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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

HDAC11 deletion reduces fructose-induced cardiac dyslipidemia, apoptosis and inflammation by attenuating oxidative stress injury

Highlights: • HDAC11-knockout improves dyslipidemia in heart of Fru-induced mice. • HDAC11-deficiency reduces apoptosis, oxidative stress and inflammation in heart of mice fed with Fru. • HDAC11-suppression suppresses oxidative stress to reduce apoptosis and inflammation in Fru-treated primary cardiomyocytes. Diabetes mellitus (DM) is a risk factor for abnormal heart development, but the molecular mechanism remains obscure. Histone deacetylase 11 (HDAC11), the most recently identified histone deacetylase, is the sole member of class IV HDACs. However, its role in diabetic cardiac injury is still poorly understood. In the present study, we attempted to explore the effects of HDAC11 on fructose (Fru)-induced cardiac injury using the wild type (HDAC11{sup +/+}) and knockout (HDAC11{sup −/−}) mice. The results indicated that HDAC11 was significantly expressed in human and mouse diabetic heart failure (DHF) hearts. HDAC11{sup −/−} reduced the body weight, inguinal fat-pad mass, and elevated blood pressure in Fru-fed mice. Compared to HDAC11{sup +/+}/Fru group, cardiac function was significantly improved in HDAC11{sup −/−}/Fru mice. HDAC11{sup −/−}/Fru mice exhibited reduced cardiac triacylglycerol (TG), total cholesterol (TC) and free fatty acid (FFA) levels, along with decreased mRNA levels of lipid synthesis-, lipid storage- and lipid oxidation-associated genes. In addition, HDAC11{sup −/−} attenuated apoptosis, oxidative stress and inflammation in the heart of Fru-fed mice, as evidenced by the reduced cleavage of Caspase-3, nicotinamide adenine dinucleotide phosphate (NADPH), and xanthine oxidase (XOD) activity, enhanced superoxide dismutase (SOD) activity, as well as the decreased interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels, which was accompanied with down-regulated p-NF-κB. The results above were verified in Fru-treated primary cardiomyocytes isolated from HDAC11{sup +/+} or HDAC11{sup −/−} mice. Intriguingly, suppressing the expressions of anti-oxidants using zinc protoporphyrin (ZnPP) or siNrf-2 siRNA markedly abolished the results that HDAC11 suppression-induced reduction of apoptosis, reactive oxygen species (ROS) production, inflammation, as well as the improvement of dyslipidemia in Fru-incubated primary cardiomyocytes. Thus, ROS production was responsible for HDAC11-modulated diabetic heart injury. These findings suggested that suppressing HDAC11 has therapeutic potential for treating diabetes mellitus-associated cardiac injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Is There a Need to Revise Goals in the Management of Dyslipidemias?

Purpose of Review: Current guidelines on the management of patients with dyslipidemias recommend specific risk-dependent low-density lipoprotein cholesterol (LDL-C) treatment goals. Recently, several randomized clinical trials have investigated further lowering of LDL-C in addition to statin therapy using novel therapeutic approaches and examined their effects on cardiovascular (CV) risk. This review summarizes newly available data on efficacy and safety of lowering LDL-C beyond statin therapy and below current treatment targets. Recent Findings: In patients at very high risk for CV events, a significant residual risk remains when failing to achieve significant LDL-C reduction on maximally tolerated statin therapy alone. Further lowering of LDL-C, even beyond current treatment targets, has been shown to be safe and was associated with a further reduced CV risk reduction. The relative risk reduction per change in LDL-C levels has been observed to be consistent even in patient populations achieving extremely low levels of LDL-C. Summary: In patients at very high CV risk, further lowering of LDL-C beyond statin therapy and present treatment targets has been observed to further reduce CV risk, which may be foremost relevant for patients at a particular high absolute CV risk, e.g., for patients with progressive and/or very extensive coronary disease.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Dyslipidemia Profiles in Patients with Peripheral Artery Disease

Purpose of Review: This review of the literature aims to discuss the evidence linking different lipid and apolipoprotein measures to peripheral artery disease. Recent Findings: Measures of atherogenic dyslipidemia, including elevations in total cholesterol and total cholesterol/high-density lipoprotein cholesterol as well as low levels of high-density lipoprotein cholesterol, are strongly associated with future risk of peripheral artery disease. Compared to coronary artery disease, there are fewer data showing an association between low-density lipoprotein cholesterol and future risk of peripheral artery disease. Novel lipid measures, including nuclear magnetic resonance-derived lipoproteins and oxidized lipids, may lead to better assessments of future peripheral artery disease risk. Summary: These data highlight the important differences between lipid risk factors for peripheral and coronary artery disease. Improved understanding of these distinctions may lead to new therapeutic options for patients with peripheral artery disease.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Suppressing Irf2bp2 expressions accelerates metabolic syndrome-associated brain injury and hepatic dyslipidemia

Highlights: • Irf2bp2 deletion promotes HFD-induced metabolic syndrome and cognitive dysfunction in mice. • Irf2bp2 knockout aggravates brain injury in HFD-fed mice. • Irf2bp2 ablation alleviates oxidative stress and inflammation in brain of HFD-fed mice. • Suppressing Irf2bp2 expressions exacerbate inflammatory response in PAL- or LPS-treated BV2 cells. Increasing studies indicate that high fat diet (HFD) induces neuroinflammation in animal models with obesity, yet the pathology of it is unclear. Interferon Regulatory Factor 2 Binding Protein 2 (Irf2bp2) is a key regulator of macrophage polarization, playing an essential role in regulating inflammatory response. This study investigated the effects of Irf2bp2 on HFD-induced brain injury, and explored the possible molecular mechanisms using wild type (WT) and Irf2bp2 knockout (KO) mice. The results indicated that HFD-increased body weight of mice was further elevated by Irf2bp2-knockout. In addition, Irf2bp2-deletion accelerated HFD-induced metabolic syndrome, as evidenced by the promoted fasting glucose and insulin levels. In the results of behavioral measurements, Irf2bp2-knockout intensified cognitive deficit in HFD-fed mice by using Y-maze, passive avoidance, and morris water maze (MWM) tests. Further, Irf2bp2-deficiency accelerated the activation of astrocytes and microglia cells, as evidenced by the promoted expressions of glial fibrillary acidic protein (GFAP) and Iba-1 in hippocampus and hypothalamus of HFD-fed mice. HFD for 16 weeks induced oxidative stress in serum and brain of mice, as proved by the up-regulated malondialdehyde (MDA) levels and down-regulated superoxide dismutase (SOD) activity, which were significantly enhanced due to Irf2bp2 knockout. Moreover, HFD-triggered systematic and central nervous inflammation by increasing the release of interleukin 1β (IL-1β) and tumor necrosis factor (TNF)-α, accompanied with elevated p-nuclear factor-κB (NF-κB) expressions. Notably, HFD-induced inflammation was significantly exacerbated by Irf2bp2 deletion. Intriguingly, HFD-induced dyslipidemia in liver of mice was further aggravated by Irf2bp2 suppression. Our in vitro results verified the effects of Irf2bp2-inhibition on the promotion of inflammatory response in BV2 cells and lipid dysfunction in primary hepatocytes. Therefore, the findings above suggested that inhibiting Irf2bp2 expression provided a potential therapeutic approach for the prevention of metabolic syndrome-associated central nervous injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Indole Glucocorticoid Receptor Antagonists Active in a Model of Dyslipidemia Act via a Unique Association with an Agonist Binding Site

To further elucidate the structural activity correlation of glucocorticoid receptor (GR) antagonism, the crystal structure of the GR ligand-binding domain (GR LBD) complex with a nonsteroidal antagonist, compound 8, was determined. This novel indole sulfonamide shows in vitro activity comparable to known GR antagonists such as mifepristone, and notably, this molecule lowers LDL (–74%) and raises HDL (+73%) in a hamster model of dyslipidemia. Here, this is the first reported crystal structure of the GR LBD bound to a nonsteroidal antagonist, and this article provides additional elements for the design and pharmacology of clinically relevant nonsteroidal GR antagonists that may have greater selectivity and fewer side effects than their steroidal counterparts.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2018

Suppression of NF-κB activation by PDLIM2 restrains hepatic lipogenesis and inflammation in high fat diet induced mice

Highlights: • PDLIM2 deficiency promotes HFD-induced mice obesity and insulin resistance. • PDLIM2 deficiency promotes hepatic dyslipidemia in HFD-induced mice. • PDLIM2 deficiency intensifies HFD-induced hepatic inflammation. • Reducing NF-κB activation attenuates PDLIM2 deficiency-exacerbated inflammation and dyslipidemia in PAL-treated primary hepatocytes. Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance, dyslipidemia and a systemic pro-inflammatory response, a leading cause of cirrhosis and hepatocellular carcinoma. Here, we showed that PDZ-LIM domain-containing protein 2 (PDLIM2) was an effective suppressor of steatohepatitis. After 16 weeks on a high fat diet (HFD), obesity, insulin resistance, hepatic dyslipidemia and inflammation were markedly aggravated in PDLIM2-knockout (KO) mice. PDLIM2 deletion resulted in lipid accumulation in liver tissue samples of HFD-induced mice, as evidenced by the significant increase of hepatic TG and TC through reducing the expression of lipogenesis- and transcriptional regulators of lipid metabolism-related genes and enhancing fatty acid oxidation-associated molecules. In addition, PDLIM2-ablation promoted the expression of pro-inflammatory cytokines by activating nuclear factor kappa-B (NF-κB) signaling pathway, as supported by the remarkable increase of phosphorylated IKKβ, IκBα and NF-κB expressions in liver of HFD-fed mice. Of note, the in vitro study demonstrated that PDLIM2 ablation-enhanced inflammatory response and disorder of lipid metabolism were abrogated by suppressing NF-κB activity. Collectively, the findings could lead to the development of potential therapeutic strategy to prevent NAFLD and associated metabolic disorders by targeting PDLIM2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Body Mass Index at Accession and Incident Cardiometabolic Risk Factors in US Army Soldiers, 2001–2011

Individuals entering US Army service are generally young and healthy, but many are overweight, which may impact cardiometabolic risk despite physical activity and fitness requirements. This analysis examines the association between Soldiers’ BMI at accession and incident cardiometabolic risk factors (CRF) using longitudinal data from 731,014 Soldiers (17.0% female; age: 21.6 [3.9] years; BMI: 24.7 [3.8] kg/m 2 ) who were assessed at Army accession, 2001–2011. CRF were defined as incident diagnoses through 2011, by ICD-9 code, of metabolic syndrome, glucose/insulin disorder, hypertension, dyslipidemia, or overweight/obesity (in those not initially overweight/obese). Multivariable-adjusted proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) between BMI categories at accession and CRF. Initially underweight (BMI<18.5 kg/m 2 ) were 2.4% of Soldiers, 53.5% were normal weight (18.5-<25), 34.2% were overweight (25-<30), and 10.0% were obese (≥30). Mean age range at CRF diagnosis was 24–29 years old, with generally low CRF incidence: 228 with metabolic syndrome, 3,880 with a glucose/insulin disorder, 26,373 with hypertension, and 13,404 with dyslipidemia. Of the Soldiers who were not overweight or obese at accession, 5,361 were eventually diagnosed as overweight or obese. Relative to Soldiers who were normal weight at accession, those who were overweight or obese, respectively, had significantly higher risk of developing each CRF after multivariable adjustment (HR [95% CI]: metabolic syndrome: 4.13 [2.87–5.94], 13.36 [9.00–19.83]; glucose/insulin disorder: 1.39 [1.30–1.50], 2.76 [2.52–3.04]; hypertension: 1.85 [1.80–1.90], 3.31 [3.20–3.42]; dyslipidemia: 1.81 [1.75–1.89], 3.19 [3.04–3.35]). Risk of hypertension, dyslipidemia, and overweight/obesity in initially underweight Soldiers was 40%, 31%, and 79% lower, respectively, versus normal-weight Soldiers. BMI in early adulthood has important implications for cardiometabolic health, even within young, physically active populations.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Cav-1 promotes atherosclerosis by activating JNK-associated signaling

Highlights: • Cav-1 expression is up-regulated in endothelial cells of atherosclerotic lesions. • Cav-1 deficiency inhibits HFD-induced inflammation in ApoE–/– mice. • Cav-1 deletion is able to suppress HFD-induced oxidative stress and dyslipidemia in ApoE–/– mice. • JNK signaling is involved in Cav-1-modulated atherosclerosis. The objective of the study is to calculate the role and underlying the molecular mechanisms of caveolin-1 (Cav-1) in atherosclerosis (AS). Cav-1 was mainly expressed in the endothelial cells of atherosclerotic lesions in both human patients and apolipoprotein E deficient (ApoE{sup –/–}) mice. Cav-1 deficiency (Cav-1{sup –/–}) attenuated high-fat diet (HFD)-induced atherosclerotic lesions in ApoE{sup –/–} mice, supported by the reduced aortic plaques. Cav-1{sup –/–} reduced the macrophage content and decreased the release of inflammation-related cytokines or chemokine in serum or abdominal aortas, accompanied with the inactivation of inhibitor κB kinase κ (IKKβ)/p65/IκBα signaling pathway. Also, the activity of mitogen-activated protein kinases 7/c-Jun-N-terminal kinase (MKK7/JNK) signaling was decreased by Cav-1{sup –/–}. In addition, oxidative stress induced by HFD in ApoE{sup –/–} mice was alleviated by Cav-1{sup –/–}. In response to HFD, Cav-1{sup –/–} markedly reduced triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDLC) and very low-density lipoprotein-cholesterol (VLDLC) in serum of HFD-fed ApoE{sup –/–} mice, whereas enhanced high-density lipoprotein-cholesterol (HDLC) contents. Consistent with these findings, haematoxylin and eosin (H&E) and Oil Red O staining showed fewer lipid droplets in the liver of Cav-1-deficient mice. Further, real time-quantitative PCR (RT-qPCR) analysis indicated that Cav-1{sup –/–} alleviated dyslipidemia both in liver and abdominal aortas of ApoE{sup −/-} mice fed with HFD. Cav-1 inhibition-induced attenuation of inflammatory response, oxidative stress and dyslipidemia were confirmed in vitro using mouse vascular smooth muscle cells (VSMCs) treated with ox-LDL. Surprisingly, the processes regulated by Cav-1-knockdown could be abolished through promoting JNK activation in ox-LDL-treated VSMCs. In conclusion, Cav-1 expression could promote HFD-induced AS in a JNK-dependent manner.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Multiple indicators, multiple causes measurement error models

Multiple indicators, multiple causes (MIMIC) models are often employed by researchers studying the effects of an unobservable latent variable on a set of outcomes, when causes of the latent variable are observed. There are times, however, when the causes of the latent variable are not observed because measurements of the causal variable are contaminated by measurement error. The objectives of this study are as follows: (i) to develop a novel model by extending the classical linear MIMIC model to allow both Berkson and classical measurement errors, defining the MIMIC measurement error (MIMIC ME) model; (ii) to develop likelihood-based estimation methods for the MIMIC ME model; and (iii) to apply the newly defined MIMIC ME model to atomic bomb survivor data to study the impact of dyslipidemia and radiation dose on the physical manifestations of dyslipidemia. Finally, as a by-product of our work, we also obtain a data-driven estimate of the variance of the classical measurement error associated with an estimate of the amount of radiation dose received by atomic bomb survivors at the time of their exposure.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2023

Structure-based mechanism and inhibition of cholesteryl ester transfer protein

Purpose of Review: Cholesteryl ester transfer proteins (CETP) regulate plasma cholesterol levels by transferring cholesteryl esters (CEs) among lipoproteins. Lipoprotein cholesterol levels correlate with the risk factors for atherosclerotic cardiovascular disease (ASCVD). This article reviews recent research on CETP structure, lipid transfer mechanism, and its inhibition. Recent Findings: Genetic deficiency in CETP is associated with a low plasma level of low-density lipoprotein cholesterol (LDL-C) and a profoundly elevated plasma level of high-density lipoprotein cholesterol (HDL-C), which correlates with a lower risk of atherosclerotic cardiovascular disease (ASCVD). However, a very high concentration of HDL-C also correlates with increased ASCVD mortality. Considering that the elevated CETP activity is a major determinant of the atherogenic dyslipidemia, i.e., pro-atherogenic reductions in HDL and LDL particle size, inhibition of CETP emerged as a promising pharmacological target during the past two decades. CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, were designed and evaluated in phase III clinical trials for the treatment of ASCVD or dyslipidemia. Although these inhibitors increase in plasma HDL-C levels and/or reduce LDL-C levels, the poor efficacy against ASCVD ended interest in CETP as an anti-ASCVD target. Nevertheless, interest in CETP and the molecular mechanism by which it inhibits CE transfer among lipoproteins persisted. Insights into the structural-based CETP-lipoprotein interactions can unravel CETP inhibition machinery, which can hopefully guide the design of more effective CETP inhibitors that combat ASCVD. Summary: Individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer and which in turn, guide the rational design of new anti-ASCVD therapeutics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Co-administration of APD668, a G protein-coupled receptor 119 agonist and linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in mice fed on a high trans-fat diet

Highlights: • GPR119 a novel therapeutic target for the treatment of dyslipidemia and NASH. • APD668, a GPR119 receptor agonist ameliorated hepatic steatosis in NASH mice. • Co-administration of APD668 and linagliptin resulted in increased GLP-1 levels. • Combination treatment demonstrated enhanced effects in NASH mice. Non-Alcoholic SteatoHepatitis (NASH) is the more severe form of Non-Alcoholic Fatty Liver Disease (NAFLD) and is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, hepatocyte injury with or without fibrosis. Recently, GPR119 receptor has emerged as a novel therapeutic target for the treatment of dyslipidemia and non-alcoholic steatohepatitis. In the present study, we investigated the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor on the progression of steatohepatitis in mice fed on a high trans-fat diet. In this study, monotherapy with either APD668 or linagliptin caused a reduction in the levels of ALT, AST, glucose, cholesterol and epididymal fat mass but the effect was more pronounced upon treatment with combination of both drugs. On the other hand, combined treatment of APD668 with linagliptin demonstrated a non-significant additive effect in reduction of hepatic triglyceride (−78%) and cholesterol (−56%) compared to monotherapy groups. Moreover, co-administration of APD668 and linagliptin resulted in enhanced levels of active GLP-1 with additional benefit of significant synergistic decrease in body weight gain (−19%) in mice. We speculated that the enhanced effect observed with the combination treatment could be due to either 1) direct activation of GPR119 receptors present in liver and intestine or 2) enhanced active GLP-1 levels or 3) decreased degradation of GLP-1 in-vivo through DPPIV inhibition. Therefore, these findings clearly suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of non-alcoholic steatohepatitis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Hyperhomocysteinemia and hyperandrogenemia share PCSK9-LDLR pathway to disrupt lipid homeostasis in PCOS

Highlights: • Hyperhomocysteinemia attenuates PI3K-AKT & WNT signalling and manifests PCOS-like phenotypes in rats. • Hyperhomocysteinemia promotes StAR and atenuates Aromatase expression, and thereby leads to hyperandrogenemia. • Hyperandrogenemia and hyperhomocysteinemia share PCSK9-LDLR pathway and independently induce atherogenic dyslipidemia. • Because of hyperandrogenemia, PCOS patients are inherently at increased risk of cardiovascular disease. • Association of HHcy further aggravates the cardiovascular risk in PCOS. Women with polycystic ovary syndrome (PCOS) are at increased risk of cardiovascular diseases (CVD); however, the independent role of PCOS in the incident CVD remains unknown. There are reports that hyperhomocysteinemia (HHcy), a potential cause of CVD, is frequently associated with PCOS. The present study investigates the independent attributes of hyperandrogenemia (HA), the integral associate of PCOS, and HHcy in causing atherogenic dyslipidemia. Twenty-five-day old rats were treated with homocysteine (Hcy) at 50 mg/kg/day dose level for 12 weeks. The HepG2 cell lines transfected with siRNA directed to PCSK9 were challenged with Hcy, homocysteine thiolactone (HTL), testosterone, 5α-dihydroxytestosterone (5α-DHT), or estradiol for 24 h. Rats administered with Hcy developed HHcy and displayed PCOS-like phenotypes with adversely altered lipid homeostasis and attenuated PI3K-AKT and Wnt signalling cascade. Overexpression of steroidogenic acute regulatory protein (StAR) and down-regulated expression of Aromatase together with elevated testosterone level marked the state of HA. In culture, the HepG2 cells responded independently to Hcy, HTL, testosterone, and 5α-DHT by an overt expression of PCSK9 and down-regulated expression of LDLR. The effect was magnified under the combined influence of Hcy and androgen(s). Estradiol, by contrast, exhibited the reverse effect. The findings suggest that HA may independently attribute to an increased cardiovascular risk in PCOS; however, the coexistence of HHcy catalyzes the risk further.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Exposure to environment chemicals and its possible role in endocrine disruption of children from a rural area

Highlights: • Rural children had elevated blood and hair Mn and Cr levels. • Disruption on thyroid function can be related to metals exposure in rural areas. • Dyslipidemia is associated to thyroid dysfunction in children exposed to metals. • Cholinesterase inhibitors insecticides affect the glucose homeostasis of children. • Children exposed to high levels of Mn can be evaluated through the prolactin. Endocrine disrupting chemicals (EDCs), including pesticides and metals, are present in rural areas, endangering the health of exposed populations. This work aimed to investigate the possible association between the exposure to these xenobiotics and thyroid dysfunction in children living in a rural community of Southern Brazil. Fifty-four children aged 5–16 years participated in this study. Peripheral biomarker evaluations were performed in periods of low and high exposure to pesticides. Thyroid ultrasonography was evaluated in the high exposure period. Blood levels of chromium (Cr), manganese (Mn), mercury (Hg), and lead (Pb), as well as hair Pb levels were positively correlated with thyroid stimulating hormone (TSH) concentrations and negatively associated with free thyroxine (fT4) levels in the low exposure period. Prolactin was positively associated with hair Mn in both periods. In the ultrasound tests, the majority of children presented a normal echogenicity of thyroid. Glucose was inversely associated with the biomarker of exposure to cholinesterase inhibitor insecticides, butyrylcholinesterase (BuChE). Lipid profile was above the recommended levels in both periods. In summary, our results show that children environmentally exposed to a mixture of xenobiotics in an agricultural community may have health impairments, especially on thyroid function, dyslipidemia, and glucose homeostasis disruption.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats

Hypothesis: 10–15% of women take antidepressant medications during pregnancy. A recent clinical study reported that the use of selective serotonin reuptake inhibitor antidepressants during pregnancy is linked with an increased risk of postnatal obesity. While obesity is often associated with fatty liver, dyslipidemia and inflammation, to date, the effects of perinatal exposure to SSRIs on these outcomes are unknown. Methods: Female nulliparous Wistar rats were given vehicle (N = 15) or fluoxetine hydrochloride (FLX 10 mg/kg/d; N = 15) orally for 2 weeks prior to mating until weaning. We assessed glucometabolic changes and hepatic pathophysiology in the offspring. Results: Fluoxetine exposed offspring demonstrated altered glucose homeostasis without any alterations to beta cell mass. FLX-exposed offspring had a significant increase in the number of offspring with mild to moderate NASH and dyslipidemia. There was also increased inflammation of the liver in FLX-exposed offspring; males had significant elevations in TNFα, IL6 and monocyte chemoattractant protein 1 (MCP1), while female offspring had higher expression of TNFα, and increased macrophage infiltration (MCP1). Limitations: This is an animal study. Further research examining the metabolic outcomes of children exposed to antidepressants in utero are required, given the increase in childhood obesity and psychiatric medication use during pregnancy. Conclusion: These data demonstrate that fetal and neonatal exposure to FLX results in evidence of increased adiposity, fatty liver and abnormal glycemic control. Since these are all hallmarks of the metabolic syndrome, this raises concerns regarding the long term metabolic sequelae of fetal exposure to SSRIs in human populations. - Highlights: • Antenatal exposure to fluoxetine results in postnatal adiposity in the offspring. • Offspring exposed to fluoxetine have abnormal glycemic control in adulthood. • Maternal exposure to fluoxetine causes fatty liver in the offspring.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Dysfunction of cholesterol sensor SCAP promotes inflammation activation in THP-1 macrophages

Highlights: • The dysfunction of SCAP interplays with inflammatory responses. • The effect above is independent of SCAP's well-known role in regulating cholesterol homeostasis. • The dysfunction of SCAP mediated the activation of NF-κB signaling pathway. Crosstalk occurs between dyslipidemia and chronic inflammation, which are both precipitants of atherosclerosis. Sterol regulatory element binding proteins cleavage-activating protein (SCAP) plays a key role in regulating cholesterol homeostasis. The present study investigated the effects of SCAP dysfunction on the expression of inflammatory cytokines and lipid metabolism in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assays. The expression of SCAP, HMGCR, pro-IL-1β and N-SREBP2, p65(N) in the nucleus were examined by real-time quantitative RT-PCR and Western blotting. The level of secretary proteins IL-1β, TNF-α and MCP-1 in the supernatants were determined by ELISA. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. Our results demonstrated that over-expression of SCAP significantly increased the expression of HMGCR, pro-IL-1β in the cytoplasm, and mature IL-1β, TNF-α, MCP-1 in the supernatants, while knocking down SCAP dramatically decreased the expression of these molecules. Betulin effectively suppressed the accumulation of intracellular cholesterol in the SCAP over-expressed THP-1 macrophages, but did not affect the expression of inflammatory cytokines, indicating that the pro-inflammatory effect of SCAP was independent of its routine role in regulating cholesterol homeostasis. Furthermore, we investigated the molecular mechanisms mediating the crosstalk between dyslipidemia and inflammatory responses. Knocking down SCAP attenuated LPS-induced IκB phosphorylation and reduced the nuclear level of p65, while over-expression of SCAP increased the nuclear level of p65. Knocking down p65 abolished the proinflammatory effect represented by elevated expression of the inflammatory mediators in the SCAP over-expressed THP-1 macrophages, suggesting that SCAP dysfunction stimulated inflammatory responses via activating the NF-κB signaling pathway. In conclusion, the cholesterol sensor SCAP plays a role in regulating the expression of inflammatory factors such as IL-1β, TNF-α, and MCP-1 in THP-1 macrophages. SCAP mediates the inflammatory response via activating the NF-κB pathway. This new function of SCAP is independent of its role in lipid metabolism.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Validation of a clinical pathway to assess asymptomatic renal transplant candidates using myocardial perfusion imaging

Abstracts: Background: An AHA/ACCF scientific statement proposed 8 risk factors to assess the need for noninvasive coronary artery disease (CAD) surveillance in asymptomatic patients undergoing evaluation for kidney transplantation. The clinical application of these risk factors and the role of noninvasive testing in this context have not been defined. Methods and Results: We retrospectively followed a cohort of 581 consecutive kidney transplant recipients of whom 401 had pre-transplant radionuclide myocardial perfusion imaging (MPI) and 90 had pre-transplant coronary angiography. The sum of pre-transplant AHA/ACCF risk factors (age >60 years, hypertension, diabetes, cardiovascular disease, dyslipidemia, smoking, dialysis >1 year, left ventricular hypertrophy) was calculated. MPI scans were analyzed by a “blinded” reader. Patients were followed for a mean of 3.7 ± 2.3 years post-transplant for major adverse cardiac events (MACE), defined as cardiac death or non-fatal myocardial infarction. The sum of risk factors was associated with modest discriminatory capacity for obstructive angiographic CAD (area under the curve [AUC], 0.70; P = 0.004), 30-day post-operative MACE (AUC, 0.60; P = 0.036), and long-term MACE (AUC, 0.63; P < 0.001). A threshold of ≥3 risk factors was optimal for identifying patients at risk. MPI provided incremental predictive value for obstructive CAD (P = 0.02) and long-term MACE (P = 0.04) but not post-operative MACE (P = 0.56). MPI was best predictive of long-term MACE in intermediate risk (3-4 risk factors) patients. Conclusions: Asymptomatic kidney transplant candidates with ≥3 AHA/ACCF risk factors are at increased cardiac risk, and should be considered for noninvasive CAD surveillance. Intermediate risk patients (3-4 factors) benefit the most from pre-transplant MPI to define long-term MACE risk.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Could FDG-PET imaging play a role in the detection of progressing atherosclerosis in HIV-infected patients?

Important progresses in the management of patients with human immunodeficiency virus, in particular the advent of new anti-retroviral therapies (ART), have turned this rapidly fatal condition into a controllable chronic disease with a life expectancy that approaches the one from the general population. Cardiovascular diseases have now become one of the leading causes of non-HIV-related mortality in this population. Several factors including the presence of HIV in the vascular wall and the development of dyslipidemia and alteration in body fat distribution under ART might play a role the progression of atherosclerosis in HIV-infected patients. The use of imaging biomarkers may help to identify the factors associated with an increased risk of cardiovascular events and select high-risk patients who will benefit the most from the early implementation of preventive treatments.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Comorbid conditions in individuals assessed by SPECT: Study of a reference cardiology center in Mexico City

Background: There is an increasing prevalence of comorbidities in patients with ischemic heart disease (IHD) in developing countries. The aim of this work is to assess the prevalence of comorbidities and associated factors for IHD among patients at a reference cardiology center. Design and Methods: This was a cross-sectional study. A complete clinical history which focused on the main comorbidities, previous myocardial infarction, and the main reason of referral was assessed. A single-photon emission computed tomography (SPECT) myocardial perfusion study (MPS) with two protocols was performed. Results: We included 1998 patients, 64.2% male, median age 63 (I.R.: 56–71) years. 1514 (75.8%) subjects had at least one associated comorbidity. The main comorbidity was diabetes (T2D) (772: 38.6%), followed by systemic hypertension (737: 36.9%), smoking (518: 25.9%), and dyslipidemia (517: 25.9%). 806 (40.3%) had histories of previous myocardial infarctions. The main cause of referral was angina (923: 46.2%). We identified 1330 (66.5%) abnormal MPS. 460 (23%) had ischemia, 292 (14.6%) infarction, and 578 (28.9%) ischemia and infarction. Conclusion: An increased prevalence of comorbidities was found in patients who were studied in the Nuclear Cardiology Department (NCD): most of them had traditional risk factors attributable to myocardial infarction. A great percentage were newly diagnosed with both ischemia and infarction.

62 RADIOLOGY AND NUCLEAR MEDICINE↗