk fever, cystic ovaries, claw, and leg problems, rumen and intestine problems or other diseases); NHP: cows with no treatments, in the first 6 weeks after calving]. Energy balance was not different among health status groups. The IHP cows had lower nonesterified fatty acids and greater insulin concentration in plasma compared with OHP. The IHP cows had lower plasma albumin concentration, lower LAI and higher haptoglobin concentration compared with OHP and NHP. Overall, EB time profiles were associated with the metabolic status of dairy cows in early lactation, but were only limitedly related with markers of inflammation and oxidative stress status. Inflammatory and metabolic status were related to disease events in early lactation and caused prolonged effects on liver metabolism.

Evaluation and economic analysis of fermented fish viscera silage in diets for tambaqui (Colossoma macropomum) and its effects on the physical quality of pellets, growth performance, health parameters.

The production of silage using fish viscera can be carried out with straightforward methods and permits the exploitation of nutrients that are usually discarded. This process fosters the concept of circular aquaculture. The aim of this study was to evaluate the inclusion of increasing levels of fish viscera silage (VS) on the physical quality of the feed pellets and their effects on their growth performance, health parameters and on economic indices when the experimental extruded feed was offered to tambaqui. A fermented fish VS produced in-house was included in increasing levels on a wet-basis in the formulation of five experimental diets (VS 0%, VS 5%; VS 10%; VS 15%and VS 20%). Juvenile tambaqui (~22.6 g) were stocked in fibreglass tanks of 700 L (n = 4; 21 fish per tank) with a recirculation system and the five experimental diets were attributed in a completely randomized design. The fish were fed with the experimental diets (to apparent satiation) for 13 weeks. At the end of the trial, no significant differences were observed for production performance. Fish fed with the highest inclusion level of VS presented the highest concentration of plasma cholesterol, but this was still within acceptable values for this species. The inclusion of fish VS in diets for juvenile tambaqui reduced the activity of the plasma ALT enzyme, confirming normal liver function. Extruded feed containing fish VS had a production cost of US$ 0.95 per kg, which does not significantly impact the economic indices. Up to 20% of fish VS can be included in the extruded feed formulation for juvenile tambaqui without impairing growth performance or affecting health parameters.

Generation of two familial hypercholesterolemia patient-specific induced pluripotent stem cell lines harboring heterozygous mutations in the LDLR gene

Familial hypercholesterolemia (FH) is a genetic disorder affecting the metabolism of lipoprotein, characterized by elevated levels of plasma concentrations of low-density lipoprotein cholesterol (LDLC). The most common FH cause is mutations within the gene that encodes for the LDL receptor (LDLR) protein. Two induced pluripotent stem cell (iPSC) lines were generated from patients with FH, each carrying a single heterozygous mutation in the LDLR gene, one is a missense mutation, c.631C > T, and the other is a splice-site mutation, c.313 + 1G > A. Both iPSC lines exhibited strong expression of pluripotency markers, demonstrated the ability to differentiate into derivatives of the three germ layers, and maintained normal karyotypes. These derived iPSC lines represent powerful tools for in vitro modeling FH and offer a promising platform for therapeutic development.

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

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): New Amterdam Pharma Background Elevated levels 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. Methods Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (µg/mL) on plasma lipids, cardiovascular disease, Lewy body dementia (LBD), as well as Parkinson’s dementia. Replication was sought by performed Apo-A1 and Apo-B weighted MR analyses of CETP variants. Genetic associations with protein expression in cerebrospinal fluid (CSF) and brain were consulted to identify potential associations of plasma CETP with dementia implicated proteins. Results MR analysis of lower CETP concentration (per µg/mL) recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on CHD (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); Figure. 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. The aforementioned associations were replicated using Apo-B and Apo-A1 weighted analyses; Figure. Additionally, MR was employed to link plasma CETP concentration to the levels of CSF and brain proteins such as EPHA2 and CSF-1, which are in development as dementia drug targets. Conclusion These results suggest that inhibition of CETP may be a viable strategy to treat dementia.