Paternal hypercholesterolemia elicits sex-specific exacerbation of atherosclerosis in adult offspring of LDL receptor-deficient mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE251713 | GEO | 2024/10/08
REPOSITORIES: GEO
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Project description:Paternal hypercholesterolemia elicits sex-specific exacerbation of atherosclerosis in adult offspring of LDL receptor-deficient mice
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Project description:Poor paternal diet has emerged as a risk factor for metabolic disease in offspring, and alterations in sperm may be a major mechanism mediating these detrimental effects of diet. Although exercise in the general population is known to improve health, the effects of paternal exercise on sperm and offspring metabolic health are largely unknown. Here, we studied 7-week-old C57BL/6 male mice fed a chow or high-fat diet and housed either in static cages (sedentary) or cages with attached running wheels (exercise trained). After 3 weeks, one cohort of males was sacrificed and cauda sperm obtained, while the other cohort was bred with chow-fed sedentary C57BL/6 females. Offspring were chow fed, sedentary, and studied during the first year of life. We found that high-fat feeding of sires impairs glucose tolerance and increases the percentage of fat mass in both male and female offspring at 52 weeks of age. Strikingly, paternal exercise suppresses the effects of paternal high-fat diet on offspring, reversing the observed impairment in glucose tolerance, percentage of fat mass, and glucose uptake in skeletal muscles of the offspring. These changes in offspring phenotype are accompanied by changes in sperm physiology, as, for example, high-fat feeding results in decreased sperm motility, an effect normalized in males subject to exercise training. Deep sequencing of sperm reveals pronounced effects of exercise training on multiple classes of small RNAs, as multiple changes to the sperm RNA payload observed in animals consuming a high-fat diet are suppressed by exercise training. Thus, voluntary exercise training of male mice results in pronounced improvements in the metabolic health of adult male and female offspring. We provide the first in-depth analysis of small RNAs in sperm from exercise-trained males, revealing a marked change in the levels of multiple small RNAs with the potential to alter phenotypes in the next generation.
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Project description:Increases in plasma LDL-cholesterol have unequivocally been established as a causal risk factor for atherosclerosis. Hence, strategies for lowering of LDL-cholesterol may have immediate therapeutic relevance. Here we study the role of human neutrophil peptide 1 (HNP1) in a mouse model of atherosclerosis and identify its potent atheroprotective effect both upon transgenic overexpression and therapeutic delivery. The effect was found to be due to a reduction of plasma LDL-cholesterol. Mechanistically, HNP1 binds to apolipoproteins enriched in LDL. This interaction facilitates clearance of LDL particles in the liver via LDL receptor. Thus, we here identify a non-redundant mechanism by which HNP1 allows for reduction of LDL-cholesterol, a process that may be therapeutically instructed to lower cardiovascular risk.
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Project description:Hyperlipidemia is a major risk factor for developing atherosclerosis in humans, and epidemiological studies have correlated specific lipoprotein levels with cardiovascular disease risk. Murine models of atherosclerosis rely on the induction of hyperlipidemia for vascular lesions to form, but the pathogenic contributions attributed to different lipoprotein populations are not well defined. To address this issue, we analyzed over 300 LDL receptor (LDLR) deficient mice that have been fed a high-fat diet and for which a full lipoprotein profile and aortic root atherosclerosis values were assessed. Overall, aortic root atherosclerosis is best predicted by plasma VLDL cholesterol levels with less predictive value derived from either LDL or HDL cholesterol. Triglyceride levels are more atherogenic in female mice, especially immune competent females, and depletion of the adaptive immune system leads to a global reduction in plasma lipid levels and aortic root lesion size yet does not appear to alter the atherogenic potential of individual lipoprotein subspecies. In contrast, HDL-cholesterol is a better predictor of aortic root atherosclerosis in apoE-deficient mice. In summary, this large scale analysis of high-fat diet fed LDLR deficient mice highlight the relationship between different plasma lipid components, especially VLDL-cholesterol, and aortic root atherosclerosis.
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Project description:Watermelon (Citrullus lanatus or C. lanatus) has many potentially bioactive compounds including citrulline, which may influence atherosclerosis. In this study, we determined the effects of C. lanatus, provided as an extract of the cultivar 'sentinel,' on hypercholesterolemia-induced atherosclerosis in mice. Male low-density lipoprotein receptor-deficient mice at 8 weeks old were given either C. lanatus 'sentinel' extract (2% vol/vol; n=10) or a mixture of matching carbohydrates (2% vol/vol; n=8) as the control in drinking water while being fed a saturated fat-enriched diet for 12 weeks ad libitum. Mice consuming C. lanatus 'sentinel' extract had significantly increased plasma citrulline concentrations. Systolic blood pressure was comparable between the two groups. Consumption of C. lanatus 'sentinel' extract led to lower body weight and fat mass without influencing lean mass. There were no differences in food and water intake and in urine output between the two groups. C. lanatus 'sentinel' extract administration decreased plasma cholesterol concentrations that were attributed to reductions of intermediate-/low-density lipoprotein cholesterol. Plasma concentrations of monocyte chemoattractant protein-1 and interferon-gamma were decreased and those of interleukin-10 were increased in mice consuming C. lanatus 'sentinel' extract. Intake of C. lanatus 'sentinel' extract resulted in reductions of atherosclerosis in both aortic arch and thoracic regions. In conclusion, consumption of C. lanatus 'sentinel' extract led to reduced body weight gain, decreased plasma cholesterol concentrations, improved homeostasis of pro- and anti-inflammatory cytokines, and attenuated development of atherosclerosis without affecting systolic blood pressure in hypercholesterolemic mice.
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Project description:Macrophages play a central role in the pathogenesis of atherosclerosis. Our previous study demonstrated that solute carrier family 37 member 2 (SLC37A2), an endoplasmic reticulum-anchored phosphate-linked glucose-6-phosphate transporter, negatively regulates macrophage Toll-like receptor activation by fine-tuning glycolytic reprogramming in vitro. Whether macrophage SLC37A2 impacts in vivo macrophage inflammation and atherosclerosis under hyperlipidemic conditions is unknown. We generated hematopoietic cell-specific SLC37A2 knockout and control mice in C57Bl/6 Ldlr-/- background by bone marrow transplantation. Hematopoietic cell-specific SLC37A2 deletion in Ldlr-/- mice increased plasma lipid concentrations after 12-16 wks of Western diet induction, attenuated macrophage anti-inflammatory responses, and resulted in more atherosclerosis compared to Ldlr-/- mice transplanted with wild type bone marrow. Aortic root intimal area was inversely correlated with plasma IL-10 levels, but not total cholesterol concentrations, suggesting inflammation but not plasma cholesterol was responsible for increased atherosclerosis in bone marrow SLC37A2-deficient mice. Our in vitro study demonstrated that SLC37A2 deficiency impaired IL-4-induced macrophage activation, independently of glycolysis or mitochondrial respiration. Importantly, SLC37A2 deficiency impaired apoptotic cell-induced glycolysis, subsequently attenuating IL-10 production. Our study suggests that SLC37A2 expression is required to support alternative macrophage activation in vitro and in vivo. In vivo disruption of hematopoietic SLC37A2 accelerates atherosclerosis under hyperlipidemic pro-atherogenic conditions.
| S-EPMC8702732 | biostudies-literature
Project description:Between 2% and 12% of adults in the general population report experiencing psychotic-like symptoms, and there is suggestive evidence that these symptoms are associated with risk of schizophrenia and other forms of psychopathology. Older parental age is an established risk factor for schizophrenia, however few studies have attempted to extend this relationship to psychotic-like symptoms. Data come from the National Comorbidity Survey-Replication and analysis is restricted to a subset of respondents who completed questions on psychosis (N=924). Lifetime occurrence of six psychotic-like symptoms (i.e., see a vision others couldn't see, hear voices others couldn't hear) was assessed by self-report. These symptoms were combined into a single binary (any vs. none) variable and analyzed using logistic regression, accounting for the complex survey design. Models were adjusted for age, sex, race/ethnicity, socioeconomic status, marital status, birth order, and history of mood, anxiety, and substance use disorders. Approximately 9% (n=103) of respondents reported at least one psychotic-like symptom. In fully-adjusted models, paternal age was significantly associated with experiencing psychotic-like symptoms (χ(2)=13.34, p=.010). Relative to respondents whose fathers were aged 25 to 29 at the time of their birth, those with fathers aged >35 had 2.12 times higher odds (95% confidence interval: 1.08-4.16) of psychotic-like symptoms. There was no relationship between maternal age (younger or older) and psychotic-like symptoms (χ(2)=0.54, p=.909). Older paternal, but not maternal, age at birth is associated with psychotic-like symptoms in adult offspring.
| S-EPMC4472338 | biostudies-literature
Project description:Nicotine intake, whether through tobacco smoking or e-cigarettes, remains a global health concern. An emerging preclinical literature indicates that parental nicotine exposure produces behavioral, physiological, and molecular changes in subsequent generations. However, the heritable effects of voluntary parental nicotine taking are unknown. Here, we show increased acquisition of nicotine taking in male and female offspring of sires that self-administered nicotine. In contrast, self-administration of sucrose and cocaine were unaltered in male and female offspring suggesting that the intergenerational effects of paternal nicotine taking may be reinforcer specific. Further characterization revealed memory deficits and increased anxiety-like behaviors in drug-naive male, but not female, offspring of nicotine-experienced sires. Using an unbiased, genome-wide approach, we discovered that these phenotypes were associated with decreased expression of Satb2, a transcription factor known to play important roles in synaptic plasticity and memory formation, in the hippocampus of nicotine-sired male offspring. This effect was sex-specific as no changes in Satb2 expression were found in nicotine-sired female offspring. Finally, increasing Satb2 levels in the hippocampus prevented the escalation of nicotine intake and rescued the memory deficits associated with paternal nicotine taking in male offspring. Collectively, these findings indicate that paternal nicotine taking produces heritable sex-specific molecular changes that promote addiction-like phenotypes and memory impairments in male offspring.
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Project description:The impact of maternal nutrition on offspring is well documented. However, the implication of pre-conceptional paternal nutrition on the metabolic health of the progeny remains underexplored. Here, we investigated the impact of paternal high-protein diet (HPD, 43.2% protein) consumption on the endocrine pancreas and the metabolic phenotype of offspring. Male Wistar rats were given HPD or standard diet (SD, 18.9% protein) for two months. The progenies (F1) were studied at fetal stage and in adulthood. Body weight, glycemia, glucose tolerance (GT), glucose-induced insulin secretion in vivo (GIIS) and whole-body insulin sensitivity were assessed in male and female F1 offspring. Insulin sensitivity, GT and GIIS were similar between F1 females from HPD (HPD/F1) and SD fathers (SD/F1). Conversely, male HPD/F1 exhibited increased insulin sensitivity (p < 0.05) and decreased GIIS (p < 0.05) compared to male SD/F1. The improvement of insulin sensitivity in HPD/F1 was sustained even after 2 months of high-fat feeding. In male HPD/F1, the β cell mass was preserved and the β cell plasticity, following metabolic challenge, was enhanced compared to SD/F1. In conclusion, we provide the first evidence of a sex-specific impact of paternal HPD on the insulin sensitivity and GIIS of their descendants, demonstrating that changes in paternal nutrition alter the metabolic status of their progeny in adulthood.
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Project description: Not available
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