ORCID Profile
0000-0002-0214-3238
Current Organisations
CSIRO
,
University of New South Wales - Randwick Campus
,
University of Virginia
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Publisher: American Chemical Society (ACS)
Date: 07-03-2023
Publisher: Informa UK Limited
Date: 2019
Publisher: Informa UK Limited
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 17-10-2018
Publisher: Portland Press Ltd.
Date: 02-10-2015
DOI: 10.1042/BJ20150602
Abstract: Null mutations of the Niemann–Pick type C1 (NPC1) gene cause NPC disease, a lysosomal storage disorder characterized by cholesterol accumulation in late endosomes (LE) and lysosomes (Ly). Nascent or mutated NPC1 is degraded through the ubiquitin–proteasome pathway, but how NPC1 degradation is regulated remains currently unknown. In the present study, we demonstrated a link between NPC1 degradation and the Akt (protein kinase B)/mTOR [mammalian (or mechanistic) target of rapamycin] signalling pathway in cervical cancer cell lines. We provided evidence that activated Akt/mTOR pathway increased NPC1 degradation by ∼50% in C33A cells when compared with SiHa or HeLa cells. NPC1 degradation in C33A cells was reversed when Akt/mTOR activation was blocked by specific inhibitors or when mTORC1 (mTOR complex 1) was disrupted by regulatory associated protein of mTOR (Raptor) knockdown. Importantly, inhibition of the Akt/mTOR pathway led to decreased NPC1 ubiquitination in C33A cells, pointing to a role of Akt/mTOR in the proteasomal degradation of NPC1. Moreover, we found that NPC1 depletion in several cancer cell lines inhibited cell proliferation and migration. Our results uncover Akt as a key regulator of NPC1 degradation and link NPC1 to cancer cell proliferation and migration.
Publisher: Springer Science and Business Media LLC
Date: 18-03-2022
DOI: 10.1038/S42003-022-03170-W
Abstract: Dysregulated glucagon secretion from pancreatic alpha-cells is a key feature of type-1 and type-2 diabetes (T1D and T2D), yet our mechanistic understanding of alpha-cell function is underdeveloped relative to insulin-secreting beta-cells. Here we show that the enzyme acetyl-CoA-carboxylase 1 (ACC1), which couples glucose metabolism to lipogenesis, plays a key role in the regulation of glucagon secretion. Pharmacological inhibition of ACC1 in mouse islets or αTC9 cells impaired glucagon secretion at low glucose (1 mmol/l). Likewise, deletion of ACC1 in alpha-cells in mice reduced glucagon secretion at low glucose in isolated islets, and in response to fasting or insulin-induced hypoglycaemia in vivo. Electrophysiological recordings identified impaired K ATP channel activity and P/Q- and L-type calcium currents in alpha-cells lacking ACC1, explaining the loss of glucose-sensing. ACC-dependent alterations in S-acylation of the K ATP channel subunit, Kir6.2, were identified by acyl-biotin exchange assays. Histological analysis identified that loss of ACC1 caused a reduction in alpha-cell area of the pancreas, glucagon content and in idual alpha-cell size, further impairing secretory capacity. Loss of ACC1 also reduced the release of glucagon-like peptide 1 (GLP-1) in primary gastrointestinal crypts. Together, these data reveal a role for the ACC1-coupled pathway in proglucagon-expressing nutrient-responsive endocrine cell function and systemic glucose homeostasis.
Publisher: Wiley
Date: 27-06-2013
DOI: 10.1096/FJ.13-228486
Publisher: Society of Exploration Geophysicists
Date: 09-11-2021
Abstract: Calculating an accurate seismic velocity model serves an important role in many seismic imaging techniques. The process of velocity model building is often time-consuming, specifically for anisotropic areas, where more than a single parameter is involved in the process. In the past few years, more time-efficient approaches have been considered to estimate seismic velocity as well as anellipticity parameter or heterogeneity factor using local event slopes. Nevertheless, some of these techniques are not practical due to curvature-dependency, or due to the lack of near-offset data. To address such limitations, we have used a curvature-independent approach for normal-moveout correction as well as parameter estimation in vertical transverse isotropic media, which is based on local estimation of vertical traveltime using a shifted-hyperbola approximation in the absence of near-offset data. The performance of our approach is tested on synthetic and field common-midpoint gathers. It is also assessed in different signal-to-noise ratios and different missing-near-offset situations. Our findings are consistent with the results achieved by the previous methods that were not developed for sparse data.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Elsevier BV
Date: 06-2012
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0NA01013H
Abstract: Biopolymer-capped silver nanoparticle synthesis. Compositional and stability analysis of synthesised particles. Proteomic analysis of particles following serum exposure. In vitro hemolytic assays. Organ distribution following administration in mice.
Publisher: American Physiological Society
Date: 08-2018
DOI: 10.1152/AJPENDO.00082.2018
Abstract: Glucose transporter 6 (GLUT6) is a member of the facilitative glucose transporter family. GLUT6 is upregulated in several cancers but is not widely expressed in normal tissues. Previous studies have shown that GLUT6 knockdown kills endometrial cancer cells that express elevated levels of the protein. However, whether GLUT6 represents a viable anticancer drug target is unclear because the role of GLUT6 in normal metabolic physiology is unknown. Herein we generated GLUT6 knockout mice to determine how loss of GLUT6 affected whole body glucose homeostasis and metabolic physiology. We found that the mouse GLUT6 ( Slc2a6) gene expression pattern was similar to humans with mRNA found primarily in brain and spleen. CRISPR-Cas9-mediated deletion of Slc2a6 did not alter mouse development, growth, or whole body glucose metabolism in male or female mice fed either a chow diet or Western diet. GLUT6 deletion did not impact glucose tolerance or blood glucose and insulin levels in male or female mice fed either diet. However, compared with wild-type littermate controls, GLUT6 null female mice had a relatively minor decrease in fat accumulation when fed Western diet and had a lower respiratory exchange ratio when fed chow diet. Collectively, these data show that GLUT6 is not a major regulator of whole body metabolic physiology therefore, GLUT6 inhibition may have minimal adverse effects if targeted for cancer therapy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2015
Publisher: Elsevier BV
Date: 05-2012
Publisher: Oxford University Press (OUP)
Date: 06-2007
Publisher: Wiley
Date: 30-03-2016
DOI: 10.1002/PATH.4702
Publisher: MDPI AG
Date: 05-09-2018
Abstract: Rodent models of liver tumorigenesis have reproducibly shown that dietary sugar intake is a powerful driver of liver tumor initiation and growth. In contrast, dietary sugar restriction with ketogenic diets or calorie restriction generally prevents liver tumor formation. Ketogenic diet is viewed positively as a therapeutic adjuvant however, most ketogenic diet studies described to date have been performed in prevention mode rather than treatment mode. Therefore, it remains unclear whether a ketogenic diet can be administered in late stages of disease to stall or reverse liver tumor growth. To model the clinically relevant treatment mode, we administered a ketogenic diet to mice after liver tumor initiation and monitored tumor growth by magnetic resonance imaging (MRI). Male C57BL/6 mice were injected with diethylnitrosamine (DEN) at 2 weeks of age and fed a chow diet until 39 weeks of age, when they underwent MRI imaging to detect liver tumors. Mice were then randomised into two groups and fed either a chow diet or switched to a ketogenic diet from 40–48 weeks of age. Serial MRIs were performed at 44 and 48 weeks of age. All mice had tumors at study completion and there were no differences in total tumor burden between diet groups. Although a ketogenic diet has marked protective effects against DEN-induced liver tumourigenesis in this mouse model, these data demonstrate that ketogenic diet cannot stop the progression of established liver tumors.
Publisher: Society of Exploration Geophysicists
Date: 02-06-2022
Abstract: Normal-moveout (NMO) correction is an inevitable part of routine seismic data processing and imaging. NMO correction suffers from an undesirable phenomenon called NMO stretching, which is more pronounced in larger emerging angles. Frequency distortions caused by NMO stretching for isotropic media have fully been studied in the literature. We express the distortions for the simplest case of anisotropy, which is vertical transverse isotropic media. This is done through different nonhyperbolic approximations, including shifted-hyperbola approximation, rational approximation, and generalized moveout approximation (GMA). To evaluate the predicted distortions, we define a trace-muting threshold and use it in the trace-muting procedure for synthetic data, as well as a field recorded ex le. Comparison between the results proves that the GMA has the highest accuracy among the other presented approximations. The proposed approach has an immediate potential to be used in industry and also to help to develop innovative nonstretch NMO correction workflows.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2018
DOI: 10.1038/S41419-017-0044-1
Abstract: Mitogen-activated protein kinase (MAPK) pathway inhibitors show promise in treating melanoma, but are unsuccessful in achieving long-term remission. Concordant with clinical data, BRAF V600E melanoma cells eliminate glycolysis upon inhibition of BRAF V600E or MEK with the targeted therapies Vemurafenib or Trametinib, respectively. Consequently, exposure to these therapies reprograms cellular metabolism to increase mitochondrial respiration and restrain cell death commitment. As the inner mitochondrial membrane (IMM) is sub-organellar site of oxidative phosphorylation (OXPHOS), and the outer mitochondrial membrane (OMM) is the major site of anti-apoptotic BCL-2 protein function, we hypothesized that suppressing these critical mitochondrial membrane functions would be a rational approach to maximize the pro-apoptotic effect of MAPK inhibition. Here, we demonstrate that disruption of OXPHOS with the mitochondria-specific protonophore BAM15 promotes the mitochondrial pathway of apoptosis only when oncogenic MAPK signaling is inhibited. Based on RNA-sequencing analyses of nevi and primary melanoma s les, increased pro-apoptotic BCL-2 family expression positively correlates with high-risk disease suggesting a highly active anti-apoptotic BCL-2 protein repertoire likely contributes to worse outcome. Indeed, combined inhibition of the anti-apoptotic BCL-2 repertoire with BH3-mimetics, OXPHOS, and oncogenic MAPK signaling induces fulminant apoptosis and eliminates clonogenic survival. Altogether, these data suggest that dual suppression of IMM and OMM functions may unleash the normally inadequate pro-apoptotic effects of oncogenic MAPK inhibition to eradicate cancer cells, thus preventing the development of resistant disease, and ultimately, supporting long-term remission.
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.CMET.2008.09.011
Abstract: The unconventional myosin Myo1c has been implicated in insulin-regulated GLUT4 translocation to the plasma membrane in adipocytes. We show that Myo1c undergoes insulin-dependent phosphorylation at S701. Phosphorylation was accompanied by enhanced 14-3-3 binding and reduced calmodulin binding. Recombinant CaMKII phosphorylated Myo1c in vitro and siRNA knockdown of CaMKIIdelta abolished insulin-dependent Myo1c phosphorylation in vivo. CaMKII activity was increased upon insulin treatment and the CaMKII inhibitors CN21 and KN-62 or the Ca(2+) chelator BAPTA-AM blocked insulin-dependent Myo1c phosphorylation and insulin-stimulated glucose transport in adipocytes. Myo1c ATPase activity was increased after CaMKII phosphorylation in vitro and after insulin stimulation of CHO/IR/IRS-1 cells. Expression of wild-type Myo1c, but not S701A or ATPase dead mutant K111A, rescued the inhibition of GLUT4 translocation by siRNA-mediated Myo1c knockdown. These data suggest that insulin regulates Myo1c function via CaMKII-dependent phosphorylation, and these events play a role in insulin-regulated GLUT4 trafficking in adipocytes likely involving Myo1c motor activity.
Publisher: The Endocrine Society
Date: 11-2012
DOI: 10.1210/EN.2012-1368
Abstract: Adiponectin is an adipokine whose plasma levels are inversely related to degrees of insulin resistance (IR) or obesity. It enhances glucose disposal and mitochondrial substrate oxidation in skeletal muscle and its actions are mediated through binding to receptors, especially adiponectin receptor 1 (AdipoR1). However, the in vivo significance of adiponectin sensitivity and the molecular mechanisms of muscle insulin sensitization by adiponectin have not been fully established. We used in vivo electrotransfer to overexpress AdipoR1 in single muscles of rats, some of which were fed for 6 wk with chow or high-fat diet (HFD) and then subjected to hyperinsulinemic-euglycemic cl . After 1 wk, the effects on glucose disposal, signaling, and sphingolipid metabolism were investigated in test vs. contralateral control muscles. AdipoR1 overexpression (OE) increased glucose uptake and glycogen accumulation in the basal and insulin-treated rat muscle and also in the HFD-fed rats, locally ameliorating muscle IR. These effects were associated with increased phosphorylation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3β. AdipoR1 OE also caused increased phosphorylation of p70S6 kinase, AMP-activated protein kinase, and acetyl-coA carboxylase as well as increased protein levels of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif-1 and adiponectin, peroxisome proliferator activated receptor-γ coactivator-1α, and uncoupling protein-3, indicative of increased mitochondrial biogenesis. Although neither HFD feeding nor AdipoR1 OE caused generalized changes in sphingolipids, AdipoR1 OE did reduce levels of sphingosine 1-phosphate, ceramide 18:1, ceramide 20:2, and dihydroceramide 20:0, plus mRNA levels of the ceramide synthetic enzymes serine palmitoyl transferase and sphingolipid Δ-4 desaturase, changes that are associated with increased insulin sensitivity. These data demonstrate that enhancement of local adiponectin sensitivity is sufficient to improve skeletal muscle IR.
Publisher: American Physiological Society
Date: 08-2015
DOI: 10.1152/AJPENDO.00007.2015
Abstract: Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1 −/− ) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1 −/− mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1 −/− mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1 −/− mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1 −/− mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1 −/− mice and between male Tbc1d1 −/− mice in different studies due to variations in body composition and nutrient handling.
Publisher: American Chemical Society (ACS)
Date: 20-11-2018
DOI: 10.1021/ACS.JMEDCHEM.7B01182
Abstract: Small molecule mitochondrial uncouplers transport protons from the mitochondrial inner membrane space into the mitochondrial matrix independent of ATP synthase, uncoupling nutrient metabolism from ATP generation. The therapeutic potential of mitochondrial uncouplers has been investigated for the treatment of metabolic diseases such as obesity and type 2 diabetes (T2D), ischemia-reperfusion injury, and neurodegenerative diseases. This communication will review the small molecule mitochondrial uncouplers reported to date and explore their potential as therapeutics.
Publisher: Springer Science and Business Media LLC
Date: 10-06-2020
DOI: 10.1038/S41467-020-16758-9
Abstract: The conversion of white adipocytes to thermogenic beige adipocytes represents a potential mechanism to treat obesity and related metabolic disorders. However, the mechanisms involved in converting white to beige adipose tissue remain incompletely understood. Here we show profound beiging in a genetic mouse model lacking the transcriptional repressor Krüppel-like factor 3 (KLF3). Bone marrow transplants from these animals confer the beige phenotype on wild type recipients. Analysis of the cellular and molecular changes reveal an accumulation of eosinophils in adipose tissue. We examine the transcriptomic profile of adipose-resident eosinophils and posit that KLF3 regulates adipose tissue function via transcriptional control of secreted molecules linked to beiging. Furthermore, we provide evidence that eosinophils may directly act on adipocytes to drive beiging and highlight the critical role of these little-understood immune cells in thermogenesis.
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.CMET.2009.06.001
Abstract: Obesity is a major risk factor for insulin resistance however, the factors linking these disorders are not well defined. Herein, we show that the noninhibitory serine protease inhibitor, pigment epithelium-derived factor (PEDF), plays a causal role in insulin resistance. Adipocyte PEDF expression and serum levels are elevated in several rodent models of obesity and reduced upon weight loss and insulin sensitization. Lean mice injected with recombinant PEDF exhibited reduced insulin sensitivity during hyperinsulinemic-euglycemic cl s. Acute PEDF administration activated the proinflammatory serine/threonine kinases c-Jun terminal kinase and extracellular regulated kinase in both muscle and liver, which corresponded with reduced insulin signal transduction. Prolonged PEDF administration stimulated adipose tissue lipolysis, resulted in ectopic lipid deposition, and reduced insulin sensitivity, while neutralizing PEDF in obese mice enhanced insulin sensitivity. Overall, these results identify a causal role for PEDF in obesity-induced insulin resistance.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-12-2013
DOI: 10.1002/HEP.26091
Publisher: Springer Science and Business Media LLC
Date: 29-02-2016
DOI: 10.1038/SREP22292
Abstract: Overnutrition can promote liver cancer in mice and humans that have liver damage caused by alcohol, viruses, or carcinogens. However, the mechanism linking diet to increased liver tumorigenesis remains unclear in the context of whether tumorigenesis is secondary to obesity, or whether nutrients like sugar or fat drive tumorigenesis independent of obesity. In male mice, liver tumor burden was recently found to correlate with sugar intake, independent of dietary fat intake and obesity. However, females are less susceptible to developing liver cancer than males and it remains unclear how nutrition affects tumorigenesis in females. Herein, female mice were exposed to the liver carcinogen diethylnitrosamine (DEN) and fed diets with well-defined sugar and fat content. Mice fed diets with high sugar content had the greatest liver tumor incidence while dietary fat intake was not associated with tumorigenesis. Diet-induced postprandial hyperglycemia and fasting hyperinsulinemia significantly correlated with tumor incidence, while tumor incidence was not associated with obesity and obesity-related disorders including liver steatosis, glucose intolerance, or elevated serum levels of estrogen, ALT and lipids. These results simplify the pathophysiology of diet-induced liver tumorigenesis by focusing attention on the role of sugar metabolism and reducing emphasis on the complex milieu associated with obesity.
Publisher: Elsevier BV
Date: 11-2019
Publisher: Springer Science and Business Media LLC
Date: 14-03-2017
DOI: 10.1038/NCOMMS14689
Abstract: The metabolic pathway of de novo lipogenesis is frequently upregulated in human liver tumours, and its upregulation is associated with poor prognosis. Blocking lipogenesis in cultured liver cancer cells is sufficient to decrease cell viability however, it is not known whether blocking lipogenesis in vivo can prevent liver tumorigenesis. Herein, we inhibit hepatic lipogenesis in mice by liver-specific knockout of acetyl-CoA carboxylase (ACC) genes and treat the mice with the hepatocellular carcinogen diethylnitrosamine (DEN). Unexpectedly, mice lacking hepatic lipogenesis have a twofold increase in tumour incidence and multiplicity compared to controls. Metabolomics analysis of ACC-deficient liver identifies a marked increase in antioxidants including NADPH and reduced glutathione. Importantly, supplementing primary wild-type hepatocytes with glutathione precursors improves cell survival following DEN treatment to a level indistinguishable from ACC-deficient primary hepatocytes. This study shows that lipogenesis is dispensable for liver tumorigenesis in mice treated with DEN, and identifies an important role for ACC enzymes in redox regulation and cell survival.
Publisher: Oxford University Press (OUP)
Date: 28-06-2007
DOI: 10.1111/J.1753-4887.2007.TB00327.X
Abstract: Lipid abnormalities such as obesity, increased circulating free fatty acid levels, and excess intramyocellular lipid accumulation are frequently associated with insulin resistance. These observations have prompted investigators to speculate that the accumulation of lipids in tissues not suited for fat storage (e.g., skeletal muscle and liver) is an underlying component of insulin resistance and the metabolic syndrome. We review the metabolic fates of lipids in insulin-responsive tissues and discuss the roles of specific lipid metabolites (e.g., ceramides, GM3 ganglioside, and diacylglycerol) as antagonists of insulin signaling and action.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2021
DOI: 10.1007/S00018-021-03958-9
Abstract: Hepatocellular carcinoma (HCC) is one of the most difficult cancer types to treat. Liver cancer is often diagnosed at late stages and therapeutic treatment is frequently accompanied by development of multidrug resistance. This leads to poor outcomes for cancer patients. Understanding the fundamental molecular mechanisms leading to liver cancer development is crucial for developing new therapeutic approaches, which are more efficient in treating cancer. Mice with a liver specific UDP-glucose ceramide glucosyltransferase (UGCG) knockout (KO) show delayed diethylnitrosamine (DEN)-induced liver tumor growth. Accordingly, the rationale for our study was to determine whether UGCG overexpression is sufficient to drive cancer phenotypes in liver cells. We investigated the effect of UGCG overexpression (OE) on normal murine liver (NMuLi) cells. Increased UGCG expression results in decreased mitochondrial respiration and glycolysis, which is reversible by treatment with EtDO-P4, an UGCG inhibitor. Furthermore, tumor markers such as FGF21 and EPCAM are lowered following UGCG OE, which could be related to glucosylceramide (GlcCer) and lactosylceramide (LacCer) accumulation in glycosphingolipid-enriched microdomains (GEMs) and subsequently altered signaling protein phosphorylation. These cellular processes lead to decreased proliferation in NMuLi/UGCG OE cells. Our data show that increased UGCG expression itself does not induce pro-cancerous processes in normal liver cells, which indicates that increased GlcCer expression leads to different outcomes in different cancer types. Graphic abstract
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-09-2020
DOI: 10.1161/CIRCRESAHA.120.316653
Abstract: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend % of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear. To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-C hi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9 , S100a8 , or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. A graphic abstract is available for this article.
Publisher: Public Library of Science (PLoS)
Date: 22-12-2016
Publisher: Elsevier BV
Date: 10-2021
Publisher: MDPI AG
Date: 29-08-2022
DOI: 10.3390/IJMS23179798
Abstract: Obesity-related insulin resistance is a highly prevalent and growing health concern, which places stress on the pancreatic islets of Langerhans by increasing insulin secretion to lower blood glucose levels. The glucose transporters GLUT1 and GLUT3 play a key role in glucose-stimulated insulin secretion in human islets, while GLUT2 is the key isoform in rodent islets. However, it is unclear whether other glucose transporters also contribute to insulin secretion by pancreatic islets. Herein, we show that SLC2A6 (GLUT6) is markedly upregulated in pancreatic islets from genetically obese leptin-mutant (ob/ob) and leptin receptor-mutant (db/db) mice, compared to lean controls. Furthermore, we observe that islet SLC2A6 expression positively correlates with body mass index in human patients with type 2 diabetes. To investigate whether GLUT6 plays a functional role in islets, we crossed GLUT6 knockout mice with C57BL/6 ob/ob mice. Pancreatic islets isolated from ob/ob mice lacking GLUT6 secreted more insulin in response to high-dose glucose, compared to ob/ob mice that were wild type for GLUT6. The loss of GLUT6 in ob/ob mice had no adverse impact on body mass, body composition, or glucose tolerance at a whole-body level. This study demonstrates that GLUT6 plays a role in pancreatic islet insulin secretion in vitro but is not a dominant glucose transporter that alters whole-body metabolic physiology in ob/ob mice.
Publisher: Oxford University Press (OUP)
Date: 13-03-2015
Abstract: This work addresses the therapeutic potential of stem cells that are obtained from diabetic donors, and the clinical focus of our work is diabetic retinopathy. This work examined how injected murine adipose-derived stem cells (ASCs) affect the retinal microvasculature in a mouse model of diabetic retinopathy. Results show that ASCs obtained from healthy mice secrete angiogenic growth factors and promote retinal vascular stability when they are injected intravitreally. The findings further suggest that ASCs obtained from diabetic mice have a diminished ability to support the retinal vasculature in this mouse model of retinal vasculopathy.
Publisher: Elsevier BV
Date: 12-2017
Publisher: The American Association of Immunologists
Date: 04-2014
Abstract: Fatty acids (FAs) are essential constituents of cell membranes, signaling molecules, and bioenergetic substrates. Because CD8+ T cells undergo both functional and metabolic changes during activation and differentiation, dynamic changes in FA metabolism also occur. However, the contributions of de novo lipogenesis to acquisition and maintenance of CD8+ T cell function are unclear. In this article, we demonstrate the role of FA synthesis in CD8+ T cell immunity. T cell–specific deletion of acetyl coenzyme A carboxylase 1 (ACC1), an enzyme that catalyzes conversion of acetyl coenzyme A to malonyl coenzyme A, a carbon donor for long-chain FA synthesis, resulted in impaired peripheral persistence and homeostatic proliferation of CD8+ T cells in naive mice. Loss of ACC1 did not compromise effector CD8+ T cell differentiation upon listeria infection but did result in a severe defect in Ag-specific CD8+ T cell accumulation because of increased death of proliferating cells. Furthermore, in vitro mitogenic stimulation demonstrated that defective blasting and survival of ACC1-deficient CD8+ T cells could be rescued by provision of exogenous FA. These results suggest an essential role for ACC1-mediated de novo lipogenesis as a regulator of CD8+ T cell expansion, and may provide insights for therapeutic targets for interventions in autoimmune diseases, cancer, and chronic infections.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 08-2004
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.YGYNO.2015.05.015
Abstract: The study objectives were to determine baseline endometrial histology in morbidly obese women undergoing bariatric surgery and to assess the surgical intervention's impact on serum metabolic parameters, quality of life (QOL), and weight. Women undergoing bariatric surgery were enrolled. Demographic and clinicopathologic data, serum, and endometrium (if no prior hysterectomy) were collected preoperatively and serum collected postoperatively. Serum global biochemical data were assessed pre ostoperatively. Welch's two s le t-tests and paired t-tests were used to identify significant differences. Mean age of the 71 women enrolled was 44.2 years, mean body mass index (BMI) was 50.9 kg/m(2), and mean weight loss was 45.7 kg. Endometrial biopsy results: proliferative (13/30 43%), insufficient (8/30 27%), secretory (6/30 20%) and hyperplasia (3/30 10%-1 complex atypical, 2 simple). QOL data showed significant improvement in physical component scores (PCS means 33.9 vs. 47.2 before/after surgery p<0.001). Twenty women underwent metabolic analysis which demonstrated significantly improved glucose homeostasis, improved insulin responsiveness, and free fatty acid levels. Significant perturbations in tryptophan, phenylalanine and heme metabolism suggested decreased inflammation and alterations in the intestinal microbiome. Most steroid hormones were not significantly impacted with the exception of decreased DHEAS and 4-androsten metabolites. Bariatric surgery is accompanied by an improved physical quality of life as well as beneficial changes in glucose homeostasis, insulin responsiveness, and inflammation to a greater extent than the hormonal milieu. The potential cancer protective effects of bariatric surgery may be due to other mechanisms other than simply hormonal changes.
Publisher: Wiley
Date: 20-09-2020
DOI: 10.1111/JCMM.15785
Publisher: MDPI AG
Date: 23-10-2021
Abstract: This series comprises 14 articles (5 original articles and 9 reviews) that investigate connections between excess body mass and cancer risk or cancer treatment response [...]
Publisher: Public Library of Science (PLoS)
Date: 09-06-2016
Publisher: American Diabetes Association
Date: 12-04-2014
DOI: 10.2337/DB13-1614
Abstract: Abnormal conditions during early development adversely affect later health. We investigated whether maternal exercise could protect offspring from adverse effects of a maternal high-fat diet (HFD) with a focus on the metabolic outcomes and epigenetic regulation of the metabolic master regulator, peroxisome proliferator-activated receptor γ coactivator-1α (Pgc-1α). Female C57BL/6 mice were exposed to normal chow, an HFD, or an HFD with voluntary wheel exercise for 6 weeks before and throughout pregnancy. Methylation of the Pgc-1α promoter at CpG site −260 and expression of Pgc-1α mRNA were assessed in skeletal muscle from neonatal and 12-month-old offspring, and glucose and insulin tolerance tests were performed in the female offspring at 6, 9, and 12 months. Hypermethylation of the Pgc-1α promoter caused by a maternal HFD was detected at birth and was maintained until 12 months of age with a trend of reduced expression of Pgc-1α mRNA (P = 0.065) and its target genes. Maternal exercise prevented maternal HFD-induced Pgc-1α hypermethylation and enhanced Pgc-1α and its target gene expression, concurrent with amelioration of age-associated metabolic dysfunction at 9 months of age in the offspring. Therefore, maternal exercise is a powerful lifestyle intervention for preventing maternal HFD-induced epigenetic and metabolic dysregulation in the offspring.
Publisher: The American Association of Immunologists
Date: 15-03-2019
Abstract: The polarization processes for M1 versus M2 macrophages are quite distinct in the context of changes in cellular metabolism. M1 macrophages are highly glycolytic, whereas M2 macrophages require a more oxidative nutrient metabolism. An important part of M1 polarization involves upregulation of the glucose transporter (GLUT) GLUT1 to facilitate increased glucose uptake and glycolytic metabolism however, the role of other glucose transporters in this process is largely unknown. In surveying the Functional Annotation of the Mammalian Genome and Gene Expression Omnibus Profiles databases, we discovered that the glucose transporter GLUT6 is highly upregulated in LPS-activated macrophages. In our previous work, we have not detected mouse GLUT6 protein expression in any noncancerous tissue therefore, in this study, we investigated the expression and significance of GLUT6 in bone marrow-derived macrophages from wild-type and GLUT6 knockout C57BL/6 mice. We show that LPS-induced M1 polarization markedly upregulated GLUT6 protein, whereas naive macrophages and IL-4-induced M2 macrophages do not express GLUT6 protein. However, despite strong upregulation of GLUT6 in M1 macrophages, the absence of GLUT6 did not alter M1 polarization in the context of glucose uptake, glycolytic metabolism, or cytokine production. Collectively, these data show that GLUT6 is dispensable for LPS-induced M1 polarization and function. These findings are important because GLUT6 is an anticancer drug target, and this study suggests that inhibition of GLUT6 may not impart detrimental side effects on macrophage function to interfere with their antitumor properties.
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.BIOCEL.2010.08.020
Abstract: Insulin resistance is the prodrome of many metabolic diseases and identifying ways to correct this pathological condition is a major goal for medical research. The foremost barrier to the development of new treatments is that the precise etiology of insulin resistance is uncertain. Recent studies suggest that changes in mitochondrial structure or function drive this condition, however much of this evidence is circumstantial. This Signaling Networks in Focus article provides a brief overview of known and speculative regulatory intersections whereby mitochondrial dysfunction at the levels of lipid oxidation, oxidative stress, calcium, adenine nucleotides, and protons may regulate insulin sensitivity. If mitochondrial dysfunction underlies the origins of metabolic disease then determining the precise molecular pathway will be essential for the development of new treatment and prevention strategies.
Publisher: American Chemical Society (ACS)
Date: 04-02-2020
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.CMET.2007.01.002
Abstract: Insulin resistance occurs in 20%-25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Collectively, these data have two important implications. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy.
Publisher: Elsevier BV
Date: 03-2023
Publisher: The Endocrine Society
Date: 2010
DOI: 10.1210/ME.2009-0133
Abstract: Adiponectin is an adipocyte-secreted, insulin-sensitizing hormone the circulating levels of which are reduced in conditions of insulin resistance and diabetes. Previous work has demonstrated the importance of posttranslational modifications, such as proline hydroxylation and lysine hydroxylation/glycosylation, in adiponectin oligomerization, secretion, and function. Here we describe the first functional characterization of adiponectin sialylation. Using a variety of biochemical approaches we demonstrated that sialylation occurs on previously unidentified O-linked glycans on Thr residues of the variable domain in human adiponectin. Enzymatic removal of sialic acid or its underlying O-linked sugars did not affect adiponectin multimer composition. Expression of mutant forms of adiponectin (lacking the modified Thr residues) or of wild-type adiponectin in cells defective in sialylation did not compromise multimer formation or secretion, arguing against a structural role for this modification. Activity of desialylated adiponectin was comparable to control adiponectin in L6 myotubes and acute assays in adiponectin−/− mice. In contrast, plasma clearance of desialylated adiponectin was accelerated compared with that of control adiponectin, implicating a role for this modification in determining the half-life of circulating adiponectin. Uptake of desialylated adiponectin by isolated primary rat hepatocytes was also accelerated, suggesting a role for the hepatic asialoglycoprotein receptor. Finally, after chronic administration in adiponectin−/− mice steady-state levels of desialylated adiponectin were lower than control adiponectin and failed to recapitulate the improvements in glucose and insulin tolerance tests observed with control adiponectin. These data suggest an important role for sialic acid content in the regulation of circulating adiponectin levels and highlight the importance of understanding mechanisms regulating adiponectin sialylation/desialylation.
Publisher: Elsevier BV
Date: 07-2016
Publisher: Elsevier BV
Date: 10-2016
Publisher: Springer Science and Business Media LLC
Date: 14-05-2020
DOI: 10.1038/S41467-020-16298-2
Abstract: Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic cl studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.
Publisher: Springer Science and Business Media LLC
Date: 21-08-2011
DOI: 10.1038/NATURE10340
Publisher: American Association for the Advancement of Science (AAAS)
Date: 25-11-2022
Abstract: Acetyl-CoA carboxylase (ACC) regulates lipid synthesis however, its role in inflammatory regulation in macrophages remains unclear. We generated mice that are deficient in both ACC isoforms in myeloid cells. ACC deficiency altered the lipidomic, transcriptomic, and bioenergetic profile of bone marrow–derived macrophages, resulting in a blunted response to proinflammatory stimulation. In response to lipopolysaccharide (LPS), ACC is required for the early metabolic switch to glycolysis and remodeling of the macrophage lipidome. ACC deficiency also resulted in impaired macrophage innate immune functions, including bacterial clearance. Myeloid-specific deletion or pharmacological inhibition of ACC in mice attenuated LPS-induced expression of proinflammatory cytokines interleukin-6 (IL-6) and IL-1β, while pharmacological inhibition of ACC increased susceptibility to bacterial peritonitis in wild-type mice. Together, we identify a critical role for ACC in metabolic regulation of the innate immune response in macrophages, and thus a clinically relevant, unexpected consequence of pharmacological ACC inhibition.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Wiley
Date: 22-07-2022
Abstract: Diffractions carry out important information about subsurface features. These features include small‐scale objects, fracture zones and faults. There have been several robust pre‐ and post‐stack diffraction imaging workflows in the literature to attribute diffraction locations and properties. Most of the traditional workflows are not fully capable of dealing with polarity reversals in the case of polarity reversed diffracted wavefields. This challenge causes null measures at the location of such diffractions. To overcome this issue, which is an ongoing subject of research, we propose to implement local semblance analysis along moveout curves. To do so, the global scanning window is sub ided into smaller windows followed by semblance analysis over each window. The final coherency measure in each image point is computed by averaging the semblance measures from all the sub ided windows. We demonstrated the proposed workflow on synthetic as well as field recorded datasets in the post‐stack domain. The results prove the capability of the proposed method in circumventing polarity reversals without any need to conduct polarity correction prior to imaging. At the end, we studied the seismic imaging resolution in the presence of white noise through the proposed approach.
Publisher: eLife Sciences Publications, Ltd
Date: 06-02-2018
DOI: 10.7554/ELIFE.32111
Abstract: Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance.
Publisher: Springer Science and Business Media LLC
Date: 29-01-2018
DOI: 10.1038/S41598-018-20104-X
Abstract: Insulin resistance is a major risk factor for metabolic diseases such as Type 2 diabetes. Although the underlying mechanisms of insulin resistance remain elusive, oxidative stress is a unifying driver by which numerous extrinsic signals and cellular stresses trigger insulin resistance. Consequently, we sought to understand the cellular response to oxidative stress and its role in insulin resistance. Using cultured 3T3-L1 adipocytes, we established a model of physiologically-derived oxidative stress by inhibiting the cycling of glutathione and thioredoxin, which induced insulin resistance as measured by impaired insulin-stimulated 2-deoxyglucose uptake. Using time-resolved transcriptomics, we found 2000 genes differentially-expressed over 24 hours, with specific metabolic and signalling pathways enriched at different times. We explored this coordination using a knowledge-based hierarchical-clustering approach to generate a temporal transcriptional cascade and identify key transcription factors responding to oxidative stress. This response shared many similarities with changes observed in distinct insulin resistance models. However, an anti-oxidant reversed insulin resistance phenotypically but not transcriptionally, implying that the transcriptional response to oxidative stress is insufficient for insulin resistance. This suggests that the primary site by which oxidative stress impairs insulin action occurs post-transcriptionally, warranting a multi-level ‘trans-omic’ approach when studying time-resolved responses to cellular perturbations.
Publisher: Elsevier BV
Date: 05-2017
Publisher: American Chemical Society (ACS)
Date: 11-05-2020
Publisher: Elsevier BV
Date: 2010
Publisher: EMBO
Date: 10-06-2020
Publisher: Society of Exploration Geophysicists
Date: 30-09-2021
Abstract: Building an accurate velocity model plays a vital role in routine seismic imaging workflows. Normal-moveout (NMO)-based seismic velocity analysis is a popular method for making the velocity models. However, traditional velocity analysis methodologies are not generally capable of handling litude variations across moveout curves, specifically polarity reversals caused by litude-variation-with-offset (AVO) anomalies. I have developed an NMO-based velocity analysis approach that circumvents this shortcoming by modifying the conventional semblance (CS) function to include polarity and litude correction terms computed using correlation coefficients of seismic traces in the velocity analysis scanning window with a reference trace. Thus, the proposed method workflow is suitable for any class of AVO effects. The approach is evaluated with four synthetic data ex les of different conditions and field data consisting of a common-midpoint gather. Lateral resolution enhancement using the proposed method workflow is evaluated by comparison between the results from the workflow and the results obtained by the application of CS and three semblance-based velocity analysis algorithms developed to circumvent the challenges associated with litude variations across moveout curves, caused by seismic attenuation and class II AVO anomalies. According to the obtained results, the proposed method is superior to all of the presented workflows in handling such anomalies.
Publisher: Elsevier BV
Date: 04-2010
Publisher: Proceedings of the National Academy of Sciences
Date: 20-10-2009
Abstract: We know a great deal about the cellular response to starvation via AMPK, but less is known about the reaction to nutrient excess. Insulin resistance may be an appropriate response to nutrient excess, but the cellular sensors that link these parameters remain poorly defined. In the present study we provide evidence that mitochondrial superoxide production is a common feature of many different models of insulin resistance in adipocytes, myotubes, and mice. In particular, insulin resistance was rapidly reversible upon exposure to agents that act as mitochondrial uncouplers, ETC inhibitors, or mitochondrial superoxide dismutase (MnSOD) mimetics. Similar effects were observed with overexpression of mitochondrial MnSOD. Furthermore, acute induction of mitochondrial superoxide production using the complex III antagonist antimycin A caused rapid attenuation of insulin action independently of changes in the canonical PI3K/Akt pathway. These results were validated in vivo in that MnSOD transgenic mice were partially protected against HFD induced insulin resistance and MnSOD+/− mice were glucose intolerant on a standard chow diet. These data place mitochondrial superoxide at the nexus between intracellular metabolism and the control of insulin action potentially defining this as a metabolic sensor of energy excess.
Publisher: Wiley
Date: 05-04-2022
Abstract: Seismic reconstruction of missing traces is an extremely important subject in seismic data processing. It includes both interpolation and extrapolation of sparsely recorded data. Extrapolation is often performed in the absence of near‐offset seismic data recorded through marine acquisition. Several reconstruction methods have been designed to circumvent this sparsity in time–offset, frequency–offset and time–frequency domains. In this research, I propose an oriented extrapolation workflow to reconstruct near‐offset missing traces. The term oriented or velocity‐independent refers to those techniques that are based on the use of local slopes. In the proposed workflow, I use an oriented time‐warping algorithm called predictive painting. This algorithm is suitable to predict two‐way traveltimes between two distinctive points of an event. Seismic events recorded by an off‐end array very rarely contain dips of both signs with respect to their zero‐offset location in common‐midpoint domain. This makes the domain an ideal choice to run the algorithm. The proposed algorithm is demonstrated on synthetic and field data ex les. I decimate near‐offset seismic traces and reconstruct them through the algorithm. The reconstruction results are compared with the original data before decimation. Furthermore, insensitivity of the proposed workflow to the presence of class II litude‐versus‐offset anomalies is demonstrated on a synthetic ex le. I also perform a velocity‐dependent (a normal‐moveout‐based) technique on the field data and compare the corresponding outcomes with the results achieved by the application of the proposed velocity‐independent approach. All the results suggest that the proposed technique has the potential to be used in the exploration industry.
Publisher: Public Library of Science (PLoS)
Date: 14-09-2015
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.BMCL.2022.128912
Abstract: We report new mitochondrial uncouplers derived from the conversion of [1,2,5]oxadiazolo[3,4-b]pyrazines to 1H-imidazo[4,5-b]pyrazines. The in situ Fe-mediated reduction of the oxadiazole fragment followed by cyclization gave access to imidazopyrazines in moderate to good yields. A selection of orthoesters also allowed functionalization on the 2-position of the imidazole ring. This method afforded a variety of imidazopyrazine derivatives with varying substitution on the 2, 5 and 6 positions. Our studies suggest that both a 2-trifluoromethyl group and N-methylation are crucial for mitochondrial uncoupling capacity.
Publisher: Elsevier BV
Date: 04-2014
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-01-2019
DOI: 10.1126/SCIIMMUNOL.AAP9520
Abstract: Impaired activity of enolase 1 limits glycolysis and effector function of tumor-infiltrating CD8 + T cells.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2020
DOI: 10.1038/S41598-020-65182-Y
Abstract: The only enzyme in the glycosphingolipid (GSL) metabolic pathway, which produces glucosylceramide (GlcCer) de novo is UDP-glucose ceramide glucosyltransferase (UGCG). UGCG is linked to pro-cancerous processes such as multidrug resistance development and increased proliferation in several cancer types. Previously, we showed an UGCG-dependent glutamine metabolism adaption to nutrient-poor environment of breast cancer cells. This adaption includes reinforced oxidative stress response and fueling the tricarboxylic acid (TCA) cycle by increased glutamine oxidation. In the current study, we investigated glycolytic and oxidative metabolic phenotypes following UGCG overexpression (OE). UGCG overexpressing MCF-7 cells underwent a metabolic shift from quiescent/aerobic to energetic metabolism by increasing both glycolysis and oxidative glucose metabolism. The energetic metabolic phenotype was not associated with increased mitochondrial mass, however, markers of mitochondrial turnover were increased. UGCG OE altered sphingolipid composition of the endoplasmic reticulum (ER)/mitochondria fractions that may contribute to increased mitochondrial turnover and increased cell metabolism. Our data indicate that GSL are closely connected to cell energy metabolism and this finding might contribute to development of novel therapeutic strategies for cancer treatment.
Publisher: MDPI AG
Date: 23-03-2022
DOI: 10.20944/PREPRINTS202203.0309.V1
Abstract: Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer. Low numbers of HCC patients being suitable for liver resection or transplantation and multidrug resistance development during pharmacotherapy leads to high death rates for HCC patients. Understanding the molecular mechanisms of HCC aetiology contributes to development of novel therapeutic strategies for prevention and treatment of HCC. UDP-glucose ceramide glycosyltransferase (UGCG), a key enzyme in glycosphingolipid metabolism, generates glucosylceramide (GlcCer), which is the precursor for all glycosphingolipids (GSLs). Since UGCG gene expression is altered in 0.8 % of HCC tumors, GSLs may play a role in cellular processes in liver cancer cells. Here, we discuss current literature about GSLs and their abundance in normal liver cells, Gaucher disease and HCC. Furthermore, we review the involvement of UGCG/GlcCer in multidrug resistance development, globosides as a potential prognostic marker for HCC, gangliosides as a potential liver cancer stem cell marker, and the role of sulfatides in tumor metastasis. Only a limited number of molecular mechanisms executed by GSLs in HCC are known, which we summarize here briefly.
Publisher: MDPI AG
Date: 25-04-2022
Abstract: Obesity is a risk factor for endometrial cancer. The aim of this study was to determine whether actively replicating microbiota in the endometrium differ between obese vs. lean and cancer vs. benign states. We performed 16S rRNA licon sequencing on endometrial tissues from lean and obese women with and without endometrial cancer, and lean and obese mice. Results displayed human endometrial microbiota clustered into three community types (R = 0.363, p = 0.001). Lactobacillus was dominant in community type 1 (C1) while community type 2 (C2) had high levels of Proteobacteria and more cancer s les when compared to C1 (p = 0.007) and C3 (p = 0.0002). A significant increase in the prevalence of the C2 community type was observed across body mass index and cancer (χ2 = 14.24, p = 0.0002). The relative abundance of Lactobacillus was lower in cancer s les (p = 0.0043), and an OTU with 100% similarity to Lactobacillus iners was enriched in control s les (p = 0.0029). Mouse endometrial microbiota also clustered into three community types (R = 0.419, p = 0.001) which were not influenced by obesity. In conclusion, obesity and cancer are associated with community type prevalence in the human endometrium, and Lactobacillus abundance is associated with normal uterine histologies in humans and mice.
Publisher: Elsevier BV
Date: 11-2015
Publisher: Springer Science and Business Media LLC
Date: 09-03-2017
DOI: 10.1038/S41598-017-00210-Y
Abstract: Hepatic glucose production (HGP) is required to maintain normoglycemia during fasting. Glucagon is the primary hormone responsible for increasing HGP however, there are many additional hormone and metabolic factors that influence glucagon sensitivity. In this study we report that the bioactive lipid lysophosphatidic acid (LPA) regulates hepatocyte glucose production by antagonizing glucagon-induced expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Treatment of primary hepatocytes with exogenous LPA blunted glucagon-induced PEPCK expression and glucose production. Similarly, knockout mice lacking the LPA-degrading enzyme phospholipid phosphate phosphatase type 1 (PLPP1) had a 2-fold increase in endogenous LPA levels, reduced PEPCK levels during fasting, and decreased hepatic gluconeogenesis in response to a pyruvate challenge. Mechanistically, LPA antagonized glucagon-mediated inhibition of STAT3, a transcriptional repressor of PEPCK. Importantly, LPA did not blunt glucagon-stimulated glucose production or PEPCK expression in hepatocytes lacking STAT3. These data identify a novel role for PLPP1 activity and hepatocyte LPA levels in glucagon sensitivity via a mechanism involving STAT3.
Publisher: Bioscientifica
Date: 14-12-2016
DOI: 10.1530/JOE-15-0444
Abstract: An important regulator of fatty acid oxidation (FAO) is the allosteric inhibition of CPT-1 by malonyl-CoA produced by the enzyme acetyl-CoA carboxylase 2 (ACC2). Initial studies suggested that deletion of Acc2 ( Acacb ) increased fat oxidation and reduced adipose tissue mass but in an independently generated strain of Acc2 knockout mice we observed increased whole-body and skeletal muscle FAO and a compensatory increase in muscle glycogen stores without changes in glucose tolerance, energy expenditure or fat mass in young mice (12–16 weeks). The aim of the present study was to determine whether there was any effect of age or housing at thermoneutrality (29 °C which reduces total energy expenditure) on the phenotype of Acc2 knockout mice. At 42–54 weeks of age, male WT and Acc2 −/− mice had similar body weight, fat mass, muscle triglyceride content and glucose tolerance. Consistent with younger Acc2 −/− mice, aged Acc2 −/− mice showed increased whole-body FAO (24 h average respiratory exchange ratio=0.95±0.02 and 0.92±0.02 for WT and Acc2 −/− mice respectively, P .05) and skeletal muscle glycogen content (+60%, P .05) without any detectable change in whole-body energy expenditure. Hyperinsulinaemic–euglycaemic cl studies revealed no difference in insulin action between groups with similar glucose infusion rates and tissue glucose uptake. Housing Acc2 −/− mice at 29 °C did not alter body composition, glucose tolerance or the effects of fat feeding compared with WT mice. These results confirm that manipulation of Acc2 may alter FAO in mice, but this has little impact on body composition or insulin action.
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.CELREP.2017.11.085
Abstract: Insulin triggers an extensive signaling cascade to coordinate adipocyte glucose metabolism. It is considered that the major role of insulin is to provide anabolic substrates by activating GLUT4-dependent glucose uptake. However, insulin stimulates phosphorylation of many metabolic proteins. To examine the implications of this on glucose metabolism, we performed dynamic tracer metabolomics in cultured adipocytes treated with insulin. Temporal analysis of metabolite concentrations and tracer labeling revealed rapid and distinct changes in glucose metabolism, favoring specific glycolytic branch points and pyruvate anaplerosis. Integrating dynamic metabolomics and phosphoproteomics data revealed that insulin-dependent phosphorylation of anabolic enzymes occurred prior to substrate accumulation. Indeed, glycogen synthesis was activated independently of glucose supply. We refer to this phenomenon as metabolic priming, whereby insulin signaling creates a demand-driven system to "pull" glucose into specific anabolic pathways. This complements the supply-driven regulation of anabolism by substrate accumulation and highlights an additional role for insulin action in adipocyte glucose metabolism.
Publisher: American Chemical Society (ACS)
Date: 13-11-2020
Publisher: American Association for Cancer Research (AACR)
Date: 14-10-2014
DOI: 10.1158/0008-5472.CAN-14-0254
Abstract: Women with metabolic disorders, including obesity and diabetes, have an increased risk of developing endometrial cancer. However, the metabolism of endometrial tumors themselves has been largely understudied. Comparing human endometrial tumors and cells with their nonmalignant counterparts, we found that upregulation of the glucose transporter GLUT6 was more closely associated with the cancer phenotype than other hallmark cancer genes, including hexokinase 2 and pyruvate kinase M2. Importantly, suppression of GLUT6 expression inhibited glycolysis and survival of endometrial cancer cells. Glycolysis and lipogenesis were also highly coupled with the cancer phenotype in patient s les and cells. To test whether targeting endometrial cancer metabolism could be exploited as a therapeutic strategy, we screened a panel of compounds known to target erse metabolic pathways in endometrial cells. We identified that the glycolytic inhibitor, 3-bromopyruvate, is a powerful antagonist of lipogenesis through pyruvylation of CoA. We also provide evidence that 3-bromopyruvate promotes cell death via a necrotic mechanism that does not involve reactive oxygen species and that 3-bromopyruvate impaired the growth of endometrial cancer xenografts Cancer Res 74(20) 5832–45. ©2014 AACR.
Publisher: Wiley
Date: 06-2021
Abstract: Obtaining accurate velocity models plays a crucial role in many routine seismic imaging algorithms. Seismic velocity models are normally made through seismic velocity analysis workflows. The routine workflows are not capable of dealing with polarity variations across moveout curves. We address this limitation by proposing a straight‐forward and robust semblance‐based workflow, which is a modified version of the conventional semblance function. The coherency function applies semblance analysis on separate clusters of receivers followed by averaging the corresponding coherency measures from all the clusters. The proposed approach is suitable for any case of litude variations including attenuation and any class of litude‐versus‐offset effects. The ability of the proposed workflow is demonstrated to two synthetic data as well as two field‐recorded common‐midpoint gathers. We perform accuracy analysis by comparing the results from the proposed approach with the results achieved from conventional velocity analysis, and another semblance‐based algorithm that is developed to address the polarity variation task. We also studied noise sensitivity analysis by computing and comparing mathematical expectations between theory and practice.
Publisher: Springer Science and Business Media LLC
Date: 12-04-2017
Publisher: Elsevier BV
Date: 05-2008
Publisher: Springer Science and Business Media LLC
Date: 21-08-2018
DOI: 10.1038/S41467-018-05613-7
Abstract: Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2019
DOI: 10.1038/S41598-019-52169-7
Abstract: UDP-glucose ceramide glucosyltransferase (UGCG) is the key enzyme in glycosphingolipid (GSL) metabolism by being the only enzyme that generates glucosylceramide (GlcCer) de novo . Increased UGCG synthesis is associated with pro-cancerous processes such as increased proliferation and multidrug resistance in several cancer types. We investigated the influence of UGCG overexpression on glutamine metabolism in breast cancer cells. We observed adapted glucose and glutamine uptake in a limited energy supply environment following UGCG overexpression. Glutamine is used for reinforced oxidative stress response shown by increased mRNA expression of glutamine metabolizing proteins such as glutathione-disulfide reductase (GSR) resulting in increased reduced glutathione (GSH) level. Augmented glutamine uptake is also used for fueling the tricarboxylic acid (TCA) cycle to maintain the proliferative advantage of UGCG overexpressing cells. Our data reveal a link between GSL and glutamine metabolism in breast cancer cells, which is to our knowledge a novel correlation in the field of sphingolipid research.
Publisher: Elsevier BV
Date: 04-2020
Publisher: American Physiological Society
Date: 03-2004
DOI: 10.1152/AJPREGU.00509.2003
Abstract: Yellow-bellied marmots ( Marmota flaviventris) exhibit a circannual cycle of hyperphagia and nutrient storage in the summer followed by hibernation in the winter. This annual cycle of body mass gain and loss is primarily due to large-scale accumulation of lipid in the summer, which is then mobilized and oxidized for energy during winter. The rapid and predictable change in body mass makes these animals ideal for studies investigating the molecular basis for body weight regulation. In the study described herein, we monitored seasonal changes in the protein levels and activity of a central regulator of anabolic metabolism, the serine-threonine kinase Akt-protein kinase B (Akt/PKB), during the months accompanying maximal weight gain and entry into hibernation (June-November). Interestingly, under fasting conditions, Akt/PKB demonstrated a tissue-specific seasonal activation. Specifically, although Akt/PKB levels did not change, the activity of Akt/PKB (isoforms 1/α and 2/β) in white adipose tissue (WAT) increased significantly in July. Moreover, glycogen synthase, which lies downstream of Akt/PKB on a linear pathway linking the enzyme to the stimulation of glycogen synthesis, demonstrated a similar pattern of seasonal activation. By contrast, Akt/PKB activity in skeletal muscle peaked much later (i.e., September). These data suggest the existence of a novel, tissue-specific mechanism regulating Akt/PKB activation during periods of marked anabolism.
Publisher: American Diabetes Association
Date: 08-2007
DOI: 10.2337/DB07-0093
Abstract: A reduced capacity for mitochondrial fatty acid oxidation in skeletal muscle has been proposed as a major factor leading to the accumulation of intramuscular lipids and their subsequent deleterious effects on insulin action. Here, we examine markers of mitochondrial fatty acid oxidative capacity in rodent models of insulin resistance associated with an oversupply of lipids. C57BL/6J mice were fed a high-fat diet for either 5 or 20 weeks. Several markers of muscle mitochondrial fatty acid oxidative capacity were measured, including 14C-palmitate oxidation, palmitoyl-CoA oxidation in isolated mitochondria, oxidative enzyme activity (citrate synthase, β-hydroxyacyl CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and carnitine palmitoyl-transferase 1), and expression of proteins involved in mitochondrial metabolism. Enzyme activity and mitochondrial protein expression were also examined in muscle from other rodent models of insulin resistance. Compared with standard diet–fed controls, muscle from fat-fed mice displayed elevated palmitate oxidation rate (5 weeks +23%, P & 0.05, and 20 weeks +29%, P & 0.05) and increased palmitoyl-CoA oxidation in isolated mitochondria (20 weeks +49%, P & 0.01). Furthermore, oxidative enzyme activity and protein expression of peroxisome proliferator–activated receptor γ coactivator (PGC)-1α, uncoupling protein (UCP) 3, and mitochondrial respiratory chain subunits were significantly elevated in fat-fed animals. A similar pattern was present in muscle of fat-fed rats, obese Zucker rats, and db/db mice, with increases observed for oxidative enzyme activity and expression of PGC-1α, UCP3, and subunits of the mitochondrial respiratory chain. These findings suggest that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.
Publisher: Elsevier BV
Date: 03-2014
Publisher: Society of Exploration Geophysicists
Date: 23-12-2022
Abstract: The normal-moveout (NMO) stretch causes decrease in the dominant frequency of seismic wavelet after conventional NMO correction and severely damages the quality of the stacked data for shallower reflectors at far offsets. Muting, which is commonly used to handle this problem, reduces seismic fold and negatively affects results of the litude-variation-with-offset analysis within the stretched area. We found a novel approach to reduce the stretching phenomenon through compensating the lost frequencies by increasing the dominant frequency of the seismic wavelet before applying the NMO correction. The added so-called compensated frequencies are defined according to the difference between the dominant frequency of the original seismic wavelet and the assumed stretched wavelet after the NMO correction. The corresponding procedure considers frequency content of each time s le along each trace in the time-frequency domain using the Gabor transform. As such, the dominant frequency of the seismic wavelets is increased in a nonstationary manner. Performance of our method is evaluated by applying it on the synthetic and field data ex les. The obtained results suggest that this approach provides common-midpoint (CMP) gathers with reduced stretching effect, with the potential to be considered as another alternative for nonstretch NMO correction. However, it should be noted that the presented method resolves neither the problem of intersecting events nor the multiples in the CMP gather. This method also cannot handle highly contaminated noise data and does not contribute in removing multiples during the frequency compensation process.
Publisher: Elsevier BV
Date: 07-2014
Publisher: Elsevier BV
Date: 02-2015
Publisher: Springer Science and Business Media LLC
Date: 12-11-2015
Publisher: Elsevier BV
Date: 2019
Publisher: MDPI AG
Date: 19-04-2022
DOI: 10.3390/IJMS23094477
Abstract: Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer. Low numbers of HCC patients being suitable for liver resection or transplantation and multidrug resistance development during pharmacotherapy leads to high death rates for HCC patients. Understanding the molecular mechanisms of HCC etiology may contribute to the development of novel therapeutic strategies for prevention and treatment of HCC. UDP-glucose ceramide glycosyltransferase (UGCG), a key enzyme in glycosphingolipid metabolism, generates glucosylceramide (GlcCer), which is the precursor for all glycosphingolipids (GSLs). Since UGCG gene expression is altered in 0.8% of HCC tumors, GSLs may play a role in cellular processes in liver cancer cells. Here, we discuss the current literature about GSLs and their abundance in normal liver cells, Gaucher disease and HCC. Furthermore, we review the involvement of UGCG/GlcCer in multidrug resistance development, globosides as a potential prognostic marker for HCC, gangliosides as a potential liver cancer stem cell marker, and the role of sulfatides in tumor metastasis. Only a limited number of molecular mechanisms executed by GSLs in HCC are known, which we summarize here briefly. Overall, the role GSLs play in HCC progression and their ability to serve as biomarkers or prognostic indicators for HCC, requires further investigation.
Publisher: Elsevier BV
Date: 02-2015
Publisher: Elsevier BV
Date: 04-2014
Publisher: Elsevier BV
Date: 04-2014
Publisher: Impact Journals, LLC
Date: 20-12-2018
No related grants have been discovered for Kyle Hoehn.