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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 703 records · Page 39
All sourcesNASA NTRSDOE OSTI
DOE OSTI2013

Phylogeonomics and Ecogenomics of the Mycorrhizal Symbiosis

Mycorrhizal fungi play critical roles in host plant health, soil community structure and chemistry, and carbon and nutrient cycling, all areas of intense interest to the US Dept. of Energy (DOE) Joint Genome Institute (JGI). To this end we are building on our earlier sequencing of the Laccaria bicolor genome by partnering with INRA-Nancy and the mycorrhizal research community in the MGI to sequence and analyze 2 dozen mycorrhizal genomes of numerous known mycorrhizal orders and several ecological types (ectomycorrhizal [ECM], ericoid, orchid, and arbuscular). JGI has developed and deployed high-throughput pipelines for genomic, transcriptomic, and re-sequencing, and platforms for assembly, annotation, and analysis. In the last 2 years we have sequenced 21 genomes of mycorrhizal fungi, and resequenced 6 additional strains of L. bicolor. Most of this data is publicly available on JGI MycoCosm?s Mycorrhizal Fungi Portal (http://jgi.doe.gov/Mycorrhizal_fungi/), which provides access to both the genome data and tools with which to analyze the data. These data allow us to address long-standing issues in mycorrhizal evolution and ecology. For example, a major observation of mycorrhizal evolution is that each of the major ecological types appears to have evolved independently in multiple fungal clades. Using an ecogenomic approach we provide preliminary evidence that 2 clades (Cantharellales and Sebacinales) of a single symbiotic ecotype (orchid) utilize some common regulatory (protein tyrosine kinase) and metabolic (lipase) paths, the latter of which may be the product of HGT. Using a phylogenomic approach we provide preliminary evidence that a particular ecotype (ericoid) may have evolved more than once within a major clade (Leotiomycetes).

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Methods for diagnosing bacterial infections

The present invention is directed to methods of determining the presence or absence of a bacterial infection in a patient using isotopically-labeled tyrosine and/or isotopically-labeled p-hydroxyphenylacetic acid.

Timmins, Graham↗
DOE OSTI2021

Self-assembling peptide polymer

A self-assembling peptide is provided that is enzymatically oxidized to form a polymeric pigment. The monomeric peptide has three amino acids (tyrosine (Y), one phenylalanine (F), and one aspartic acid (D) or one lysine (K)) and, following self-assembly and treatment with a tyrosinase enzyme oxidizes and polymerizes into a material with predetermined properties.

Ulijn, Rein Vincent↗
DOE OSTI2013

Interference of silibinin with IGF-1R signalling pathways protects human epidermoid carcinoma A431 cells from UVB-induced apoptosis

Highlights: ► Silibinin protects A431 cells from UVB irradiation-induced apoptosis. ► Up-regulation of the IGF-1R-JNK/ERK pathways by UVB induces cell apoptosis. ► Silibinin inhibits IGF-1R pathways to repress caspase-8-mediated apoptosis. -- Abstract: Ultraviolet B (UVB) from sunlight is a major cause of cutaneous lesion. Silibinin, a traditional hepatic protectant, elicits protective effects against UVB-induced cellular damage. In A431 cells, the insulin-like growth factor-1 receptor (IGF-1R) was markedly up-regulated by UVB irradiation. The activation of the IGF-1R signalling pathways contributed to apoptosis of the cells rather than rescuing the cells from death. Up-regulated IGF-1R stimulated downstream mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinases (JNK) and extracellular signal-regulated protein kinases 1/2 (ERK1/2). The subsequent activation of caspase-8 and caspase-3 led to apoptosis. The activation of IGF-1R signalling pathways is the cause of A431 cell death. The pharmacological inhibitors and the small interfering RNA (siRNA) targeting IGF-1R suppressed the downstream activation of JNK/ERK-caspases to help the survival of the UVB-irradiated A431 cells. Indeed, silibinin treatment suppressed the IGF-1R-JNK/ERK pathways and thus protected the cells from UVB-induced apoptosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Targeting SHP2 for EGFR inhibitor resistant non-small cell lung carcinoma

Highlights: •SHP2 is required for EGFR inhibitor resistant NSCLC H1975 cell proliferation. •SHP2 inhibitor blocks EGF-stimulated ERK1/2 activation and proliferation. •SHP2 inhibitor exhibits marked anti-tumor activity in H1975 xenograft mice. •SHP2 inhibitor synergizes with PI3K inhibitor in suppressing cell growth. •Targeting SHP2 represents a novel strategy for EGFR inhibitor resistant NSCLCs. -- Abstract: Targeted therapy with inhibitors of epidermal growth factor receptor (EGFR) has produced a noticeable benefit to non-small cell lung cancer (NSCLC) patients whose tumors carry activating mutations (e.g. L858R) in EGFR. Unfortunately, these patients develop drug resistance after treatment, due to acquired secondary gatekeeper mutations in EGFR (e.g. T790M). Given the critical role of SHP2 in growth factor receptor signaling, we sought to determine whether targeting SHP2 could have therapeutic value for EGFR inhibitor resistant NSCLC. We show that SHP2 is required for EGF-stimulated ERK1/2 phosphorylation and proliferation in EGFR inhibitor resistant NSCLC cell line H1975, which harbors the EGFR T790M/L858R double-mutant. We demonstrate that treatment of H1975 cells with II-B08, a specific SHP2 inhibitor, phenocopies the observed growth inhibition and reduced ERK1/2 activation seen in cells treated with SHP2 siRNA. Importantly, we also find that II-B08 exhibits marked anti-tumor activity in H1975 xenograft mice. Finally, we observe that combined inhibition of SHP2 and PI3K impairs both the ERK1/2 and PI3K/AKT signaling axes and produces significantly greater effects on repressing H1975 cell growth than inhibition of either protein individually. Collectively, these results suggest that targeting SHP2 may represent an effective strategy for treatment of EGFR inhibitor resistant NSCLCs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Trisomy of the Dscr1 gene suppresses early progression of pancreatic intraepithelial neoplasia driven by oncogenic Kras

Highlights: •A single extra copy of Dscr1 restrains progression of PanIN-1A to PanIN-1B lesions. •Dscr1 trisomy attenuates calcineurin–NFAT pathway in neoplastic ductal epithelium. •Dscr1 trisomy leads to upregulation of p15{sup INK4b} in neoplastic ductal epithelium. •A single extra copy of Dscr1 reduces epithelial proliferation in early PanIN lesions. •Dscr1 trisomy may protect Down syndrome individuals from pancreatic cancer. -- Abstract: Individuals with Down syndrome exhibit remarkably reduced incidence of most solid tumors including pancreatic cancer. Multiple mechanisms arising from the genetic complexity underlying Down syndrome has been suggested to contribute to such a broad cancer protection. In this study, utilizing a genetically engineered mouse model of pancreatic cancer, we demonstrate that trisomy of the Down syndrome critical region-1 (Dscr1), an endogenous calcineurin inhibitor localized on chromosome 21, suppresses the progression of pancreatic intraepithelial neoplasia-1A (PanIN-1A) to PanIN-1B lesions without affecting the initiation of PanIN lesions mediated by oncogenic Kras{sup G12D}. In addition, we show that Dscr1 trisomy attenuates nuclear localization of nuclear factor of activated T-cells (NFAT) accompanied by upregulation of the p15{sup Ink4b} tumor suppressor and reduction of cell proliferation in early PanIN lesions. Our data suggest that attenuation of calcineurin–NFAT signaling in neoplastic pancreatic ductal epithelium by a single extra copy of Dscr1 is sufficient to inhibit the progression of early PanIN lesions driven by oncogenic Kras, and thus may be a potential mechanism underlying reduced incidence of pancreatic cancer in Down syndrome individuals.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Selection of DNA aptamers against epidermal growth factor receptor with high affinity and specificity

Highlights: • This is the first report of DNA aptamer against EGFR in vitro. • Aptamer can bind targets with high affinity and selectivity. • DNA aptamers are more stable, cheap and efficient than RNA aptamers. • Our selected DNA aptamer against EGFR has high affinity with K{sub d} 56 ± 7.3 nM. • Our selected DNA aptamer against EGFR has high selectivity. - Abstract: Epidermal growth factor receptor (EGFR/HER1/c-ErbB1), is overexpressed in many solid cancers, such as epidermoid carcinomas, malignant gliomas, etc. EGFR plays roles in proliferation, invasion, angiogenesis and metastasis of malignant cancer cells and is the ideal antigen for clinical applications in cancer detection, imaging and therapy. Aptamers, the output of the systematic evolution of ligands by exponential enrichment (SELEX), are DNA/RNA oligonucleotides which can bind protein and other substances with specificity. RNA aptamers are undesirable due to their instability and high cost of production. Conversely, DNA aptamers have aroused researcher’s attention because they are easily synthesized, stable, selective, have high binding affinity and are cost-effective to produce. In this study, we have successfully identified DNA aptamers with high binding affinity and selectivity to EGFR. The aptamer named TuTu22 with K{sub d} 56 ± 7.3 nM was chosen from the identified DNA aptamers for further study. Flow cytometry analysis results indicated that the TuTu22 aptamer was able to specifically recognize a variety of cancer cells expressing EGFR but did not bind to the EGFR-negative cells. With all of the aforementioned advantages, the DNA aptamers reported here against cancer biomarker EGFR will facilitate the development of novel targeted cancer detection, imaging and therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Matrix metalloproteinase-14 mediates formation of bile ducts and hepatic maturation of fetal hepatic progenitor cells

Fetal hepatic stem/progenitor cells, called hepatoblasts, play central roles in liver development; however, the molecular mechanisms regulating the phenotype of these cells have not been completely elucidated. Matrix metalloproteinase (MMP)-14 is a type I transmembrane proteinase regulating pericellular proteolysis of the extracellular matrix and is essential for the activation of several MMPs and cytokines. However, the physiological functions of MMP-14 in liver development are unknown. Here we describe a functional role for MMP-14 in hepatic and biliary differentiation of mouse hepatoblasts. MMP-14 was upregulated in cells around the portal vein in perinatal stage liver. Formation of bile duct-like structures in MMP-14–deficient livers was significantly delayed compared with wild-type livers in vivo. In vitro biliary differentiation assays showed that formation of cholangiocytic cysts derived from MMP-14–deficient hepatoblasts was completely impaired, and that overexpression of MMP-14 in hepatoblasts promoted the formation of bile duct-like cysts. In contrast, the expression of molecules associated with metabolic functions in hepatocytes, including hepatic nuclear factor 4α and tryptophan 2,3-dioxygenase, were significantly increased in MMP-14–deficient livers. Expression of the epidermal growth factor receptor and phosphorylation of mitogen-activated protein kinases were significantly upregulated in MMP-14–deficient livers. We demonstrate that MMP-14–mediated signaling in fetal hepatic progenitor cells promotes biliary luminal formation around the portal vein and negatively controls the maturation of hepatocytes. - Highlights: • Loss of MMP-14 delayed formation of bile duct-like structures in perinatal liver. • Overexpression of MMP-14 in hepatobalsts promoted the biliary formation in vitro. • Loss of MMP-14 promoted hepatocyte maturation of hepatoblasts in vivo. • MMP-14–mediated signaling regulates terminal differentiation of hepatoblasts.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

PAK1 translocates into nucleus in response to prolactin but not to estrogen

Tyrosyl phosphorylation of the p21-activated serine–threonine kinase 1 (PAK1) has an essential role in regulating PAK1 functions in breast cancer cells. We previously demonstrated that PAK1 serves as a common node for estrogen (E2)- and prolactin (PRL)-dependent pathways. We hypothesize herein that intracellular localization of PAK1 is affected by PRL and E2 treatments differently. We demonstrate by immunocytochemical analysis that PAK1 nuclear translocation is ligand-dependent: only PRL but not E2 stimulated PAK1 nuclear translocation. Tyrosyl phosphorylation of PAK1 is essential for this nuclear translocation because phospho-tyrosyl-deficient PAK1 Y3F mutant is retained in the cytoplasm in response to PRL. We confirmed these data by Western blot analysis of subcellular fractions. In 30 min of PRL treatment, only 48% of pTyr-PAK1 is retained in the cytoplasm of PAK1 WT clone while 52% re-distributes into the nucleus and pTyr-PAK1 shuttles back to the cytoplasm by 60 min of PRL treatment. In contrast, PAK1 Y3F is retained in the cytoplasm. E2 treatment causes nuclear translocation of neither PAK1 WT nor PAK1 Y3F. Finally, we show by an in vitro kinase assay that PRL but not E2 stimulates PAK1 kinase activity in the nuclear fraction. Thus, PAK1 nuclear translocation is ligand-dependent: PRL activates PAK1 and induces translocation of activated pTyr-PAK1 into nucleus while E2 activates pTyr-PAK1 only in the cytoplasm. - Highlights: • Prolactin but not estrogen causes translocation of PAK1 into nucleus. • Tyrosyl phosphorylation of PAK1 is required for nuclear localization. • Prolactin but not estrogen stimulates PAK1 kinase activity in nucleus.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Inhibition of VEGF-dependent angiogenesis by the anti-CD82 monoclonal antibody 4F9 through regulation of lipid raft microdomains

CD82 (also known as KAI1) belongs to the tetraspanin superfamily of type III transmembrane proteins, and is involved in regulating cell adhesion, migration and proliferation. In contrast to these well-established roles of CD82 in tumor biology, its function in endothelial cell (EC) activity and tumor angiogenesis is yet to be determined. In this study, we show that suppression of CD82 negatively regulates vascular endothelial growth factor (VEGF)-induced angiogenesis. Moreover, we demonstrate that the anti-CD82 mAb 4F9 effectively inhibits phosphorylation of VEGF receptor 2 (VEGFR2), which is the principal mediator of the VEGF-induced angiogenic signaling process in tumor angiogenesis, by regulating the organization of the lipid raft microdomain signaling platform in human EC. Our present work therefore suggests that CD82 on EC is a potential target for anti-angiogenic therapy in VEGFR2-dependent tumor angiogenesis. -- Highlights: •Knockdown of CD82 decreases EC migration, proliferation and angiogenesis. •Anti-CD82 mAb 4F9 inhibits EC migration, proliferation and angiogenesis. •4F9 inhibits VEGFR2 phosphorylation via control of CD82 distribution in lipid rafts.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Soluble FLT-1 rules placental destiny

Highlights: • Placenta previa is an obstetric complication which can cause massive hemorrhage. • Some pregnant women recover from placenta previa due to a phenomenon called “migration” of the placenta. • The sFLT-1 expression level is locally high in the caudal part of the human placenta in patients with placenta previa. • In mice, sFlt-1 expression level was significantly increased by ablation of uterine arteries. • Our study suggests that “migration” of the placenta is derived from placental degeneration and sFlt-1 plays an important role in placental degeneration. Placenta previa is an abnormality in which the placenta covers the internal uterine os, and it can cause serious morbidity and mortality in both mother and fetus due to catastrophic hemorrhage. Some pregnant women recover from placenta previa due to a phenomenon called “migration.” However, the mechanism of “migration” of the placenta has not been elucidated.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Proinflammatory adipokine leptin mediates disinfection byproduct bromodichloromethane-induced early steatohepatitic injury in obesity

Today's developed world faces a major public health challenge in the rise in the obese population and the increased incidence in fatty liver disease. There is a strong association among diet induced obesity, fatty liver disease and development of nonalcoholic steatohepatitis but the environmental link to disease progression remains unclear. Here we demonstrate that in obesity, early steatohepatitic lesions induced by the water disinfection byproduct bromodichloromethane are mediated by increased oxidative stress and leptin which act in synchrony to potentiate disease progression. Low acute exposure to bromodichloromethane (BDCM), in diet-induced obesity produced oxidative stress as shown by increased lipid peroxidation, protein free radical and nitrotyrosine formation and elevated leptin levels. Exposed obese mice showed histopathological signs of early steatohepatitic injury and necrosis. Spontaneous knockout mice for leptin or systemic leptin receptor knockout mice had significantly decreased oxidative stress and TNF-α levels. Co-incubation of leptin and BDCM caused Kupffer cell activation as shown by increased MCP-1 release and NADPH oxidase membrane assembly, a phenomenon that was decreased in Kupffer cells isolated from leptin receptor knockout mice. In obese mice that were BDCM-exposed, livers showed a significant increase in Kupffer cell activation marker CD68 and, increased necrosis as assessed by levels of isocitrate dehydrogenase, events that were decreased in the absence of leptin or its receptor. In conclusion, our results show that exposure to the disinfection byproduct BDCM in diet-induced obesity augments steatohepatitic injury by potentiating the effects of leptin on oxidative stress, Kupffer cell activation and cell death in the liver. - Highlights: ► BDCM acute exposure sensitizes liver to increased free radical stress in obesity. ► BDCM-induced higher leptin contributes to early steatohepatitic lesions. ► Increased leptin mediates protein radical and 3-nitrotyrosine formation. ► BDCM exposure in obesity activates Kupffer cells and NADPH oxidase. ► BDCM/leptin synergy promotes necrotic cell-death and augments steatohepatitis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Low functional programming of renal AT{sub 2}R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal caffeine exposure

Our previous study has indicated that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) of offspring. Recent research suggested that IUGR is a risk factor for glomerulosclerosis. However, whether PCE could induce glomerulosclerosis and its underlying mechanisms remain unknown. This study aimed to demonstrate the induction to glomerulosclerosis in adult offspring by PCE and its intrauterine programming mechanisms. A rat model of IUGR was established by PCE, male fetuses and adult offspring at the age of postnatal week 24 were euthanized. The results revealed that the adult offspring kidneys in the PCE group exhibited glomerulosclerosis as well as interstitial fibrosis, accompanied by elevated levels of serum creatinine and urine protein. Renal angiotensin II receptor type 2 (AT{sub 2}R) gene expression in adult offspring was reduced by PCE, whereas the renal angiotensin II receptor type 1a (AT{sub 1a}R)/AT{sub 2}R expression ratio was increased. The fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, accompanied by a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio. Observation by electronic microscope revealed structural damage of podocytes; the reduced expression level of podocyte marker genes, nephrin and podocin, was also detected by q-PCR. Moreover, AT{sub 2}R gene and protein expressions in fetal kidneys were inhibited by PCE, associated with the repression of the gene expression of glial-cell-line-derived neurotrophic factor (GDNF)/tyrosine kinase receptor (c-Ret) signaling pathway. These results demonstrated that PCE could induce dysplasia of fetal kidneys as well as glomerulosclerosis of adult offspring, and the low functional programming of renal AT{sub 2}R might mediate the developmental origin of adult glomerulosclerosis. - Highlights: • Prenatal caffeine exposure induces glomerulosclerosis in adult offspring. • Prenatal caffeine exposure inhibits fetal kidney development. • Prenatal caffeine exposure causes low functional programming of renal AT{sub 2}R.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Natural products induce a G protein-mediated calcium pathway activating p53 in cancer cells

Paclitaxel, etoposide, vincristine and doxorubicin are examples of natural products being used as chemotherapeutics but with adverse side effects that limit their therapeutic window. Natural products derived from plants and having low toxicity, such as quercetin, resveratrol, epigallocatechin gallate and piceatannol, have been shown to inhibit tumor cell growth both in vitro and in pre-clinical models of cancer, but their mechanisms of action have not been fully elucidated, thus restricting their use as prototypes for developing synthetic analogs with improved anti-cancer properties. We and others have demonstrated that one of the earliest and consistent events upon exposure of tumor cells to these less toxic natural products is a rise in cytoplasmic calcium, activating several pro-apoptotic pathways. We describe here a G protein/inositol 1,4,5-trisphosphate pathway (InsP3) in MDA-MB-231 human breast cancer cells that mediates between these less toxic natural products and the release of calcium from the endoplasmic reticulum. Further, we demonstrate that this elevation of intracellular calcium modulates p53 activity and the subsequent transcription of several pro-apoptotic genes encoding PIG8, CD95, PIDD, TP53INP, RRM2B, Noxa, p21 and PUMA. We conclude from our findings that less toxic natural products likely bind to a G protein coupled receptor that activates a G protein-mediated and calcium-dependent pathway resulting selectively in tumor cell death. - Highlights: • Natural products having low toxicity increase cytoplasmic calcium in cancer cells. • A G-protein/IP{sub 3} pathway mediates the release of calcium from the ER. • The elevation of intracellular calcium modulates p53 activity. • p53 and other Ca{sup 2+}-dependent pro-apoptotic pathways inhibit cancer cell growth.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system

Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease. - Highlights: • Metformin treatment decreases microglial activation in the MPTP model of Parkinson's disease. • Metformin treatment increases the neurodegeneration in the MPTP model of Parkinson's disease, both in vivo and vitro. • Metformin treatment could be a risk factor for the development of Parkinson's disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid- and perfluorooctanesulfonic acid-induced hepatocellular dysfunction

Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), chemicals present in a multitude of consumer products, are persistent organic pollutants. Both compounds induce hepatotoxic effects in rodents, including steatosis, hepatomegaly and liver cancer. The mechanisms of PFOA- and PFOS-induced hepatic dysfunction are not completely understood. We present evidence that PFOA and PFOS induce their hepatic effects via targeting hepatocyte nuclear factor 4-alpha (HNF4α). Human hepatocytes treated with PFOA and PFOS at a concentration relevant to occupational exposure caused a decrease in HNF4α protein without affecting HNF4α mRNA or causing cell death. RNA sequencing analysis combined with Ingenuity Pathway Analysis of global gene expression changes in human hepatocytes treated with PFOA or PFOS indicated alterations in the expression of genes involved in lipid metabolism and tumorigenesis, several of which are regulated by HNF4α. Further investigation of specific HNF4α target gene expression revealed that PFOA and PFOS could promote cellular dedifferentiation and increase cell proliferation by down regulating positive targets (differentiation genes such as CYP7A1) and inducing negative targets of HNF4α (pro-mitogenic genes such as CCND1). Furthermore, in silico docking simulations indicated that PFOA and PFOS could directly interact with HNF4α in a similar manner to endogenous fatty acids. Collectively, these results highlight HNF4α degradation as novel mechanism of PFOA and PFOS-mediated steatosis and tumorigenesis in human livers. - Highlights: • PFOA and PFOS cause decreased HNF4α protein expression in human hepatocytes. • PFOA and PFOS promote changes associated with lipid metabolism and carcinogenesis. • PFOA and PFOS induced changes in gene expression associated with cellular dedifferentiation. • PFOA and PFOS induce expression of Nanog, a transcription factor involved in stem cell development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Endogenous glucocorticoids exacerbate cholestasis-associated liver injury and hypercholesterolemia in mice

Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18 ± 5 ng/ml vs 472 ± 58 ng/ml; P < 0.001) and disrupted the metabolic and anti-inflammatory glucocorticoid function. Adrenal removal did not exacerbate the cholestasis extent. In contrast, the cholestasis-associated liver injury was markedly lower in adrenalectomized mice as compared to controls as evidenced by a 84%–93% decrease in liver necrosis and plasma alanine aminotransferase and bile acid levels (P < 0.001 for all). Gene expression analysis on livers from adrenalectomized mice suggested the absence of bile acid toxicity-associated farnesoid X receptor signaling in the context of a 44% (P < 0.01) and 82% (P < 0.001) reduction in sodium/bile acid cotransporter member 1 transcript level as compared to respectively control and non-diseased mice. Adrenalectomy reduced the expression of the cholesterol synthesis gene HMG-CoA reductase by 70% (P < 0.05), which translated into a 73% lower plasma total cholesterol level (P < 0.05). Treatment of C57BL/6 mice with the glucocorticoid receptor antagonist RU-486 recapitulated the protective effect of adrenalectomy on indices of liver injury and hypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice. - Highlights: • Cholestasis is associated with increased plasma glucocorticoid levels in mice. • Adrenalectomy lowers cholestasis-associated liver injury and hypercholesterolemia. • GR antagonist RU-486 similarly improves the cholestasis phenotype. • Endogenous glucocorticoids promote re-uptake of circulating bile acids into liver.

60 APPLIED LIFE SCIENCES↗