Plasma Lipid Concentrations Research Articles

Elevated Lipid Concentrations in Seminal Plasma Can Reduce Sperm Motility in Simmental Bulls.

Sperm motility is a key factor influencing male fertility and is associated with metabolic and lipid profiles across species. The aim of this study was to investigate the relationship between sperm motility and the seminal plasma lipid profile in Simmental bulls, and to identify key lipids potentially influencing sperm motility. Semen samples were collected from 26 healthy Simmental bulls with an average age of 4.9 years. Sperm quality was evaluated using computer-assisted sperm analysis (CASA). Based on motility, the samples were divided into two groups: high sperm motility (HSM > 65%) and low sperm motility (LSM < 65%). Compared to the LSM group, the HSM group exhibited significantly higher sperm viability, motility, straight-line velocity, beat-cross frequency, and sperm acrosome integrity, while the sperm malformation rate was lower (p < 0.05). Lipid profiles were determined using LC-MS/MS, and 40 differential lipids were identified by multivariate statistical analysis. Among them, 39 lipids were upregulated in the LSM group compared to the HSM group. They were primarily triglycerides and carnitines, mainly involved in four metabolic pathways related to glycerophospholipid and linoleic acid metabolism. Notably, PC (16:0/20:4; 14:0/18:3), LPC (22:4/0:0; 22:6/0:0), and PE (14:0/18:1; 18:1/20:3) were diagnosed with great accuracy (AUC > 0.7), which means they may serve as potential biomarkers for sperm motility.

Maternal Plasma Lipid Concentration in Early Pregnancy and Risk of Preeclampsia

Objective: To determine the relationship between maternal plasma lipid concentration in early pregnancy and risk of preeclampsia. Study Design: Cross-sectional study. Place and Duration of Study: Gynecology and Obstetrics Department Pak Emirates Military Hospital, Rawalpindi Pakistan, Jan 2019 to Jan 2020. Methodology: A total of 500 pregnant women who came for routine antenatal checkup and underwent serum lipid profile testing at 13th week of pregnancy were included in our study. They were followed up till the end of pregnancy for any signs and symptoms of pre-eclampsia. Age and lipid profile parameters were correlated with the presence of preeclampsia in the study participants. Results: Out of 500 pregnant women studied, 443(88.6%) had no preeclampsia during the course of pregnancy while 53(11.4%) had preeclampsia. Mean age of participants was 33.72±6.731 years. With binary logistic regression analysis, it was found that raised levels of total cholesterol, triglycerides and low density lipoprotein cholesterol at 13 weeks of pregnancy had statistically significant relationship with presence of preeclampsia later among the target population. Conclusion: Deranged lipid profile emerged as strong predictor of preeclampsia in our target population. Raised total cholesterol level, triglyceride levels and low density lipoprotein levels were significantly more in patients who developed preeclampsia as compared to those who did not develop this condition.

Metabolic Effects of Loquat Juice (Eriobotrya japonica Lindl Mkarkeb Variety) on Lipid Homeostasis, Liver Steatosis, and Oxidative Stress in Hyperlipidemic Mice Fed a High-Fat-High-Fructose Diet.

Loquat fruit is consumed for its flavorful taste and a rich array of health-promoting compounds like phenolics, flavonoids, and carotenoids. This study aimed at the biochemical characterization of fresh juice from the Moroccan Mkarkeb variety of loquat and evaluating its effects on lipid homeostasis and liver steatosis in hyperlipidemic mice. The biochemical characterization followed AOAC methods. In vivo study involved hyperlipidemic mice fed a high-fat, high-fructose diet for 6 weeks and treated with loquat juice at 3.5 and 7 mL kg-1 or fenofibrate at 4 mg·kg-1. The concentrations of lipids in plasma, liver, adipose tissue, feces, and bile and blood glucose levels were quantified. Liver steatosis was visually examined and confirmed histologically, and liver injury markers (AST, ALT, ALP, LDH, and TB) were measured. Liver oxidative stress was assessed by measuring MDA content and antioxidative enzyme activities. Our findings indicate that fresh loquat juice is poor in fat and protein and contains moderate sugars with a low energy value (40.82 ± 0.25 kcal/100 g). It is also rich in minerals, vitamin C, phenolic acids, flavonoids, and carotenoids. The juice effectively restored lipid metabolism by enhancing reverse cholesterol transport and lowering LDL-cholesterol, triglycerides, and the atherogenic index. The studied juice decreases blood glucose and prevents weight gain and lipid accumulation in the liver and adipose tissue. The juice prevents lipotoxicity-induced liver injury, corrects toxicity markers, and improves the liver's morphological and histological structures. It also reduces oxidative stress by lowering MDA and activating SOD and catalase. The juice holds high nutritional and medicinal value, potentially preventing lipid disorders and cardiovascular issues.

Assessing lipid-lowering and plasma cholesteryl ester transfer protein activity of Centranthus longiflorus and β-Sitosterol following administration to triton WR1339- treated rats.

The aim of this study was to evaluate the lipid-lowering and plasma cholesteryl ester transfer protein(CETP) activity of Centranthus longiflorus(CL) and β-Sitosterol(βS) following intraperitoneal administration of Triton-WR 1339 (=Tyloxapol) (TWR) to male Wistar rats. Hyperlipidemia(HL) was developed by intraperitoneal injection of TWR. The animals were divided into main eight groups of six rats each. Rats were housed in separate cages and fed a standard diet for 7 days. After 7 days, ethanol extraction of CL plant, aqueous suspension of βS and anacetrapib was given to rats by oral gavage 1 h before the triton injection. Blood samples were collected and used for the biochemical parameters analysis. Histopathological studies were also performed on liver tissue. In hyperlipidemic rats(HR), CL extract and βS reduced total cholesterol similarly. βS lowered low-density lipoprotein(LDL-C) more than CL extract. Both CL extract and βS approximated impaired Alanine transaminase(ALT) and Aspartate transaminase(AST) levels in HR's to the level of control. CL extract provided better protection than βS against deterioration in liver tissue samples seen in hyperlipidemic rats. Finally, CL extract and βS inhibited CETP, at which point βS was more effective. These findings showed that CL extract and βS reduce plasma lipid concentration and may have a hypolipidemic effect due to their anti-CETP properties.

Sedentary behavior reduction and blood lipids in adults with metabolic syndrome: a 6-month randomized controlled trial

The aim of this study was to investigate whether a reduction in accelerometer-measured sedentary behavior (SB) improves blood lipids in inactive adults with metabolic syndrome (MetS). Sixty-four participants were randomly assigned into intervention (INT, n = 33) and control (CONT, n = 31) groups. The INT group was instructed to reduce SB by 1 h/day without increasing formal exercise, whereas the CONT group was advised to maintain usual SB habits. SB and physical activity (PA) were measured with accelerometers throughout the intervention. Plasma lipid concentrations and dietary intake by food diaries were assessed at baseline and at the end of the intervention. High-density lipoprotein percentage of total cholesterol decreased during the intervention similarly in both groups (p = 0.047). Other blood lipids did not change from baseline to six months in either group. The CONT group had a statistically significant reduction in the intake of saturated fatty acids compared to the INT group (p = 0.03). Intervention resulting in a 40-minute reduction in daily SB and 20-minute increase in habitual MVPA seems to not be effective in improving blood lipids in adults with MetS. Reducing SB together with a higher volume and/or intensity of PA and proper nutrition may be needed to reduce the risk of cardiometabolic diseases.Trial registration. This study is registered at ClinicalTrials.gov (NCT03101228, 05/04/2017). https://www.clinicaltrials.gov/ct2/show/NCT03101228?term=NCT03101228&draw=2&rank=1.

Comparative Analysis of Physiological Responses and Intestinal Microbiota in Juvenile Soft-Shelled Turtle (Pelodiscus sinensis) Fed Four Types of Dietary Carbohydrates.

A 60 day feeding trial was conducted to evaluate the impacts of dietary carbohydrates with different complexities and configurations on the growth, plasma parameters, apparent digestibility, intestinal microbiota, glucose, and lipid metabolism of soft-shelled turtles (Pelodiscus sinensis). Four experimental diets were formulated by adding 170 g/kg glucose, fructose, α-starch, or cellulose, respectively. A total of 280 turtles (initial body weight 5.11 ± 0.21 g) were distributed into 28 tanks and were fed twice daily. The results showed that the best growth performance and apparent digestibility was observed in the α-starch group, followed by the glucose, fructose, and cellulose groups (p < 0.05). Monosaccharides (glucose and fructose) significantly enhanced the postprandial plasma glucose levels and hepatosomatic index compared to polysaccharides, due to the un-inhibited gluconeogenesis (p < 0.05). Starch significantly up-regulated the expression of the genes involved in glycolysis, pentose phosphate pathway, lipid anabolism and catabolism, and the transcriptional regulation factors of glycolipid metabolism (srebp and chrebp) (p < 0.05), resulting in higher plasma triglyceride levels and lipid contents in the liver and the whole body. The fructose group exhibited a lower lipid deposition compared with the glucose group, mainly by inhibiting the expression of srebp and chrebp. Cellulose enhanced the proportion of opportunistic pathogenic bacteria. In conclusion, P. sinensis utilized α-starch better than glucose, fructose, and cellulose.

Integration of Lipidomics and Transcriptomics Identifies the Regulation of Lipid Homeostasis as Potential Mechanisms of Konjac Glucomannan against Hepatic Steatosis.

Hepatic steatosis is characterized by substantial disruption in the liver's lipid level regulation. Konjac glucomannan (KGM) is acknowledged as a nutritious food that has the potential to prevent hyperlipidemia. This study utilized lipidomics and transcriptomics to investigate the efficacy of KGM in alleviating high-fat diet-induced hepatic steatosis by regulating lipid homeostasis. The findings indicated that supplementation of KGM for a duration of 10 weeks led to significant decreases in body weight, liver weight, and epididymal fat tissue weight. Furthermore, improvements in lipid concentrations in plasma and liver samples were observed, along with enhancements in glucose tolerance and the mitigation of liver damage. Additionally, lipidomics analysis revealed that the primary differential lipid metabolites were mainly associated with fatty acid metabolism pathways. Transcriptomic analysis showed that KGM significantly altered the gene expression of the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the liver. Moreover, KGM demonstrated a significant regulatory impact on the hepatic expression of PPARγ, potentially mitigating hepatic steatosis through modulation of the PPARγ-mediated lipid metabolism pathway. In conclusion, these findings suggest that KGM effectively mitigates steatosis by modulating hepatic lipid metabolites and controlling PPARγ-mediated genes in the liver.

Abstract 1005: Hypertriglyceridemia Promotes Aortic Aneurysm Formation And Rupture In Angiotensin Ii Infused Mice

Plasma total cholesterol (TC) and triglyceride (TG) are reported to be positively associated with the risk of abdominal aortic aneurysm (AAA). Our group discovered that hypercholesterolemia augments angiotensin II-induced AAA in mice. We also found that remnants of triglyceride-rich lipoproteins (TRLs) may be crucial for AngII-induced AAA. Recently, it was reported that hypertriglyceridemia (HTG) caused by inducible lipoprotein lipase deficiency (iLpl-/-) results in uptake and accumulation of TRL lipid in aortic endothelial cells in vivo. Based upon these findings, we hypothesized that HTG stimulates AAA formation. Methods: Adult male and female Lplf/f.beta-actin-Mer/Cre/Mer 1/0 and Lplf/f mice were administered 75 mg/kg/day tamoxifen for 5 consecutive days. Mice were fed either a standard diet (SD) throughout the study or a Western-type diet (WD) starting 1 wk after the completion of tamoxifen administration and continuing for a total of 5 wks. Mini osmotic pumps were implanted in mice 2 wks after completion of tamoxifen administration and delivered saline or AngII at 1,000 ng/kg/min for 4 wks. Results: AngII infused and SD fed iLpl-/- versus Lplf/f mice had elevated plasma TG and TC levels but similar abdominal aortic external diameter and AAA incidence. Since the SD was low in fat, a high fat WD was then fed to AngII-infused mice. Plasma TG and TC were increased in female iLpl-/- versus Lplf/f mice. However, plasma lipid concentrations could not be measured in male iLpl-/- because 10 of 11 animals had died from aortic rupture. In contrast, none of the male Lplf/f mice died and only 4 of 11 had abdominal aortic dilation. Female compared to male iLpl-/- mice were protected from AngII-induced aortic rupture (1/11 died) and only 1 of 9 females had abdominal aortic dilation. To eliminate the possibility that HTG alone caused aortic rupture in male mice, the study was repeated with the addition of saline infusion. In agreement with the first study, AngII plus WD lead to death by aortic rupture in all male iLpl-/- mice (9/9). In contrast, iLpl-/- male mice infused with saline had markedly greater survival (1/5 died of unknown cause). Conclusions: HTG causes aortic aneurysm development in AngII-infused male iLpl-/- mice. Thus, treating HTG could reduce AAA risk.

Regulation of the Novel MSTN-GAL3-NOX1 Axis Reverses Obesity-Induced Skeletal Muscle Quality Decline Resulting in Improved Glycemic Indices and Restored Angiogenesis Following Ischemia

Objective: To test the hypothesis that restored muscle quality achieved through myostatin KO improves angiogenesis in obese mice through the resolution of GAL3-NOX1-mediated endothelial dysfunction.Methods: db/db mice, a well-described model of obesity, were crossed with mice lacking myostatin (MSTN KO), a myokine that negatively regulates muscle differentiation and growth, galectin-3 (GAL3 KO), a pro-inflammatory/atherogenic RAGE (receptor for advanced glycation endproducts), and NADPH oxidase-1 (NOX1 KO), a TGF-b-stimulated primary producer of the reactive oxygen species (ROS) O2−, to generate db+/−-MSTN+/−, db+/−-GAL3+/−, and db+/−-NOX1+/− mice. We utilized nuclear magnetic resonance (NMR) spectroscopy to assess skeletal muscle (SKM) lean/fat content in db+/−-MSTN+/− mice. Muscle and plasma lipid content were analyzed via mass spectrometry. Mice were placed in metabolic cages and monitored with CLAMS (Comprehensive Lab Animal Monitoring System) in order to determine their whole-body metabolism. Insulin metabolism indices were determined via appropriate blood and plasma testing kits. Morphology of SKM was determined via microscopy of H&amp;E and Mason’s Trichrome-stained gastrocnemius cross sections. Femoral artery ligation was used to stimulate in vivo angiogenesis in response to hind limb ischemia (HLI); whereas 1mm aortic rings cultured in ECBM (2% FBS) were used to study ex vivo angiogenesis. Gene expression was assessed by RNA-Seq and RT-qPCR. Results: MSTN deletion results in significantly increased SKM mass and restored SKM quality (i.e. morphology and metabolic function) without altering whole-body mass, fat percentage, or activity in obese (db−) mice. We observed that obesity inhibits and MSTN KO restores angiogenesis in both HLI and aortic ring assay models. Previous studies in our lab revealed that MSTN deletion was suffcient to restore endothelial function in db/db mice. Additionally, our lab has shown that GAL3 or NOX1 KO in db/db mice phenocopied the vascular improvements seen in db−-MSTN− mice without restoring SKM size or quality. RNA-Seq and RT-qPCR analysis of SKM and endothelial cells (ECs) revealed significant upregulation of GAL3 and NOX1 expression in db−-MSTN+ mice but not in db−-MSTN− and db−-GAL3− mice. Finally, either GAL3 or NOX1 deletion results in amended angiogenesis in obese animals. Conclusion: In summary, restoration of muscle quality in obese individuals provides potent protection of vascular and metabolic health. A correlate of this improvement is the attenuation of a novel MSTN-GAL3-NOX1 axis, which we have shown to mediate vascular inflammation/redox signaling in obesity. These data suggest that pharmacological targeting of upstream MSTN, downstream GAL3 and/or NOX1 could be effective in treating cardiovascular disease in the context of obesity and metabolic syndrome. A. C. Speese is supported by NIH 1F31HL165858-01A1. D.W. Stepp and D. J. Fulton are supported by NIH 1R01HL147159. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Identification of Plasma Lipid Alterations Associated with Melanoma Metastasis.

The aim of this study was to apply a state-of-the-art quantitative lipidomic profiling platform to uncover lipid alterations predictive of melanoma progression. Our study included 151 melanoma patients; of these, 83 were without metastasis and 68 with metastases. Plasma samples were analyzed using a targeted Lipidyzer™ platform, covering 13 lipid classes and over 1100 lipid species. Following quality control filters, 802 lipid species were included in the subsequent analyses. Total plasma lipid contents were significantly reduced in patients with metastasis. Specifically, levels of two out of the thirteen lipid classes (free fatty acids (FFAs) and lactosylceramides (LCERs)) were significantly decreased in patients with metastasis. Three lipids (CE(12:0), FFA(24:1), and TAG47:2-FA16:1) were identified as more effective predictors of melanoma metastasis than the well-known markers LDH and S100B. Furthermore, the predictive value substantially improved upon combining the lipid markers. We observed an increase in the cumulative levels of five lysophosphatidylcholines (LPC(16:0); LPC(18:0); LPC(18:1); LPC(18:2); LPC(20:4)), each individually associated with an elevated risk of lymph node metastasis but not cutaneous or distant metastasis. Additionally, seventeen lipid molecules were linked to patient survival, four of which (CE(12:0), CE(14:0), CE(15:0), SM(14:0)) overlapped with the lipid panel predicting metastasis. This study represents the first comprehensive investigation of the plasma lipidome of melanoma patients to date. Our findings suggest that plasma lipid profiles may serve as important biomarkers for predicting clinical outcomes of melanoma patients, including the presence of metastasis, and may also serve as indicators of patient survival.

A Study on the Modifying Effect of Raspberry Seed Oil on Rabbit Meat Quality and Chemical Composition.

The purpose of the study was to determine the effects of raspberry seed oil on the slaughter performance traits, plasma lipid concentration and meat quality of purebred Termond White rabbits (n = 42; 18♂, 24♀). In each group (3 × n = 14; 6♂, 8♀), the experimental animals were fed a complete pelleted feed with constant access to drinking water. Rabbits in the first experimental group received a feed ration enriched with a 1% addition of raspberry seed oil, while rabbits in the second experimental group were given a 2% addition of the same oil. These animals were slaughtered on day 84. The addition of raspberry seed oil did not significantly affect the slaughter performance traits of the rabbits (p > 0.05). It also did not significantly affect the fat content, shear force, hardness, springiness, cohesiveness or chewiness of the meat obtained from the rabbits' longissimus lumborum muscle. However, the experiment showed that the addition of raspberry seed oil had a significant effect on the fatty acid profile of rabbit meat (p ≤ 0.05). Even a small share of this oil in the feed ration significantly increased the level of linoleic acid (p ≤ 0.05). This study showed that feeding pellets containing an oil supplement with a high content of unsaturated fatty acids had a positive effect on rabbits' plasma lipid levels.

Dietary habits and plasma lipid concentrations in a general Japanese population

IntroductionAccumulating data on the associations between food consumption and lipid composition in the body is essential for understanding the effects of dietary habits on health.ObjectivesAs part of omics research in the Tohoku Medical Megabank Community-Based Cohort Study, this study sought to reveal the dietary impact on plasma lipid concentration in a Japanese population.MethodsWe conducted a correlation analysis of food consumption and plasma lipid concentrations measured using mass spectrometry, for 4032 participants in Miyagi Prefecture, Japan.ResultsOur analysis revealed 83 marked correlations between six food categories and the concentrations of plasma lipids in nine subclasses. Previously reported associations, including those between seafood consumption and omega-3 fatty acids, were validated, while those between dairy product consumption and odd-carbon-number fatty acids (odd-FAs) were validated for the first time in an Asian population. Further analysis suggested that dairy product consumption is associated with odd-FAs via sphingomyelin (SM), which suggests that SM is a carrier of odd-FAs. These results are important for understanding odd-FA metabolism with regards to dairy product consumption.ConclusionThis study provides insight into the dietary impact on plasma lipid concentration in a Japanese population.

Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult

Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is the initially responding site or if atherogenic dyslipidemia affects other organs simultaneously is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA sequencing revealed a Kupffer-cell-specific transcriptional program that was not activated by a high-fat diet alone or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins while simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis.

Associations of drusen location with risk factors and incidence of late age-related macular degeneration in the Alienor study.

To test the hypothesis that central drusen location is strongly linked with known Age-related Macular Degeneration (AMD) risk factors and risk of incident late AMD. The Alienor study is a prospective population-based cohort study of residents of Bordeaux, France, followed from 2009 to 2017. On retinal photographs, we defined central drusen as at least one soft drusen (>63 μm) within 500 μm from fovea and pericentral drusen as at least one drusen 500-3000 μm from fovea, in the absence of any central drusen. Late AMD (atrophic and/or neovascular) was diagnosed using multimodal imaging. In total, 481 eyes were included in the analysis: 160 central and 321 pericentral. We investigated associations with systemic (age, sex, smoking, medical prescriptions, plasma concentrations of lipids and nutrients, UV exposure, blood pressure), ocular (retinal thickness, cataract extraction) and genetic risk scores (GRS). In multivariate logistic regression central drusen were associated with smoking (OR, 2.95 for smoking more than 20 pack-years, p = 0.02), HDL-cholesterol (OR, 1.57 for 1 standard deviation (SD) increase, p = 0.0048), pulse pressure (OR, 0.77 for 1 SD increase, p = 0.04), Age-Related Maculopathy Susceptibility 2 (ARMS2) GRS (OR, 1.42; 95% CI, 1.11-1.83) and complement GRS (OR, 1.55; 95% CI, 1.15-2.10). In Cox modelling, the central location of drusen (at baseline or during the follow-up) was associated with a 4.41-fold increased risk (95% CI,1.98-9.81) for an incident late AMD. Central drusen were strongly associated with AMD risk factors and incident late AMD, suggesting that it represents a key marker for AMD progression.

Inulin alleviates atherosclerosis through improving lipid metabolism, inflammation, and gut microbiota in ApoE-knockout mice: the short-chain is more efficacious.

Atherosclerosis (AS) is considered the underlying cause of many diseases, particularly cardiovascular and cerebrovascular diseases. Inulin, a type of fructan, has shown potential in improving atherosclerosis, although there are conflicting findings. It is hypothesized that the polymerization degree of inulin may largely influence its therapeutic effectiveness. Therefore, this study aimed to investigate the effects and mechanisms of short-chain and long-chain inulin in AS. ApoE-/- mice fed a high fat diet (HFD) were used to establish an atherosclerosis model. These mice received daily oral administration of either short-chain or long-chain inulin for 12weeks. Plasma lipid metabolism-related indices were measured using biochemical analysis, and plasma immunological indices were analyzed via ELISA. The aorta, aortic root regions, liver tissue, adipose tissue, and colon tissue were examined through various staining techniques, including ORO staining, hematoxylin and eosin staining, Alcian blue staining, and immunofluorescent or immunohistochemical assays. Microbiome analysis was conducted in the cecal content. The results indicated that both short-chain and long-chain inulin substantially reduced the formation of atherosclerotic plaques. Inulin also improved plasma lipid concentrations and hepatic lipid metabolism, and partially alleviated both localized (atherosclerotic lesions) and systemic inflammation. Short-chain inulin was more effective than long-chain inulin in reducing atherosclerotic plaques formation, enhancing lipid metabolism and reducing inflammation. Additionally, both types of inulin showed similar effectiveness in enhancing intestinal epithelial barrier integrity, gut microbiota composition and functionality. These findings suggest that inulin has a protective role against atherosclerosis by enhancing lipid metabolism, reducing inflammation, and improving intestinal barrier and gut microbiota. As a dietary intervention, short-chain inulin is more effective than long-chain inulin, offering clinical implications for using inulin as a therapeutic agent for atherosclerosis.

Plasma lipids in Pseudoxanthoma Elasticum (PXE) patients: A comparative study with population-based reference values and Non-PXE controls

- Pseudoxanthoma elasticum (PXE) is a rare genetic disease caused by pathogenic mutations in the ABCC6 gene, resulting in low values of inorganic pyrophosphate (PPi). While low PPi is thought to contribute to arterial calcification, it remains unclear whether this fully explains premature calcification in PXE. It has been hypothesized that the ABCC6 gene could be related to dyslipidemia, which could contribute to vascular calcification seen in PXE. The aim of this study is to evaluate the relation between PXE and plasma lipid concentrations in a large cohort of PXE patients compared with reference values for the general population and compared with non-PXE controls. - The plasma concentrations of total cholesterol, HDL-cholesterol, tiglycerides, and LDL-cholesterol of 312 PXE patients were compared to age- and sex-matched modeled data of the general Dutch population. Differences in median lipid levels were compared with Mann-Whitney-U test. Secondly, plasma lipid concentrations of 44 PXE patients were compared to 44 not-genetically related relatives (spouses or friends), with linear models adjusted for age, sex and BMI. - Total cholesterol in PXE patients was 5.6 [IQR 4.6-6.4] mmol/L versus 5.3 [IQR 4.7-6.0] mmol/L (p<0.01) in the general population; triglycerides were 1.1 [IQR 0.9-1.7] mmol/L versus 1.0 [0.7-1.4] mmol/L (p<0.01); HDL-c was 1.4 [IQR 1.2-1.7] mmol/L versus 1.5 [IQR 1.2-1.8] mmol/L (p=0.03) and LDL-c was 3.3 [IQR 2.7-4.1] mmol/L versus 3.2 [IQR 2.7-3.8] mmol/L (p=0.01). In the patient control analysis with 44 pairs and age, sex and BMI adjusted, comparison with the non-PXE controls only triglycerides were significantly different (mean difference: 0.38 (0.13-0.63)). -The lipid profiles of PXE patients are marginally different from the general population or compared to a matched control group, but the differences are unlikely to be clinically relevant. It is therefore unlikely that plasma lipids contribute to the premature vascular calcifications in PXE patients.

Sex-dependent relationship of polymorphisms in CLOCK and REV-ERBα genes with body mass index and lipid levels in children

Circadian rhythms, which are governed by a circadian clock, regulate important biological processes associated with obesity. SNPs in circadian clock genes have been linked to energy and lipid homeostasis. The aim of our study was to evaluate the associations of CLOCK and REV-ERBα SNPs with BMI and plasma lipid levels in pre-pubertal boys and girls. The study sample population comprised 1268 children aged 6–8 years. Information regarding anthropometric parameters and plasma lipid concentrations was available. Genotyping of CLOCK SNPs rs1801260, rs4580704, rs3749474, rs3736544 and rs4864548 and REV-ERBα SNPs rs2017427, rs20711570 and rs2314339 was performed by RT-PCR. The CLOCK SNPs rs3749474 and rs4864548 were significantly associated with BMI in girls but no in boys. Female carriers of the minor alleles for these SNPs presented lower BMI compared to non-carriers. A significant association of the REV-ERBα SNP rs2071570 with plasma total cholesterol, LDL-cholesterol and Apo B in males was also observed. Male AA carriers showed lower plasma levels of total cholesterol, LDL-cholesterol and Apo B levels as compared with carriers of the C allele. No significant associations between any of the studied REV-ERBα SNPs and plasma lipid levels were observed in females. In summary, CLOCK and REV-ERBα SNPs were associated with BMI and plasma lipid levels respectively in a sex-dependent manner. Our findings suggest that sex-related factors may interact with Clock genes SNPs conditioning the effects of these polymorphisms on circadian alterations.

An Intestinal FXR Agonist Mitigates Dysbiosis, Intestinal Tight Junctions, and Inflammation in High-Fat Diet-Fed Mice.

To analyze the effects of fexaramine (FEX), as an intestinal FXR agonist, on the modulation of the intestinal microbiota and ileum of mice fed a high-fat (HF) diet. Three-month-old C57Bl/6 male mice are divided into two groups and received a control (C, 10% of energy from lipids) or HF (50% of energy from lipids) diet for 12 weeks. They are subdivided into the C, C+FEX, HF, and HF+FEX groups. FEX is administered (FEX-5mgkg-1 ) via orogastric gavage for three weeks. Body mass (BM), glucose metabolism, qPCR16SrRNA gene expression, and ileum gene expression, bile acids (BAs), tight junctions (TJs), and incretin are analyzed. FEX reduces BM and glucose intolerance, reduces plasma lipid concentrations and the Firmicutes/Bacteroidetes ratio, increases the Lactobacillus sp. and Prevotella sp. abundance, and reduces the Escherichia coli abundance. Consequently, the ileal gene expression of Fxr-Fgf15, Tgr5-Glp1, and Cldn-Ocldn-Zo1 is increased, and Tlr4-Il6-Il1beta is decreased. FEX stimulates intestinal FXR and improves dysbiosis, intestinal TJs, and the release of incretins, mitigating glucose intolerance and BM increases induced by an HF diet. However, FEX results in glucose intolerance, insulin resistance, and reduces intestinal TJs in a control group, thus demonstrating limitations to this dietary model.

SMPD3 expression is spatially regulated in the developing embryo by SOXE factors

During epithelial-to-mesenchymal transition (EMT), significant rearrangements occur in plasma membrane protein and lipid content that are important for membrane function and acquisition of cell motility. To gain insight into how neural crest cells regulate their lipid content at the transcriptional level during EMT, here we identify critical enhancer sequences that regulate the expression of SMPD3, a gene responsible for sphingomyelin hydrolysis to produce ceramide and necessary for neural crest EMT. We uncovered three enhancer regions within the first intron of the SMPD3 locus that drive reporter expression in distinct spatial and temporal domains, together collectively recapitulating the expression domains of endogenous SMPD3 within the ectodermal lineages. We further dissected one enhancer that is specifically active in the migrating neural crest. By mutating putative transcriptional input sites or knocking down upstream regulators, we find that the SOXE-family transcription factors SOX9 and SOX10 regulate the expression of SMPD3 in migrating neural crest cells. Further, ChIP-seq and nascent transcription analysis reveal that SOX10 directly regulates expression of an SMPD3 enhancer specific to migratory neural crest cells. Together these results shed light on how core components of developmental gene regulatory networks interact with metabolic effector genes to control changes in membrane lipid content.

Abstract 12411: Fatty Acid Saturation Status in Murine High Fat Diets Modulates Platelet Reactivity

Introduction: We have recently shown that membrane fatty acids are key modulators of megakaryocyte differentiation and platelet formation. In obesity, patients have an altered plasma lipid composition, which coincides with enhanced platelet responsiveness to activation. However, the mechanism underlying this platelet phenotype remains unknown. Hypothesis: We hypothesized that the obese plasma lipidome alters the composition of the megakaryocyte membrane, which ultimately leads to the generation of hyper-reactive platelets. Aim: To investigate the impact of high fat diets with different fatty acid compositions on megakaryocyte development and platelet reactivity. Results: Mice were fed chow or high fat diets enriched in either saturated fatty acids (50% SFAs) or polyunsaturated fatty acids (50% PUFAs, omega-6-enriched). Neither high fat diet resulted in changes in megakaryocyte numbers, but both caused a significant increase in the size of bone marrow megakaryocytes, suggesting diet-derived lipid uptake into megakaryocytes. When examining platelet reactivity, we found that mice fed the SFA-enriched high fat diet exhibited increased expression of the active form of integrin αIIbβ3 (JON/A) in resting platelets and that both JON/A and P-selectin expression were significantly decreased after platelets were stimulated with ADP and the thromboxane A 2 analogue U46619. In contrast, platelets from mice fed the PUFA omega-6-enriched high fat diet had no differences in platelet reactivity compared to mice fed normal chow. Conclusions: Our data reveal that dietary fatty acid saturation status affects platelet reactivity, consistent with previous human studies showing variability in platelet reactivity in obese individuals. Further explorations will elucidate if plasma and/or platelet lipid content may be an indicator of risk for thrombosis or cardiovascular disease.