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2. AMPK-mediated regulation of endogenous cholesterol synthesis does not affect atherosclerosis in a murine Pcsk9-AAV model

Author

Smith, Tyler K.T., Ghorbani, Peyman, LeBlond, Nicholas D., Nunes, Julia R.C., O'Dwyer, Conor, Ambursley, Nia, Fong-McMaster, Claire, Minarrieta, Lucía, Burkovsky, Leah A., El-Hakim, Rama, Trzaskalski, Natasha A., Locatelli, Cassandra A.A., Stotts, Cameron, Pember, Ciara, Rayner, Katey J., Kemp, Bruce E., Loh, Kim, Harper, Mary-Ellen, Mulvihill, Erin E., St-Pierre, Julie, and Fullerton, Morgan D.

Published
2024
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4. Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers

Author

Loesch, Danuta Z, Kemp, Bruce E, Bui, Minh Q, Fisher, Paul R, Allan, Claire Y, Sanislav, Oana, Ngoei, Kevin RW, Atkinson, Anna, Tassone, Flora, Annesley, Sarah J, and Storey, Elsdon

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Fragile X Syndrome, Genetics, Rare Diseases, Neurodegenerative, Intellectual and Developmental Disabilities (IDD), Clinical Research, Neurosciences, Behavioral and Social Science, Brain Disorders, Neurological, Mental health, FMR1 premutation, Fragile X-associated tremor, ataxia syndrome, motor scores, SCL-90 scale, lymphoblasts' bioenergetics measures, AMPK, TORC1, cognitive measures, Fragile X-associated tremor/ataxia syndrome, Public Health and Health Services, Psychology, Clinical sciences
Abstract

Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder affecting carriers of premutation alleles (PM) of the X-linked FMR1 gene, which contain CGG repeat expansions of 55-200 range in a non-coding region. This late-onset disorder is characterised by the presence of tremor/ataxia and cognitive decline, associated with the white matter lesions throughout the brain, especially involving the middle cerebellar peduncles. Nearly half of older male and ~ 20% of female PM carriers develop FXTAS. While there is evidence for mitochondrial dysfunction in neural and some peripheral tissues from FXTAS patients (though less obvious in the non-FXTAS PM carriers), the results from peripheral blood mononuclear cells (PBMC) are still controversial. Motor, cognitive, and neuropsychiatric impairments were correlated with measures of mitochondrial and non-mitochondrial respiratory activity, AMPK, and TORC1 cellular stress-sensing protein kinases, and CGG repeat size, in a sample of adult FXTAS male and female carriers. Moreover, the levels of these cellular measures, all derived from Epstein- Barr virus (EBV)- transformed and easily accessible blood lymphoblasts, were compared between the FXTAS (N = 23) and non-FXTAS (n = 30) subgroups, and with baseline data from 33 healthy non-carriers. A significant hyperactivity of cellular bioenergetics components as compared with the baseline data, more marked in the non-FXTAS PMs, was negatively correlated with repeat numbers at the lower end of the CGG-PM distribution. Significant associations of these components with motor impairment measures, including tremor-ataxia and parkinsonism, and neuropsychiatric changes, were prevalent in the FXTAS subgroup. Moreover, a striking elevation of AMPK activity, and a decrease in TORC1 levels, especially in the non-FXTAS carriers, were related to the size of CGG expansion. The bioenergetics changes in blood lymphoblasts are biomarkers of the clinical status of FMR1 carriers. The relationship between these changes and neurological involvement in the affected carriers suggests that brain bioenergetic alterations are reflected in this peripheral tissue. A possible neuroprotective role of stress sensing kinase, AMPK, in PM carriers, should be addressed in future longitudinal studies. A decreased level of TORC1-the mechanistic target of the rapamycin complex, suggests a possible future approach to therapy in FXTAS.

Published
2021

7. The Spectrum of Neurological and White Matter Changes and Premutation Status Categories of Older Male Carriers of the FMR1 Alleles Are Linked to Genetic (CGG and FMR1 mRNA) and Cellular Stress (AMPK) Markers

Author

Loesch, Danuta Z, Trost, Nicholas, Bui, Minh Q, Hammersley, Eleanor, Lay, Sui T, Annesley, Sarah J, Sanislav, Oana, Allan, Claire Y, Tassone, Flora, Chen, Zhi-Ping, Ngoei, Kevin RW, Kemp, Bruce E, Francis, David, Fisher, Paul R, and Storey, Elsdon

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Neurodegenerative, Clinical Research, Aging, Rare Diseases, Fragile X Syndrome, Neurosciences, Neurological, FMR1 premutation, CGG repeats, FMR1 mRNA, AMPK kinase, cellular stress, motor scores, cognitive status, white matter hyperintensities, Clinical Sciences, Law
Abstract

The fragile X premutation (PM) allele contains a CGG expansion of 55-200 repeats in the FMR1 gene's promoter. Male PM carriers have an elevated risk of developing neurological and psychiatric changes, including an approximately 50% risk of the fragile X-associated tremor/ataxia syndrome (FXTAS). The aim of this study was to assess the relationships of regional white matter hyperintensities (wmhs) semi-quantitative scores, clinical status, motor (UPDRS, ICARS, Tremor) scales, and cognitive impairments, with FMR1-specific genetic changes, in a sample of 32 unselected male PM carriers aged 39-81 years. Half of these individuals were affected with FXTAS, while the non-FXTAS group comprised subcategories of non-affected individuals and individuals affected with non-syndromic changes. The dynamics of pathological processes at the cellular level relevant to the clinical status of PM carriers was investigated using the enzyme AMP-activated protein kinase (AMPK), which is a highly sensitive cellular stress-sensing alarm protein. This enzyme, as well as genetic markers - CGG repeat number and the levels of the FMR1 mRNA - were assessed in blood lymphoblasts. The results showed that the repeat distribution for FXTAS individuals peaked at 85-90 CGGs; non-FXTAS carriers were distributed within the lowest end of the PM repeat range, and non-syndromic carriers assumed an intermediate position. The size of the CGG expansion was significantly correlated, across all three categories, with infratentorial and total wmhs and with all motor scores, and the FMR1 mRNA levels with all the wmh scores, whilst AMPK activity showed considerable elevation in the non-FXTAS combined group, decreasing in the FXTAS group, proportionally to increasing severity of the wmhs and tremor/ataxia. We conclude that the size of the CGG expansion relates to the risk for FXTAS, to severity of infratentorial wmhs lesions, and to all three motor scale scores. FMR1 mRNA shows a strong association with the extent of wmhs, which is the most sensitive marker of the pathological process. However, the AMPK activity findings - suggestive of a role of this enzyme in the risk of FXTAS - need to be verified and expanded in future studies using larger samples and longitudinal assessment.

Published
2018

8. Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms

Author

Pinkosky, Stephen L., Scott, John W., Desjardins, Eric M., Smith, Brennan K., Day, Emily A., Ford, Rebecca J., Langendorf, Christopher G., Ling, Naomi X. Y., Nero, Tracy L., Loh, Kim, Galic, Sandra, Hoque, Ashfaqul, Smiles, William J., Ngoei, Kevin R. W., Parker, Michael W., Yan, Yan, Melcher, Karsten, Kemp, Bruce E., Oakhill, Jonathan S., and Steinberg, Gregory R.

Published
2020
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9. AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation

Author

Lepropre, Sophie, Kautbally, Shakeel, Octave, Marie, Ginion, Audrey, Onselaer, Marie-Blanche, Steinberg, Gregory R., Kemp, Bruce E., Hego, Alexandre, Wéra, Odile, Brouns, Sanne, Swieringa, Frauke, Giera, Martin, Darley-Usmar, Victor M., Ambroise, Jérôme, Guigas, Bruno, Heemskerk, Johan, Bertrand, Luc, Oury, Cécile, Beauloye, Christophe, and Horman, Sandrine

Published
2018
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10. Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2β2γ1 by the Glucose Importagog SC4

Author

Ngoei, Kevin R.W., Langendorf, Christopher G., Ling, Naomi X.Y., Hoque, Ashfaqul, Varghese, Swapna, Camerino, Michelle A., Walker, Scott R., Bozikis, Ylva E., Dite, Toby A., Ovens, Ashley J., Smiles, William J., Jacobs, Roxane, Huang, He, Parker, Michael W., Scott, John W., Rider, Mark H., Foitzik, Richard C., Kemp, Bruce E., Baell, Jonathan B., and Oakhill, Jonathan S.

Published
2018
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20. Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis

Author

Neopane, Katyayanee, primary, Kozlov, Natalie, additional, Negoita, Florentina, additional, Murray-Segal, Lisa, additional, Brink, Robert, additional, Hoque, Ashfaqul, additional, Ovens, Ashley J., additional, Tjin, Gavin, additional, McAloon, Luke M., additional, Yu, Dingyi, additional, Ling, Naomi X.Y., additional, Sanders, Matthew J., additional, Oakhill, Jonathan S., additional, Scott, John W., additional, Steinberg, Gregory R., additional, Loh, Kim, additional, Kemp, Bruce E., additional, Sakamoto, Kei, additional, and Galic, Sandra, additional

Published
2022
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21. Immortalized Parkinson's disease lymphocytes have enhanced mitochondrial respiratory activity

Author

Annesley, Sarah, Lay, Sui, De Piazza, Shawn, Sanislav, Oana, Hammersley, Eleanor, Allan, Claire, Francione, Lisa, Bui, Minh Q, Chen, Zhi-Ping, Ngoei, Kevin RW, Tassone, Flora, Kemp, Bruce E, Storey, Elsdon, Evans, Andrew, Loesch-Mdzewska, Danuta, and Fisher, Paul

Subjects
Uncategorized
Abstract

In combination with studies of post-mortem Parkinson's disease (PD) brains, pharmacological and genetic models of PD have suggested that two fundamental interacting cellular processes are impaired-proteostasis and mitochondrial respiration. We have re-examined the role of mitochondrial dysfunction in lymphoblasts isolated from individuals with idiopathic PD and an age-matched control group. As previously reported forvarious PD cell types, the production of reactive oxygen species (ROS) by PD lymphoblasts was significantly elevated. However, this was not due to an impairment of mitochondrial respiration, as is often assumed. Instead, basal mitochondrial respiration and ATP synthesis are dramatically elevated in PD lymphoblasts. The mitochondrial mass, genome copy number and membrane potential were unaltered, but the expression of indicative respiratory complex proteins was also elevated. This explains the increased oxygen consumption rates by each of the respiratory complexes in experimentally uncoupled mitochondria of iPD cells. However, it was not attributable to increased activity of the stress- and energy-sensing protein kinase AMPK, a regulator of mitochondrial biogenesis and activity. The respiratory differences between iPD and control cells were sufficiently dramatic as to provide a potentially sensitive and reliable biomarker of the disease state, unaffected by disease duration (time since diagnosis) or clinical severity. Lymphoblasts from control and PD individuals thus occupy two distinct, quasi-stable steady states; a 'normal' and a 'hyperactive' state characterized by two different metabolic rates. The apparent stability of the 'hyperactive' state in patient-derived lymphoblasts in the face of patient ageing, ongoing disease and mounting disease severity suggests an early, permanent switch to an alternative metabolic steady state. With its associated, elevated ROS production, the 'hyperactive' state might not cause pathology to cells that are rapidly turned over, but brain cells might accumulate long-term damage leading ultimately to neurodegeneration and the loss of mitochondrial function observed post-mortem. Whether the 'hyperactive' state in lymphoblasts is a biomarker specifically of PD or more generally of neurodegenerative disease remains to be determined.

Published
2023
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24. An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice

Author

Rohm, Maria, Schäfer, Michaela, Laurent, Victor, Üstünel, Bilgen Ekim, Niopek, Katharina, Algire, Carolyn, Hautzinger, Oksana, Sijmonsma, Tjeerd P, Zota, Annika, Medrikova, Dasa, Pellegata, Natalia S, Ryden, Mikael, Kulyte, Agné, Dahlman, Ingrid, Arner, Peter, Petrovic, Natasa, Cannon, Barbara, Amri, Ez-Zoubir, Kemp, Bruce E, Steinberg, Gregory R, Janovska, Petra, Kopecky, Jan, Wolfrum, Christian, Blüher, Matthias, Berriel Diaz, Mauricio, and Herzig, Stephan

Subjects
Protein kinases -- Research, Peptides -- Health aspects, Cachexia -- Health aspects -- Genetic aspects -- Research, Adipose tissue -- Health aspects, Biological sciences, Health
Abstract

Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia., Author(s): Maria Rohm [1, 2, 3]; Michaela Schäfer [1, 2, 3]; Victor Laurent [1, 2, 3]; Bilgen Ekim Üstünel [1, 2, 3]; Katharina Niopek [1, 2, 3]; Carolyn Algire [1, [...]

Published
2016
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26. Calcium/calmodulin-dependent protein kinase kinase 2 regulates hepatic fuel metabolism

Author

Stork, Brittany A., primary, Dean, Adam, additional, Ortiz, Andrea R., additional, Saha, Pradip, additional, Putluri, Nagireddy, additional, Planas-Silva, Maricarmen D., additional, Mahmud, Iqbal, additional, Rajapakshe, Kimal, additional, Coarfa, Cristian, additional, Knapp, Stefan, additional, Lorenzi, Philip L., additional, Kemp, Bruce E., additional, Turk, Benjamin E., additional, Scott, John W., additional, Means, Anthony R., additional, and York, Brian, additional

Published
2022
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27. Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis

Author

Lee, Man K.S., primary, Cooney, Olivia D., additional, Lin, Xuzhu, additional, Nadarajah, Shaktypreya, additional, Dragoljevic, Dragana, additional, Huynh, Kevin, additional, Onda, Danise-Ann, additional, Galic, Sandra, additional, Meikle, Peter J., additional, Edlund, Thomas, additional, Fullerton, Morgan D., additional, Kemp, Bruce E., additional, Murphy, Andrew J., additional, and Loh, Kim, additional

Published
2022
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28. Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator

Author

Ovens, Ashley J., primary, Gee, Yi Sing, additional, Ling, Naomi X.Y., additional, Yu, Dingyi, additional, Hardee, Justin P., additional, Chung, Jin D., additional, Ngoei, Kevin R.W., additional, Waters, Nicholas J., additional, Hoffman, Nolan J., additional, Scott, John W., additional, Loh, Kim, additional, Spengler, Katrin, additional, Heller, Regine, additional, Parker, Michael W., additional, Lynch, Gordon S., additional, Huang, Fei, additional, Galic, Sandra, additional, Kemp, Bruce E., additional, Baell, Jonathan B., additional, Oakhill, Jonathan S., additional, and Langendorf, Christopher G., additional

Published
2022
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29. Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis

Author

Lee, Man K.S., Cooney, Olivia D., Lin, Xuzhu, Nadarajah, Shaktypreya, Dragoljevic, Dragana, Huynh, Kevin, Onda, Danise-Ann, Galic, Sandra, Meikle, Peter J., Edlund, Thomas, Fullerton, Morgan D., Kemp, Bruce E., Murphy, Andrew J., Loh, Kim, Lee, Man K.S., Cooney, Olivia D., Lin, Xuzhu, Nadarajah, Shaktypreya, Dragoljevic, Dragana, Huynh, Kevin, Onda, Danise-Ann, Galic, Sandra, Meikle, Peter J., Edlund, Thomas, Fullerton, Morgan D., Kemp, Bruce E., Murphy, Andrew J., and Loh, Kim

Abstract

Objectives: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis. Methods: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe−/−/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe−/− and Apoe−/−/Hmgcr KI mice. Results: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe−/−/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe−/−/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe−/−/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs. Conclusions: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O–3O4 and PXL 770 for reducing ather

Published
2022
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32. Protein Serine/Threonine Kinases

Author

Heierhorst, Jörg, Pearson, Richard, Horne, James, Bozinovski, Steven, Kobe, Bostjan, Kemp, Bruce E., Conn, P. Michael, editor, and Means, Anthony R., editor

Published
2000
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39. AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice

Author

O’Neill, Hayley M., Lally, James S., Galic, Sandra, Thomas, Melissa, Azizi, Paymon D., Fullerton, Morgan D., Smith, Brennan K., Pulinilkunnil, Thomas, Chen, Zhiping, Samaan, M. Constantine, Jorgensen, Sebastian B., Dyck, Jason R. B., Holloway, Graham P., Hawke, Thomas J., van Denderen, Bryce J., Kemp, Bruce E., and Steinberg, Gregory R.

Published
2014
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42. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin

Author

Fullerton, Morgan D., Galic, Sandra, Marcinko, Katarina, Sikkema, Sarah, Pulinilkunnil, Thomas, Chen, Zhi-Ping, O'Neill, Hayley M., Ford, Rebecca J., Palanivel, Rengasamy, O'Brien, Matthew, Hardie, D. Grahame, Macaulay, S. Lance, Schertzer, Jonathan D., Dyck, Jason R.B., van Denderen, Bryce J., Kemp, Bruce E., and Steinberg, Gregory R.

Subjects
Lipids -- Synthesis, Homeostasis -- Physiological aspects, Insulin -- Physiological aspects, Phosphorylation -- Physiological aspects, Biological sciences, Health
Abstract

The obesity epidemic has led to an increased incidence of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. AMP-activated protein kinase (Ampk) regulates energy homeostasis and is activated by [...]

Published
2013
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45. Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers

Author

Loesch, Danuta Z., primary, Kemp, Bruce E., additional, Bui, Minh Q., additional, Fisher, Paul R., additional, Allan, Claire Y., additional, Sanislav, Oana, additional, Ngoei, Kevin R. W., additional, Atkinson, Anna, additional, Tassone, Flora, additional, Annesley, Sarah J., additional, and Storey, Elsdon, additional

Published
2021
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46. Novel torin1-sensitive phosphorylation sites on the metabolic regulator AMPK revealed by label-free mass spectrometry

Author

Smiles, William J., primary, Ovens, Ashley J., additional, Yu, Dingyi, additional, Ling, Naomi X.Y., additional, Morrison, Kaitlin R., additional, Hoque, Ashfaqul, additional, Scott, John W., additional, Galic, Sandra, additional, Langendorf, Christopher G., additional, Kemp, Bruce E., additional, Peterson, Janni, additional, and Oakhill, Jonathan S., additional

Published
2021
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