A novel Y-specific long non-coding RNA associated with cellular lipid accumulation in HepG2 cells and Atherosclerosis-related genes
- Authors: Molina, Elsa , Chew, Guat , Myers, Stephen , Clarence, Elyse , Eales, James , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. 1 (2017), p. 1-12
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
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- Description: There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentified. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream effect contributing to the chronic inflammatory process that underpin CAD. Our findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.
Caveolin-1 is necessary for hepatic oxidative lipid metabolism: evidence for crosstalk between caveolin-1 and bile acid signaling
- Authors: Fernandez Rojo, Manuel , Gongora, Milena , Fitzsimmons, Rebecca L. , Martel, Nick , Martin, Sheree D. , Nixon, Susan , Brooks, Andrew J. , Ikonomopoulou, Maria P. , Martin, Sally , Lo, Harriet P. , Myers, Stephen , Restall, Christina , Ferguson, Charles , Pilch, Paul F. , McGee, Sean , Anderson, Robin L. , Waters, Michael J. , Hancock, John F. , Grimmond, Sean M. , Muscat, George , Parton, Robert G.
- Date: 2013
- Type: Text , Journal article
- Relation: Cell Reports Vol. 4, no. 2 (2013), p. 238-247
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- Description: Highlights • Lipid metabolism is the major cell and tissue process affected by CAV1 • CAV1 is necessary for hepatic PPAR
Co-learning in marine protected areas for integrated coastal zone management
- Authors: Siddique, Mohammed , Myers, Stephen , Smith, Timothy , Babcock, R , Carter, Bill
- Date: 2013
- Type: Text , Book chapter
- Relation: Global challenges in integrated coastal zone management p.
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Community based early intervention for the prevention of type 2 diabetes: A case report of the Kahnawake schools diabetes prevention project
- Authors: Nield, Alex , Quarrell, Sean , Myers, Stephen
- Date: 2013
- Type: Text , Journal article
- Relation: Journal of Diabetes and Metabolism Vol. 4, no. 6 (2013), p. 1-6
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- Description: Type 2 diabetes (T2D) is a chronic metabolic disorder that is predominately associated with lifestyle changes including reduced physical activity, poor nutrition and obesity. Despite major medical advances in the treatment of T2D, its prevalence is still increasing at an alarming rate. Accordingly, better management and prevention strategies are urgently needed to prevent the development and progression of this disease. In the last decade there have been considerable efforts to improve public health through alternative research paradigms. Community-Based Participatory Research (CBPR) is one such process by which researchers form an equal and transparent partnership with the community with the final goal of creating empowerment and societal change to facilitate action and provide solutions to promote health and well-being. One CBPR program, the Kahnawake Schools Diabetes Prevention Project (KSDPP), was initiated to promote increased physical activity and healthier eating habits among school children based on the Mohawk’s “Living in Balance” philosophy. Utilizing CBPR principles, KSDPP engaged researchers and the community in all stages of the research processes. This project was community driven from the beginning and was independent of any external institutional change agent to facilitate community action and the implementation of strategies to find solutions. Although the project has been instrumental in community empowerment and societal change, several challenges remain. Accordingly, understanding the unique social, environmental and historical context that shapes lifestyle and risk factors for T2D in Native populations will help to understand the unique nature of this disease in these groups.
Direct progesterone receptor and indirect androgen receptor interactions with the kallikrein-related peptidase 4 gene promoter in breast and prostate cancer
- Authors: Lai, John , Myers, Stephen , Lawrence, Mitchell , Odorico, Dimitri , Clements, Judith
- Date: 2009
- Type: Text , Journal article
- Relation: Molecular Cancer Research Vol. 7, no. 1 (2009), p. 129-141
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- Description: Kallikrein 4 (KLK4) is a member of the human KLK gene family of serine proteases, many of which are implicated in hormone-dependent cancers. Like other KLKs, such as KLK3/PSA and KLK2, KLK4 gene expression is also regulated by steroid hormones in hormone-dependent cancers, although the transcriptional mechanisms are ill defined. Here, we have investigated the mechanisms mediating the hormonal regulation of KLK4 in breast (T47D) and prostate (LNCaP and 22Rv1) cancer cells. We have shown that KLK4 is only expressed in breast and prostate cancers that express the progesterone receptor (PR) and androgen receptor (AR), respectively. Expression analysis in PR- and AR-positive cells showed that the two predominant KLK4 variants that use either TIS1 or TIS2a/b are both up-regulated by progesterone in T47D cells and androgens in LNCaP cells. Two putative hormone response elements, K4.pPRE and K4.pARE at -2419 bp and -1005 bp, respectively, were identified in silico. Electrophoretic mobility shift assays and luciferase reporter experiments suggest that neither K4.pARE nor ∼2.8 kb of the KLK4 promoter interacts directly with the AR to mediate KLK4 expression in LNCaP and 22Rv1 cells. However, we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells. Further, chromatin immunoprecipitation experiments showed a time-dependent recruitment of the PR to the KLK4 promoter (-2496 to -2283), which harbors K4.pPRE. This is the first study to show that progesterone- regulated KLK4 expression in T47D cells is mediated partly by a hormone response element (K4.pPRE) at -2419 bp. (Mol Cancer Res 2009;7(1):129-41)Copyright © 2009 American Association for Cancer Research.
Interleukin-6 Induces the down regulation of human peroxisome proliferator activated receptor alpha via the MAPK-induced STAT pathway in human hepatocytes
- Authors: Chew, Guatsiew , Myers, Stephen , Ooi, Kheng Leong , Alexander Chong, Shu-Chien , Sifzizul Tengku Muhammad, Tengku
- Date: 2013
- Type: Text , Journal article
- Relation: Journal of Biochemical and Pharmacological Research Vol. 1, no. 4 (December 2013 2013), p. 204-211
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- Description: IL-6 plays a crucial role in the development of acute phase response. One of the important regulators of IL-6-activated APR is peroxisome proliferator activated receptor alpha (PPAR
Interleukin-6 inhibition of peroxisome proliferator-activated receptor alpha expression is mediated by JAK2- and PI3K-induced STAT1/3 in HepG2 hepatocyte cells
- Authors: Chew, Guatsiew , Myers, Stephen , Shu-Chien, A. C. , Muhammad, Tengku
- Date: 2014
- Type: Text , Journal article
- Relation: Molecular and Cellular Biochemistry Vol. 388, no. 1-2 (2014), p. 25-37
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- Description: Interleukin-6 (IL-6) is the major activator of the acute phase response (APR). One important regulator of IL-6-activated APR is peroxisome proliferator-activated receptor alpha (PPAR
Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure
- Authors: Tomaszewski, Maciej , Eales, James , Denniff, Matthew , Myers, Stephen , Chew, Guatsiew , Nelson, Christopher , Christofidou, Paraskevi , Desai, Aishwarya , Büsst, Cara , Wojnar, Lukasz , Musialik, Katarzyna , Jozwiak, Jacek , Debiec, Radoslaw , Dominiczak, Anna , Navis, Gerjan , van Gilst, Wiek , van der Harst, Pim , Samani, Nilesh , Harrap, Stephen , Bogdanski, Pawel , Zukowska-Szczechowska, Ewa , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of the American Society of Nephrology Vol. 26, no. 12 (2015), p. 3151-3160
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
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- Description: The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65 x10(-5)) and diastolic BP (P=7.61 x10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0x10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, reninangiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.
The Zinc Transporter, Slc39a7 (Zip7) Is Implicated in Glycaemic Control in Skeletal Muscle Cells
- Authors: Myers, Stephen , Nield, Alex , Chew, Guatsiew , Myers, Mark
- Date: 2013
- Type: Text , Journal article
- Relation: Plos One Vol. 8, no. 11 (November 2013 2013), p. 15
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- Description: Dysfunctional zinc signaling is implicated in disease processes including cardiovascular disease, Alzheimer's disease and diabetes. Of the twenty-four mammalian zinc transporters, ZIP7 has been identified as an important mediator of the 'zinc wave' and in cellular signaling. Utilizing siRNA targeting Zip7 mRNA we have identified that Zip7 regulates glucose metabolism in skeletal muscle cells. An siRNA targeting Zip7 mRNA down regulated Zip7 mRNA 4.6-fold (p = 0.0006) when compared to a scramble control. This was concomitant with a reduction in the expression of genes involved in glucose metabolism including Agl, Dlst, Galm, Gbe1, Idh3g, Pck2, Pgam2, Pgm2, Phkb, Pygm, Tpi1, Gusb and Glut4. Glut4 protein expression was also reduced and insulin-stimulated glycogen synthesis was decreased. This was associated with a reduction in the mRNA expression of Insr, Irs1 and Irs2, and the phosphorylation of Akt. These studies provide a novel role for Zip7 in glucose metabolism in skeletal muscle and highlight the importance of this transporter in contributing to glycaemic control in this tissue.
Zinc transporters, mechanisms of action and therapeutic utility : Implications for type 2 diabetes mellitus
- Authors: Myers, Stephen , Nield, Alex , Myers, Mark
- Date: 2012
- Type: Text , Journal article
- Relation: Journal of Nutrition and Metabolism Vol. 2012, no. (2012), p. 1-13
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- Description: Zinc is an essential trace element that plays a vital role in maintaining many biological processes and cellular homeostasis. Dysfunctional zinc signaling is associated with a number of chronic disease states including cancer, cardiovascular disease, Alzheimer's disease, and diabetes. Cellular homeostasis requires mechanisms that tightly control the uptake, storage, and distribution of zinc. This is achieved through the coordinated actions of zinc transporters and metallothioneins. Evidence on the role of these proteins in type 2 diabetes mellitus (T2DM) is now emerging. Zinc plays a key role in the synthesis, secretion and action of insulin in both physiological and pathophysiological states. Moreover, recent studies highlight zinc's dynamic role as a "cellular second messenger" in the control of insulin signaling and glucose homeostasis. This suggests that zinc plays an unidentified role as a novel second messenger that augments insulin activity. This previously unexplored concept would raise a whole new area of research into the pathophysiology of insulin resistance and introduce a new class of drug target with utility for diabetes pharmacotherapy. © 2012 Stephen A. Myers et al.
- Description: 2003010692
Zinc, zinc transporters and Type 2 Diabetes
- Authors: Myers, Stephen , Nield, Alex
- Date: 2014
- Type: Text , Book chapter
- Relation: Endocrine diseases Chapter 2 p.
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- Description: Insulin resistance is an important characteristic of Type 2 Diabetes (T2D) and is commonly associated with obesity, hypertension and cardiovascular disease (Carsten, 2000; Hulver and Lynis, 2004). Insulin resistance reduces insulin-stimulated glucose disposal due to multiple post-recepter intracellular defects in insulin signaling with subsequent reductions in glucose transport, glucose oxidation and incorporation of glucose into glycogen (Abdul-Ghani and DeFronzo, 2010; Peppa et al., 2010). The intracellular post-receptor regulatory effects of insulin include the regulation of the cellular glucose transport system, adaptive changes in gene expression and subsequent biosynthesis and action of the enzymes involved in the preservation of metabolism, and the modulation of genes that contribute to increased pro-mitotic, proliferative and anti-apoptotic activity of cells (Taton et al., 2010). Accordingly, the reduced activity of insulin action in any, or all of these post-receptor regulatory actions is insulin resistance. Given that insulin resistance usually precedes the development of T2D and is a major component of the progressive nature of this disease (Pagel-Langenickel et al., 2010), understanding the pathophysiology of insulin resistance will enable the development of therapeutic strategies to prevent or manage disease progression. Although many theories have been forthcoming, the primary mechanism of insulin resistance remains largely elusive.
β-Adrenergic signaling regulates NR4A nuclear receptor and metabolic gene expression in multiple tissues
- Authors: Myers, Stephen , Eriksson, Natalie , Burow, Rachel , Wang, Mary Shu-Ching , Muscat, George
- Date: 2009
- Type: Text , Journal article
- Relation: Molecular and Cellular Endocrinology Vol. 309, no. 1-2 (2009), p. 101-108
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- Description: The nuclear hormone receptor (NR) 4A subgroup of orphan nuclear receptors includes three members, Nur77 (NR4A1), Nurr1 (NR4A2) and Nor-1 (NR4A3). Previously we have identified the rapid and robust (in vitro and in vivo) induction of the NR4A subgroup following β-adrenergic stimulation in mouse skeletal muscle. This was concomitant with changes in the expression of genes involved in the regulation of nutrient metabolism. We have isolated mouse tissue of cardiovascular, endocrine and gastrointestinal origin at 1, 4, 8 and 24 h after a single intraperitoneal injection of the β-adrenergic agonist, isoprenaline. We similarly identified the significant induction (between 1 and 4 h) of the NR4A genes in many of these tissues. Moreover, we have utilized TaqMan ® Low Density Arrays to determine the β-adrenergic-sensitive metabolic gene expression in liver, white adipose and heart. In summary, cross-talk between β-adrenergic and NR4A signaling occurs in several tissues, and is accompanied by modulation of metabolic gene expression. © 2009 Elsevier Ireland Ltd. All rights reserved.