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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 451 records · Page 25
All sourcesNASA NTRSDOE OSTI
NASA NTRS2016

Unpredictable Variable Prenatal Stress Programs Expression of Genes Involved in Appetite Control and Energy Expenditure

Exposure to stress in the womb shapes neurobiological and physiological outcomes of offspring in later life, including body weight regulation and metabolic profiles. Our previous work utilizing a centrifugation-induced hypergravity demonstrated significantly increased (8-15) body mass in male, but not female, rats exposed throughout gestation to chronic 2-g from conception to birth. We reported the same outcome in adult offspring exposed throughout gestation to Unpredictable Variable Prenatal Stress (UVPS). Here we examine gene expression changes using our UVPS model to identify a potential role for prenatal stress in this hypergravity programming effect. Specifically we focused on appetite control and energy expenditure pathways in prenatally stressed adult (90-day-old) male Sprague-Dawley rats. Time-mated female rats were exposed throughout their 22-day pregnancy to UVPS consisting of white noise, strobe light, and tube restraint individually once per day on an unpredictable schedule for 15, 30 or 60 min. To control for potential changes in postnatal maternal care, newborn pups were fostered to non-manipulated, newly parturient dams. At 90-days of age, we analyzed plasma concentrations of hormones involved in appetite control and energy expenditure (leptin and adiponectin), and quantified expression of key genes in epididymal fat pads harvested from adult male offspring and controls. Leptin regulates energy balance by inhibiting hunger, and adiponectin modulates glucose levels and fatty acid breakdown. Our findings indicate significantly elevated plasma leptin concentrations and reduced expression of epididymal fat leptin (OB) and adiponectin (ADIPOQ) genes compared to controls. Analyses presently underway include quantification of plasma insulin and glucose, and the expression of ghrelin, a peptide that acts on the central nervous system and the body's perception of hunger. Collectively, these findings will further understanding of the consequences of UVPS on body weight regulation and metabolism, and provide further insight into the effect of gravity modulation on mammalian fetal development.

Appetite Control↗
DOE OSTI2019

Methods for elevating fat/oil content in plants

In some embodiments, the present invention provides a method of elevating lipid content in vegetative (non-seed) plant or algae cells, plant tissues, or whole plants by genetically modifying the plant or algae to express a lipid droplet-associated protein or polypeptide (such as fat-specific protein 27) of mammalian origin. Also provided are genetically-modified plant or algae cells, plant tissues, or whole plants with elevated cellular lipid content, expressing a lipid droplet-associated protein or polypeptide (such as fat-specific protein 27) of mammalian (e.g. human) origin.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

DCIS integration tests for Lungmen nuclear power plant - 370

The factory acceptance tests (FAT) for distributed control and information systems (DCIS) of Lungmen nuclear power plant (LMNPP) Units 1 and 2 were separately performed by individual suppliers for their supplied scopes. The FAT also included overlap interface tests between the separately supplied scopes, but did not include an overall integration test. There were concerned by the regulator and the public over the lack of an integration test, which was believed to be indispensable to verify the correctness and completeness of a digital system of such large scale ever applied by Taiwan Power Company (Taipower). To address these concerns and enhance confidence in the DCIS, the DCIS integration tests, including reactor water level integration test, reactor pressure integration test, integration test for turbine generator and reactor protection system, integration test for proper plant response to safety and non-safety network equipment failures, and DCIS dynamic integration test, were performed at site during Unit 1| site tests. It is to be noted that these tests were beyond the post construction tests, the pre-operational tests, and the start-up tests, which are the normal industry practice and formally required by the regulator. A common goal for these integration tests is to verify the capability of the DCIS to transmit signal/data properly across various suppliers' equipment to actuate the final equipment. The methods and principle, the test purpose/test items/acceptance criteria and the test results for these tests are described. (authors)

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗
DOE OSTI2019

Reference range of liver corrected T1 values in a population at low risk for fatty liver disease—a UK Biobank sub-study, with an appendix of interesting cases

Purpose: Corrected T1 (cT1) value is a novel MRI-based quantitative metric for assessing a composite of liver inflammation and fibrosis. It has been shown to distinguish between non-alcoholic fatty liver disease (NAFL) and non-alcoholic steatohepatitis. However, these studies were conducted in patients at high risk for liver disease. This study establishes the normal reference range of cT1 values for a large UK population, and assesses interactions of age and gender. Methods: MR data were acquired on a 1.5 T system as part of the UK Biobank Imaging Enhancement study. Measures for Proton Density Fat Fraction and cT1 were calculated from the MRI data using a multiparametric MRI software application. Data that did not meet quality criteria were excluded from further analysis. Inter and intra-reader variability was estimated in a set of data. A cohort at low risk for NAFL was identified by excluding individuals with BMI ≥ 25 kg/m{sup 2} and PDFF ≥ 5%. Of the 2816 participants with data of suitable quality, 1037 (37%) were classified as at low risk. Results: The cT1 values in the low-risk population ranged from 573 to 852 ms with a median of 666 ms and interquartile range from 643 to 694 ms. Iron correction of T1 was necessary in 36.5% of this reference population. Age and gender had minimal effect on cT1 values. Conclusion: The majority of cT1 values are tightly clustered in a population at low risk for NAFL, suggesting it has the potential to serve as a new quantitative imaging biomarker for studies of liver health and disease.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Pathological variants of hepatocellular carcinoma on MRI: emphasis on histopathologic correlation

Hepatocellular carcinoma (HCC) is a unique tumor because it is one of the few cancers which can be treated based on imaging alone. Magnetic resonance imaging (MRI) carries higher sensitivity and specificity for the diagnosis of HCC than either computed tomography (CT) or ultrasound. MRI is imaging modality of choice for the evaluation of complex liver lesions and HCC because of its inherent ability to depict cellularity, fat, and hepatocyte composition with high soft tissue contrast. The imaging features of progressed HCC are well described. However, many HCC tumors do not demonstrate classical imaging features, posing a diagnostic dilemma to radiologists. Some of these can be attributed to variations in tumor biology and histology, which result in radiological features that differ from the typical progressed HCC. This pictorial review seeks to demonstrate the appearance of different variants of HCC on MRI imaging, in relation to their histopathologic features.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

LI-RADS for CT diagnosis of hepatocellular carcinoma: performance of major and ancillary features

Purpose: To evaluate the diagnostic performance of Liver Imaging Reporting and Data System (LI-RADS) v2017 major features, the impact of ancillary features, and categories on contrast-enhanced computed tomography (CECT) for the diagnosis of hepatocellular carcinoma (HCC). Materials and methods: This retrospective study included 59 patients (104 observations including 72 HCCs) with clinical suspicion of HCC undergoing CECT between 2013 and 2016. Two radiologists independently assessed major and ancillary imaging features for each liver observation and assigned a LI-RADS category based on major features only and in combination with ancillary features. The composite reference standard included pathology or imaging. Per-lesion estimates of diagnostic performance of major features, ancillary features, and LI-RADS categories were assessed by generalized estimating equation models. Results: Major features (arterial phase hyperenhancement, washout, capsule, and threshold growth) respectively had a sensitivity of 86.1%, 81.6%, 20.7%, and 26.1% and specificity of 39.3%, 67.9%, 89.9%, and 85.0% for HCC. Ancillary features (ultrasound visibility as discrete nodule, subthreshold growth, and fat in mass more than adjacent liver) respectively had a sensitivity of 42.6%, 50.8%, and 15.1% and a specificity of 79.2%, 66.9%, and 96.4% for HCC. Ancillary features modified the final category in 4 of 104 observations. For HCC diagnosis, categories LR-3, LR-4, LR-5, and LR-TIV (tumor in vein) had a sensitivity of 5.3%, 29.0%, 53.7%, and 10.7%; and a specificity of 49.1%, 84.4%, 97.3%, and 96.4%, respectively. Conclusion: On CT, LR-5 category has near-perfect specificity for the diagnosis of HCC and ancillary features modifies the final category in few observations.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Magnetic resonance imaging features of pubic symphysis urinary fistula with pubic bone osteomyelitis in the treated prostate cancer patient

Introduction: Pubic bone osteomyelitis with pubic symphysis urinary fistula represents a debilitating complication of radiation and ablative treatments for prostate cancer. The definitive radiographic diagnosis of this clinical entity is not described. In this study, we characterize the plain film and magnetic resonance imaging findings of pubic osteomyelitis. Materials and Methods: We reviewed a database of prostate cancer survivors with diagnosed pubic osteomyelitis from 2011 to 2015. These patients underwent pelvic plain radiographs and magnetic resonance imaging with T1-weighted and fat-suppressed T2-weighted fast spin echo sequences. Intravenous gadolinium was utilized. The diagnosis was verified with extirpative surgery. 16 patients with diagnosed pubic osteomyelitis from 2011 to 2015 underwent imaging at our institution. Results: All patients demonstrated increased signal on T2- weighted sequences and decreased signal on T1-weighted sequences along the pubic symphysis and the marrow of the involved pubic rami. Inflammatory myositis with diastasis of the pubic symphysis and cortical bone erosion were identified in the majority of patients. Fluid collections were identified in 75% of patients. 63% of conventional radiographs demonstrated no radiographic evidence of pubic osteomyelitis. Conclusion: Magnetic resonance imaging of pubic symphysis osteomyelitis in the prostate cancer survivor is characterized by high signal on T2-weighted images and low signal on T1-weighted images of the involved pubic rami, with the majority of patients demonstrating regional myositis. Imaging data combined with clinical assessment should prompt diagnosis and management of pubic osteomyelitis. Conventional radiography is generally insensitive to these findings. We consider magnetic resonance imaging to be the definitive diagnostic modality for this clinical entity.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Comparison of navigator-gated and breath-held image acquisition techniques for multi-echo quantitative dixon imaging of the liver in children and young adults

Purpose: Acquired over a breath hold, multi-echo Dixon (mDixon) magnetic resonance imaging (MRI) of the liver can be used to quantify proton density fat fraction (PDFF) and iron-related signal decay. However, young, obese, and co-morbid patients may have limited breath holding capacity and could benefit from a motion-robust mDixon acquisition. The purpose of this study was to compare hepatic PDFF and R2* values between navigator-gated and breath-held mDixon MRI acquisition techniques in children and young adults with suspected liver disease. Materials and methods: This retrospective study was institutional review board-approved with a waiver of informed consent. Patients who underwent liver MRI with breath-held and navigator-gated mDixon sequences between January 2017 and July 2018 were included. One reviewer, blinded to sequence, measured PDFF and R2* on four images from each sequence. Another blinded reviewer graded respiratory motion (5-point Likert scale). Pearson correlation (r), Lin’s concordance coefficients (r{sub c}), and Bland–Altman analyses were used to assess agreement between techniques. Frequency of clinically limiting motion (score ≥ 3) was compared with Fisher’s exact test. Results: Forty-two patients were included (15 female, 27 male; mean age: 15.7 ± 4.6 years). Mean PDFF and R2* were 16.6 ± 13.1% and 29.3 ± 4.7 s{sup −1} (breath-held) versus 17.0 ± 13.2% and 29.6 ± 5.2 s{sup −1} (navigator-gated). PDFF agreed almost perfectly between sequences (r{sub c} = 0.997, 95% CI 0.994–0.998; mean bias: 0.3%; 95% limits of agreement: − 2.4 to +1.7%), while R2* values correlated very strongly but with poor agreement (r = 0.837, r{sub c} = 0.832, 95% CI 0.716–0.910). Navigator-gated images exhibited significantly higher frequency of clinically limiting respiratory motion (88% vs. 48%, p = 0.0001). Conclusion: Despite greater respiratory motion artifact, a free-breathing navigator-gated mDixon sequence produces PDFF values with almost perfect agreement to a breath-held sequence.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

MR-Guided Freehand Biopsy of Liver Lesions With Fast Continuous Imaging Using a 1.0-T Open MRI Scanner: Experience in 50 Patients

The purpose of this study was to assess a new open system with a field-strength of 1.0 T for the feasibility of liver biopsy using the freehand technique with fast continuous imaging. Fifty patients with focal liver lesions measuring 5 to 30 mm in diameter were included in the study. Guidance and monitoring was performed using a 1.0-T open magnetic resonance (MR) scanner (Panorama HFO; Philips Healthcare, Best, The Netherlands). With fast continuous imaging using a T1-weighted (T1W) gradient echo (GRE) sequence after administration of gadolinium (Gd)-EOB-DTPA, the needle was placed into the lesion. An interface for interactive dynamic viewing in two perpendicular planes prevented needle deviations T2-weighted turbo spin echo (TSE) fat-suppressed sequence was added to rule out postinterventional hematoma or biloma. All lesions were visible on the interventional images. Biopsy was technically successful, and solid specimens were obtained in all cases. Forty-six patients showed a histopathologic pattern other than native liver tissue, thus confirming correct position of the needle. Time between determination of the lesion and performance of the control scan was on average 18 min. No major complications were recorded. MR guidance with the new 1-T open system must be considered an attractive alternative for liver punction. An interface for dynamic imaging of needle guidance and T1W-GRE imaging with administration of Gd-EOB-DTPA for contrast enhancement allows the pinpoint puncture of liver lesions.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Enhanced Therapeutic Potency of Nanoemulsified Garlic Oil Blend Towards Renal Abnormalities in Pre-diabetic Rats

The therapeutic potency of ultrasonic nanoemulsified garlic oil blend using a non-ionic surfactant (Tween 80) was assessed on pre-diabetic Wistar rats with microalbuminuria. The pre-diabetic condition was induced in male albino Wistar rats by supplementing high-fat diet. The prolonged period of the pre-diabetic state caused renal dysfunctioning, which was indicated by microalbuminuria. Treatment of pre-diabetic rats with nanoemulsified garlic oil blend significantly ameliorated the lipid profile (p < 0.001), urinary albumin (p < 0.01), microprotein (p < 0.001), urinary triglycerides (p < 0.01), serum triglycerides (p < 0.01), serum albumin (p < 0.05), and protein levels (p < 0.01) in comparison to treatment of pre-diabetic rats with garlic oil blend or atorvastatin. Similarly, histopathological investigations indicated a remarkable attenuation in the mesangial expansion and proliferation, glomerular and tubular basement membrane thickening, and the tubular lipid deposits on administering nanoemulsified garlic oil blend than garlic oil blend or atorvastatin. Moreover, nanoemulsified garlic oil blend significantly promoted renal podocin gene expression by 3.98-fold (p < 0.001) and attenuated increased urinary podocin level by 2.92-fold (p < 0.01). Thus, our study affirms that the efficacy of garlic oil blend was augmented upon nanoemulsification, which substantially ameliorated the renal abnormalities observed in the pre-diabetic condition than garlic oil blend or atorvastatin.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2011

Atrial natriuretic peptide regulates lipid mobilization and oxygen consumption in human adipocytes by activating AMPK

Highlights: {yields} Treatment of differentiated human adipocytes with atrial natriuretic peptide (ANP) increased lipolysis and oxygen consumption by activating AMP-activated protein kinase (AMPK). {yields} ANP stimulated lipid mobilization by selective activation of the alpha2 subunit of AMPK and increased energy utilization through activation of both the alpha1 and alpha2 subunits of AMPK. {yields} ANP enhanced adipocyte mitochondrial oxidative capacity as evidenced by induction of oxidative mitochondrial genes and increase in oxygen consumption. {yields} Exposure of human adipocytes to fatty acids and (TNF{alpha}) induced insulin resistance and decreased expression of mitochondrial genes which was restored to normal by ANP. -- Abstract: Atrial natriuretic peptide (ANP) has been shown to regulate lipid and carbohydrate metabolism providing a possible link between cardiovascular function and metabolism by mediating the switch from carbohydrate to lipid mobilization and oxidation. ANP exerts a potent lipolytic effect via cGMP-dependent protein kinase (cGK)-I mediated-stimulation of AMP-activated protein kinase (AMPK). Activation of the ANP/cGK signaling cascade also promotes muscle mitochondrial biogenesis and fat oxidation. Here we demonstrate that ANP regulates lipid metabolism and oxygen utilization in differentiated human adipocytes by activating the alpha2 subunit of AMPK. ANP treatment increased lipolysis by seven fold and oxygen consumption by two fold, both of which were attenuated by inhibition of AMPK activity. ANP-induced lipolysis was shown to be mediated by the alpha2 subunit of AMPK as introduction of dominant-negative alpha2 subunit of AMPK attenuated ANP effects on lipolysis. ANP-induced activation of AMPK enhanced mitochondrial oxidative capacity as evidenced by a two fold increase in oxygen consumption and induction of mitochondrial genes, including carnitine palmitoyltransferase 1A (CPT1a) by 1.4-fold, cytochrome C (CytC) by 1.3-fold, and peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} (PGC-1{alpha}) by 1.4-fold. Treatment of human adipocytes with fatty acids and tumor necrosis factor {alpha} (TNF{alpha}) induced insulin resistance and down-regulation of mitochondrial genes, which was restored by ANP treatment. These results show that ANP regulates lipid catabolism and enhances energy dissipation through AMPK activation in human adipocytes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Recombinant fusion protein of albumin-retinol binding protein inactivates stellate cells

Highlights: Black-Right-Pointing-Pointer We designed novel recombinant albumin-RBP fusion proteins. Black-Right-Pointing-Pointer Expression of fusion proteins inactivates pancreatic stellate cells (PSCs). Black-Right-Pointing-Pointer Fusion proteins are successfully internalized into and inactivate PSCs. Black-Right-Pointing-Pointer RBP moiety mediates cell specific uptake of fusion protein. -- Abstract: Quiescent pancreatic- (PSCs) and hepatic- (HSCs) stellate cells store vitamin A (retinol) in lipid droplets via retinol binding protein (RBP) receptor and, when activated by profibrogenic stimuli, they transform into myofibroblast-like cells which play a key role in the fibrogenesis. Despite extensive investigations, there is, however, currently no appropriate therapy available for tissue fibrosis. We previously showed that the expression of albumin, composed of three homologous domains (I-III), inhibits stellate cell activation, which requires its high-affinity fatty acid-binding sites asymmetrically distributed in domain I and III. To attain stellate cell-specific uptake, albumin (domain I/III) was coupled to RBP; RBP-albumin{sup domain} {sup III} (R-III) and albumin{sup domain} {sup I}-RBP-albumin{sup III} (I-R-III). To assess the biological activity of fusion proteins, cultured PSCs were used. Like wild type albumin, expression of R-III or I-R-III in PSCs after passage 2 (activated PSCs) induced phenotypic reversal from activated to fat-storing cells. On the other hand, R-III and I-R-III, but not albumin, secreted from transfected 293 cells were successfully internalized into and inactivated PSCs. FPLC-purified R-III was found to be internalized into PSCs via caveolae-mediated endocytosis, and its efficient cellular uptake was also observed in HSCs and podocytes among several cell lines tested. Moreover, tissue distribution of intravenously injected R-III was closely similar to that of RBP. Therefore, our data suggest that albumin-RBP fusion protein comprises of stellate cell inactivation-inducing moiety and targeting moiety, which may lead to the development of effective anti-fibrotic drug.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

The PDZ protein TIP-1 facilitates cell migration and pulmonary metastasis of human invasive breast cancer cells in athymic mice

Highlights: Black-Right-Pointing-Pointer This study has revealed novel oncogenic functions of TIP-1 in human invasive breast cancer. Black-Right-Pointing-Pointer Elevated TIP-1 expression levels in human breast cancers correlate to the disease prognosis. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the cell migration and pulmonary metastasis of human breast cancer cells. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the expression and functionality of motility-related genes. -- Abstract: Tax-interacting protein 1 (TIP-1, also known as Tax1bp3) inhibited proliferation of colon cancer cells through antagonizing the transcriptional activity of beta-catenin. However, in this study, elevated TIP-1 expression levels were detected in human invasive breast cancers. Studies with two human invasive breast cancer cell lines indicated that RNAi-mediated TIP-1 knockdown suppressed the cell adhesion, proliferation, migration and invasion in vitro, and inhibited tumor growth in mammary fat pads and pulmonary metastasis in athymic mice. Biochemical studies showed that TIP-1 knockdown had moderate and differential effects on the beta-catenin-regulated gene expression, but remarkably down regulated the genes for cell adhesion and motility in breast cancer cells. The decreased expression of integrins and paxillin was accompanied with reduced cell adhesion and focal adhesion formation on fibronectin-coated surface. In conclusion, this study revealed a novel oncogenic function of TIP-1 suggesting that TIP-1 holds potential as a prognostic biomarker and a therapeutic target in the treatment of human invasive breast cancers.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Integrator complex plays an essential role in adipose differentiation

Highlights: •IntS6 and IntS11 are subunits of the Integrator complex. •Expression levels of IntS6 and IntS11 were very low in 3T3-L1 fibroblast. •IntS6 and IntS11 were upregulated during adipose differentiation. •Suppression of IntS6 or IntS11 expression inhibited adipose differentiation. -- Abstract: The dynamic process of adipose differentiation involves stepwise expressions of transcription factors and proteins specific to the mature fat cell phenotype. In this study, it was revealed that expression levels of IntS6 and IntS11, subunits of the Integrator complex, were increased in 3T3-L1 cells in the period when the cells reached confluence and differentiated into adipocytes, while being reduced to basal levels after the completion of differentiation. Suppression of IntS6 or IntS11 expression using siRNAs in 3T3-L1 preadipocytes markedly inhibited differentiation into mature adipocytes, based on morphological findings as well as mRNA analysis of adipocyte-specific genes such as Glut4, perilipin and Fabp4. Although Pparγ2 protein expression was suppressed in IntS6 or IntS11-siRNA treated cells, adenoviral forced expression of Pparγ2 failed to restore the capacity for differentiation into mature adipocytes. Taken together, these findings demonstrate that increased expression of Integrator complex subunits is an indispensable event in adipose differentiation. Although further study is necessary to elucidate the underlying mechanism, the processing of U1, U2 small nuclear RNAs may be involved in cell differentiation steps.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Reciprocal regulation of LXRα activity by ASXL1 and ASXL2 in lipogenesis

Highlights: •ASXL1 and ASXL2 directly interact with ligand-bound LXRα. •Ligand-induced LXRα activity is repressed by ASXL1 and activated by ASXL2. •ASXL1 and ASXL2 bind to the LXRE of the LXRα target promoter. •ASXL1 and ASXL2 reciprocally regulate lipogenesis in liver cells. -- Abstract: Liver X receptor alpha (LXRα), a member of the nuclear receptor superfamily, plays a pivotal role in hepatic cholesterol and lipid metabolism, regulating the expression of genes associated with hepatic lipogenesis. The additional sex comb-like (ASXL) family was postulated to regulate chromatin function. Here, we investigate the roles of ASXL1 and ASXL2 in regulating LXRα activity. We found that ASXL1 suppressed ligand-induced LXRα transcriptional activity, whereas ASXL2 increased LXRα activity through direct interaction in the presence of the ligand. Chromatin immunoprecipitation (ChIP) assays showed ligand-dependent recruitment of ASXLs to ABCA1 promoters, like LXRα. Knockdown studies indicated that ASXL1 inhibits, while ASXL2 increases, lipid accumulation in H4IIE cells, similar to their roles in transcriptional regulation. We also found that ASXL1 expression increases under fasting conditions, and decreases in insulin-treated H4IIE cells and the livers of high-fat diet-fed mice. Overall, these results support the reciprocal role of the ASXL family in lipid homeostasis through the opposite regulation of LXRα.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

CDKN2B expression and subcutaneous adipose tissue expandability: Possible influence of the 9p21 atherosclerosis locus

Highlights: • The tumor suppressor gene CDKN2B is highly expressed in human adipose tissue. • Risk alleles at the 9p21 locus modify CDKN2B expression in a BMI-dependent fashion. • There is an inverse relationship between expression of CDKN2B and adipogenic genes. • CDKN2B expression influences to postprandial triacylglycerol clearance. • CDKN2B expression in adipose tissue is linked to markers of hepatic steatosis. - Abstract: Risk alleles within a gene desert at the 9p21 locus constitute the most prevalent genetic determinant of cardiovascular disease. Previous research has demonstrated that 9p21 risk variants influence gene expression in vascular tissues, yet the biological mechanisms by which this would mediate atherosclerosis merits further investigation. To investigate possible influences of this locus on other tissues, we explored expression patterns of 9p21-regulated genes in a panel of multiple human tissues and found that the tumor suppressor CDKN2B was highly expressed in subcutaneous adipose tissue (SAT). CDKN2B expression was regulated by obesity status, and this effect was stronger in carriers of 9p21 risk alleles. Covariation between expression of CDKN2B and genes implemented in adipogenesis was consistent with an inhibitory effect of CDKN2B on SAT proliferation. Moreover, studies of postprandial triacylglycerol clearance indicated that CDKN2B is involved in down-regulation of SAT fatty acid trafficking. CDKN2B expression in SAT correlated with indicators of ectopic fat accumulation, including markers of hepatic steatosis. Among genes regulated by 9p21 risk variants, CDKN2B appears to play a significant role in the regulation of SAT expandability, which is a strong determinant of lipotoxicity and therefore might contribute to the development of atherosclerosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Mitochondrial translocation of Nur77 induced by ROS contributed to cardiomyocyte apoptosis in metabolic syndrome

Highlights: • Metabolic syndrome exacerbated MI/R induced injury accompanied by decreased Nur77. • ROS led to Nur77 translocation in metabolic syndrome. • Inhibiting relocation of Nur77 to mitochondria reduced ROS-induced cardiomyocyte injury in metabolic syndrome. - Abstract: Metabolic syndrome is a major risk factor for cardiovascular diseases, and increased cardiomyocyte apoptosis which contributes to cardiac dysfunction after myocardial ischemia/reperfusion (MI/R) injury. Nur77, a nuclear orphan receptor, is involved in such various cellular events as apoptosis, proliferation, and glucose and lipid metabolism in several cell types. Apoptosis is positively correlated with mitochondrial translocation of Nur77 in the cancer cells. However, the roles of Nur77 on cardiac myocytes in patients with metabolic syndrome remain unclear. The objective of this study was to determine whether Nur77 may contribute to cardiac apoptosis in patients with metabolic syndrome after I/R injury, and, if so, to identify the underlying molecular mechanisms responsible. We used leptin-deficient (ob/ob) mice to make metabolic syndrome models. In this report, we observed that, accompanied by the substantial decline in apoptosis inducer Nur77, MI/R induced cardiac dysfunction was manifested as cardiomyopathy and increased ROS. Using the neonatal rat cardiac myocytes cultured in a high-glucose and high-fat medium, we found that excessive H{sub 2}O{sub 2} led to the significant alteration in mitochondrial membrane potential and translocation of Nur77 from the nucleus to the mitochondria. However, inhibition of the relocation of Nur77 to mitochondria via Cyclosporin A reversed the changes in membrane potential mediated by H{sub 2}O{sub 2} and reduced myocardial cell injury. Therefore, these data provide a potential underlying mechanism for cardiac dysfunction in metabolic syndrome and the suppression of Nur77 translocation may provide an effective approach to reduce cardiac injury in the process.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

PPARγ and MyoD are differentially regulated by myostatin in adipose-derived stem cells and muscle satellite cells

Myostatin (MSTN) is a secreted protein belonging to the transforming growth factor-β (TGF-β) family that is primarily expressed in skeletal muscle and also functions in adipocyte maturation. Studies have shown that MSTN can inhibit adipogenesis in muscle satellite cells (MSCs) but not in adipose-derived stem cells (ADSCs). However, the mechanism by which MSTN differently regulates adipogenesis in these two cell types remains unknown. Peroxisome proliferator-activated receptor-γ (PPARγ) and myogenic differentiation factor (MyoD) are two key transcription factors in fat and muscle cell development that influence adipogenesis. To investigate whether MSTN differentially regulates PPARγ and MyoD, we analyzed PPARγ and MyoD expression by assessing mRNA, protein and methylation levels in ADSCs and MSCs after treatment with 100 ng/mL MSTN for 0, 24, and 48 h. PPARγ mRNA levels were downregulated after 24 h and upregulated after 48 h of treatment in ADSCs, whereas in MSCs, PPARγ levels were downregulated at both time points. MyoD expression was significantly increased in ADSCs and decreased in MSCs. PPARγ and MyoD protein levels were upregulated in ADSCs and downregulated in MSCs. The CpG methylation levels of the PPARγ and MyoD promoters were decreased in ADSCs and increased in MSCs. Therefore, this study demonstrated that the different regulatory adipogenic roles of MSTN in ADSCs and MSCs act by differentially regulating PPARγ and MyoD expression. - Highlights: • PPARγ and MyoD mRNA and protein levels are upregulated by myostatin in ADSCs. • PPARγ and MyoD mRNA and protein levels are downregulated by myostatin in MSCs. • PPARγ exhibited different methylation levels in myostatin-treated ADSCs and MSCs. • MyoD exhibited different methylation levels in myostatin-treated ADSCs and MSCs. • PPARγ and MyoD are differentially regulated by myostatin in ADSCs and MSCs.

60 APPLIED LIFE SCIENCES↗