Staff Profile

Roles and Responsibilities

Principal Investigator for research on liver metabolism in Non-alcoholic fatty liver disease (NAFLD) with focus on intracellular homeostasis and impact of calorie excess and genetic variants as risk factors for liver disease, and development of new drugs for NAFLD. Research projects funded by MRC, MICA Exploring a new perspective on the mechanism of action of Glucokinase Activators in liver: a preclinical study (2017-2020); Targeting glucose metabolism in Nonalcoholic fatty liver disease (2018-2020).

Qualifications

D.Sc. Oxon, 2003
D.Phil. Oxon, 1981
M.Sc. University of Malta, 1978
B.Sc. University of Malta, 1977

Previous Positions

1978 - 81: Commonwealth Scholar, University of Oxford
1981 - 82: Postdoctoral Fellow, State University of Utrecht
1982 - 86: Postdoctoral Fellow, University of Newcastle
1986 - 91: Lecturer, University of Newcastle
1991 - 94: Senior Lecturer, University of Newcastle
1994 - 03: Reader, University of Newcastle

Memberships

Diabetes UK and Biochemical Society.

Research Interests

Liver carbohydrate and lipid metabolism in health and disease with focus on Glucokinase and its regulatory protein, cellular metabolite homeostasis, metabolic control of gene expression in Nonalcoholic fatty liver disease (NAFLD), development of new drugs for NAFLD targeting liver glucose metabolism and intracellular homeostasis.

Other Expertise

Mechanism of action of anti-hyperglycaemic compounds and development of in vitro methods for screening mode of action.

Future Research

Preclinical studies on drug development for NAFLD.

Research Roles

Principal Investigator on two MRC Project Grants on mechanism of action of candidate drugs for NAFLD.

Funding

Current Research Funding is from: the Medical Research Council

Undergraduate Teaching:   Biomedical Sciences, Stage 2, Membrane Transport and Cell Signalling in Health and Disease, (PSC2002).  Postgraduate Teaching:  MRES Modules on Cell Signalling and Diabetes.

• Moonira T, Chachra SS, Ford BE, Marin S, Alshawi A, Adam-Primus NS, Arden C, Al-Oanzi ZH, Foretz M, Viollet B, Cascante M, Agius L. Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation. Journal of Biological Chemistry 2020, 295(10), 3330-3346.
• Barr D, Szennyes E, Bokor E, Al-Oanzi ZH, Moffatt C, Kun S, Docsa T, Sipos A, Davies MP, Mathomes RT, Snape TJ, Agius L, Somsak L, Hayes JM. Identification of C‑β‑D‑Glucopyranosyl Azole-Type Inhibitors of Glycogen Phosphorylase That Reduce Glycogenolysis in Hepatocytes: In Silico Design, Synthesis, in Vitro Kinetics, and ex Vivo Studies. ACS Chemical Biology 2019, 14(7), 1460-1470.
• Alshawi A, Agius L. Low metformin causes a more oxidized mitochondrial NADH/NAD redox state in hepatocytes and inhibits gluconeogenesis by a redox-independent mechanism. Journal of Biological Chemistry 2019, 294(8), 2839-2853.
• Codner GF, Mianné J, Caulder A, Loeffler J, Fell R, King R, Allan AJ, Mackenzie M, Pike FJ, McCabe CV, Christou S, Joynson S, Hutchison M, Stewart ME, Kumar S, Simon MM, Agius L, Anstee QM, Volynski KE, Kullmann DM, Wells S, Teboul L. Application of long single-stranded DNA donors in genome editing: generation and validation of mouse mutants. BioMedCentral Biology 2018, 16, 70.
• Codner GF, Mianne J, Caulder A, Loeffler J, Fell R, King R, Allan AJ, Mackenzie M, Pike FJ, McCabe CV, Christou S, Joynson S, Hutchison M, Stewart ME, Kumar S, Simon MM, Agius L, Anstee QM, Volynski KE, Kullmann DM, Wells S, Teboul L. Application of long single-stranded DNA donors in genome editing: Generation and validation of mouse mutants. BMC Biology 2018, 16(1), 70.
• Leitch AC, Lakey AF, Hotham WE, Agius L, Kass GE, Blain PG, Wright MC. The ionic liquid 1-octyl-3-methylimidazolium (M8OI) is an activator of the human estrogen receptor alpha. Biochemical and Biophysical Research Communications 2018, 503(3), 2167-2178.
• Al-Oanzi ZH, Fountana S, Moonira T, Tudhope SJ, Petrie JL, Alshawi A, Patman G, Arden C, Reeves HL, Agius L. Opposite effects of a glucokinase activator and metformin on glucose-regulated gene expression in hepatocytes. Diabetes, Obesity and Metabolism 2017, 19(8), 1078-1087.
• Agius L. Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein. Proceedings of the Nutrition Society 2016, 75(1), 10-18.
• Agius L. Hormonal and Metabolite Regulation of Hepatic Glucokinase. Annual Review of Nutrition 2016, 36, 389-415.
• Moonira TN, Al-Oanzi Z, Arden C, Agius L. Metformin action in hepatocytes is not mimicked by selective activation of AMPactivated protein kinase. In: Diabetes UK Professional Conference 2016. 2016, Glasgow, UK: Wiley-Blackwell.
• Al-Oanzi Z, Fountana S, Agius L. Mechanism of action of metformin in regulating hepatic gene expression. In: Diabetes UK Professional Conference. 2015, London, UK: Wiley-Blackwell Publishing Ltd.
• Agius L. Role of glycogen phosphorylase in liver glycogen metabolism. Molecular Aspects of Medicine 2015, 46, 34-45.
• Cullen KS, Al-Oanzi ZH, O'Harte FPM, Agius L, Arden C. Glucagon induces translocation of glucokinase from the cytoplasm to the nucleus of hepatocytes by transfer between 6-phosphofructo 2-kinase/fructose 2,6-bisphosphatase-2 and the glucokinase regulatory protein. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 2014, 1843(6), 1123-1134.
• Agius L. Lessons from glucokinase activators: the problem of declining efficacy. Expert Opinion on Therapeutic Patents 2014, 24(11), 1155-1159.
• Petrie JL, Fountana S, Agius L. Opposite effects of glucokinase activators and metformin on gene expression in hepatocytes. In: Diabetes UK Professional Conference 2014. 2014, Liverpool, UK: Wiley-Blackwell.
• Parmenopoulou V, Kantsadi AL, Tsirkone VG, Chatzileontiadou DSM, Manta S, Zographos SE, Molfeta C, Archontis G, Agius L, Hayes JM, Leonidas DD, Komiotis D. Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-ᴅ-glucopyranosylamines. Bioorganic & Medicinal Chemistry 2014, 22(17), 4810-4825.
• Probert PM, Chung GW, Cockell SJ, Agius L, Mosesso P, White SA, Oakley F, Brown CD, Wright MC. Utility of B-13 Progenitor-Derived Hepatocytes in Hepatotoxicity and Genotoxicity Studies. Toxicological Sciences 2014, 137(2), 350-370.
• Arden C, Cullen KS, Al-Oanzi ZH, O'Harte FP, Agius L. A role for glucagon in the post-translational regulation of hepatic glucokinase activity. In: Diabetes UK Professional Conference. 2013, Manchester, UK: Wiley-Blackwell.
• Petrie JL, Al-Oanzi ZH, Arden C, Tudhope SJ, Mann J, Kieswich J, Yaqoob MM, Towle HC, Agius L. Glucose induces protein targeting to glycogen in hepatocytes by fructose 2,6-bisphosphate-mediated recruitment of MondoA to the promoter. Molecular and Cellular Biology 2013, 33(4), 725-738.
• Agius L. High-carbohydrate diets induce hepatic insulin resistance to protect the liver from substrate overload. Biochemical Pharmacology 2013, 85(3), 306-312.
• Bechmann LP, Vetter D, Ishida J, Hannivoort RA, Lang UE, Kocabayoglu P, Fiel MI, Muñoz U, Patman GL, Ge F, Yakar S, Li X, Agius L, Lee YM, Zhang W, Hui KY, Televantou D, Schwartz GJ, Leroith D, Berk PD, Nagai R, Suzuki T, Reeves HL, Friedman SL. Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis. Journal of Hepatology 2013, 58(5), 1000-1006.
• Petrie JL, Patman GL, Sinha I, Alexander TD, Reeves HL, Agius L. The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis. American Journal of Physiology 2013, 305(10), E1255-E1265.
• Tudhope SJ, Wang CC, Petrie JL, Potts L, Malcomson F, Kieswich J, Yaqoob MM, Arden C, Hampson LJ, Agius L. A Novel Mechanism for Regulating Hepatic Glycogen Synthesis Involving Serotonin and Cyclin-Dependent Kinase-5. Diabetes 2012, 61(1), 49-60.
• Agius L. Comment on: Stefanovski et al. Estimating Hepatic Glucokinase Activity Using a Simple Model of Lactate Kinetics. Diabetes Care 2012;35: 1015-1020. Diabetes Care 2012, 35(12), E90-E90.
• Arden C, Tudhope SJ, Petrie JL, Al-Oanzi ZH, Cullen KS, Lange AJ, Towle HC, Agius L. Fructose 2,6-bisphosphate is essential for glucose-regulated genetranscription of glucose-6-phosphatase and other ChREBP target genes inhepatocytes. Biochemical Journal 2012, 443(1), 111-123.
• Al-Oanzi ZH, Petrie JL, Tudhope S, Arden C, Agius L. The insulin-independent glucose-induction of the hepatic gluconeogenic enzyme glucose 6-phosphatase involves distinct metabolic pathways and transcription factors. In: 48th General Assembly of the European Association for the Study of Diabetes. 2012, Berlin, Germany: Springer.
• Daniele GA, Reeves HL, Agius L, Gaggini M, Comassi M, Miccoli R, Del Prato S, Gastaldelli A. The Kruppel-like factor 6-IVS1-27A (KLF6) polymorphism is associated with more favourable postprandial glucose metabolism in subjects at high risk of type 2 diabetes. In: 48th General Assembly of the European Association for the Study of Diabetes. 2012, Berlin, Germany: Springer.
• Marin de Mas I, Selivanov VA, Marin S, Roca J, Oresic M, Agius L, Cascante M. Compartmentation of glycogen metabolism revealed from 13C isotopologuedistributions. BMC Systems Biology 2011, 5(1), 175.
• Arden C, Petrie JL, Tudhope SJ, Al-Oanzi Z, Claydon AJ, Beynon RJ, Towle HC, Agius L. Elevated glucose represses liver glucokinase and induces its regulatory protein to safeguard hepatic phosphate homeostasis. Diabetes 2011, 60(12), 3110-3120.
• Cullen KS, Matschinsky FM, Agius L, Arden C. Susceptibility of Glucokinase-MODY Mutants to Inactivation by Oxidative Stress in Pancreatic β-Cells. Diabetes 2011, 60(12), 3175-3185.
• Bechmann LP, Vetter D, Hannivoort RA, Patman G, Lee UE, Fiel MI, Agius L, Reeves H, Friedman SL. Liver-specific deletion of KLF6 uncovers novel transcriptional pathways linked to lipid and glucose homeostasis. In: 61st Annual Meeting of the American Association for the Study of Liver Diseases. 2010, Boston, MA: Hepatology: Wiley-Blackwell.
• Arden C, Trainer A, De La Iglesia N, Scougall KT, Gloyn AL, Lange AJ, Shaw J, Matschinsky FM, Agius L. Cell biology assessment of glucokinase mutations V62M and G72R in pancreatic β-cells: Evidence for cellular instability of catalytic activity. Diabetes 2007, 56(7), 1773-1782.
• Payne VA, Arden C, Lange AJ, Agius L. Contributions of glucokinase and phosphofructokinase-2/fructose bisphosphatase-2 to the elevated glycolysis in hepatocytes from Zucker fa/fa rats. American Journal of Physiology - Regulatory Integrative and Comparative Physiology 2007, 293(2), R618-R625.
• Hampson LJ, Mackin P, Agius L. Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs. Diabetologia 2007, 50(8), 1743-1751.
• Hampson LJ, Arden C, Agius L, Ganotidis M, Kosmopoulou MN, Tiraidis C, Elemes Y, Sakarellos C, Leonidas DD, Oikonomakos NG. Bioactivity of glycogen phosphorylase inhibitors that bind to the purine nucleoside site. Bioorganic and Medicinal Chemistry 2006, 14(23), 7835-7845.
• Arden C, Baltrusch S, Agius L. Glucokinase regulatory protein is associated with mitochondria in hepatocytes. FEBS Letters 2006, 580(8), 2065-2070.
• Oikonomakos NG, Tiraidis C, Leonidas DD, Zographos SE, Kristiansen M, Jessen CU, Norskov-Lauritsen L, Agius L. Iminosugars as potential inhibitors of glycogenolysis: Structural insights into the molecular basis of glycogen phosphorylase inhibition. Journal of Medicinal Chemistry 2006, 49(19), 5687-5701.
• Arden C, Green AR, Hampson LJ, Aiston S, Harndahl L, Greenberg CC, Brady MJ, Freeman S, Poucher SM, Agius L. Increased sensitivity of glycogen synthesis to phosphorylase-a and impaired expression of the glycogen-targeting protein R6 in hepatocytes from insulin-resistant Zucker fa/fa rats. FEBS Journal 2006, 273(9), 1989-1999.
• Harndahl L, Schmoll D, Herling AW, Agius L. The role of glucose 6-phosphate in mediating the effects of glucokinase overexpression on hepatic glucose metabolism. FEBS Journal 2006, 273(2), 336-346.
• Aiston S, Hampson LJ, Arden C, Iynedjian PB, Agius L. The role of protein kinase B/Akt in insulin-induced inactivation of phosphorylase in rat hepatocytes. Diabetologia 2006, 49(1), 174-182.
• Payne VA, Arden C, Wu C, Lange AJ, Agius L. Dual role of phosphofructokinase-2/fructose bisphosphatase-2 in regulating the compartmentation and expression of glucokinase in hepatocytes. Diabetes 2005, 54(7), 1949-1957.
• Hampson LJ, Agius L. Increased potency and efficacy of combined phosphorylase inactivation and glucokinase activation in control of hepatocyte glycogen metabolism. Diabetes 2005, 54(3), 617-623.
• Brocklehurst KJ, Davies RA, Agius L. Differences in regulatory properties between human and rat glucokinase regulatory protein. Biochemical Journal 2004, 378(2), 693-697.
• Arden C, Harboottle A, Baltrusch S, Tiedge M, Agius L. Glucokinase is an integral component of the insulin granules in glucose-responsive insulin secretory cells and does not translocate during glucose stimulation. Diabetes 2004, 53(9), 2346-2352.
• Aiston S, Green A, Mukhtar M, Agius L. Glucose 6-phosphate causes translocation of phosphorylase in hepatocytes and inactivates the enzyme synergistically with glucose. Biochemical Journal 2004, 377(1), 195-204.
• Brocklehurst KJ, Payne VA, Davies RA, Carroll D, Vertigan HL, Wightman HJ, Aiston S, Waddell ID, Leighton B, Coghlan MP, Agius L. Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators. Diabetes 2004, 53(3), 535-541.
• Green AR, Aiston S, Greenberg CC, Freeman S, Poucher SM, Brady MJ, Agius L. The glycogenic action of protein targeting to glycogen in hepatocytes involves multiple mechanisms including phosphorylase inactivation and glycogen synthase translocation. Journal of Biological Chemistry 2004, 279(45), 46474-46482.
• Aiston S, Andersen B, Agius L. Glucose 6-phosphate regulates hepatic glycogenolysis through inactivation of phosphorylase. Diabetes 2003, 52(6), 1333-1339.
• Aiston S, Coghlan MP, Agius L. Inactivation of phosphorylase is a major component of the mechanism by which insulin stimulates hepatic glycogen synthesis. European Journal of Biochemistry 2003, 270(13), 2773-2781.
• Tavridou A, Agius L. Phosphorylase regulates the association of glycogen synthase with a proteoglycogen substrate in hepatocytes. FEBS Letters 2003, 551(1-3), 87-91.
• Latsis T, Andersen B, Agius L. Diverse effects of two allosteric inhibitors on the phosphorylation state of glycogen phosphorylase in hepatocytes. Biochemical Journal 2002, 368, 309-316.
• Agius L, Centelles J, Cascante M. Multiple glucose 6-phosphate pools or channelling of flux in diverse pathways?. In: Biochemical Society Transactions: Meeting on High-Throughput Screening - The Way Ahead. 2002, Bedford, UK: Portland Press Ltd.
• Aiston S, Hampson L, Gomez-Foix AM, Guinovart JJ, Agius L. Hepatic glycogen synthesis is highly sensitive to phosphorylase activity: Evidence from metabolic control analysis. Journal of Biological Chemistry 2001, 276(26), 23858-23866.
• De Atauri P, Acerenza L, Kholodenko BN, De La Iglesia N, Guinovart JJ, Agius L, Cascante M. Occurrence of paradoxical or sustained control by an enzyme when overexpressed: Necessary conditions and experimental evidence with regard to hepatic glucokinase. Biochemical Journal 2001, 355(3), 787-793.
• Aiston S, Peak M, Agius L. Impaired glycogen synthesis in hepatocytes from Zucker fatty fa/fa rats: The role of increased phosphorylase activity. Diabetologia 2000, 43(5), 589-597.
• Agius L, Stubbs M. Investigation of the mechanism by which glucose analogues cause translocation of glucokinase in hepatocytes: Evidence for two glucose binding sites. Biochemical Journal 2000, 346(2), 413-421.
• Stubbs M, Aiston S, Agius L. Subcellular localization, mobility, and kinetic activity of glucokinase in glucose-responsive insulin-secreting cells. Diabetes 2000, 49(12), 2048-2055.
• Agius L, Aiston S, Newgard CB. The control strength of glucokinase in hepatocytes: A predictor of metabolic defects in maturity onset diabetes of the young, type 2. In: NATO Advanced Research Workshop on Technological and Medical Implications of metabolic Control Analysis. 2000, Visegrad, Hungary: Springer.
• De La Iglesia N, Mukhtar M, Seoane J, Guinovart JJ, Agius L. The role of the regulatory protein of glucokinase in the glucose sensory mechanism of the hepatocyte. Journal of Biological Chemistry 2000, 275(14), 10597-10603.
• Cascante M, Centelles JJ, Agius L. Use of α-toxin from Staphylococcus aureus to test for channelling of intermediates of glycolysis between glucokinase and aldolase in hepatocytes. Biochemical Journal 2000, 352(3), 899-905.
• Mukhtar M, Stubbs M, Agius L. Evidence for glucose and sorbitol-induced nuclear export of glucokinase regulatory protein in hepatocytes. FEBS Letters 1999, 462(3), 453-458.
• Aiston S, Trinh KY, Lange AJ, Newgard CB, Agius L. Glucose-6-phosphatase overexpression lowers glucose 6-phosphate and inhibits glycogen synthesis and glycolysis in hepatocytes without affecting glucokinase translocation. Evidence against feedback inhibition of glucokinase. Journal of Biological Chemistry 1999, 274(35), 24559-24566.
• Dixon M, Agius L, Yeaman SJ, Day CP. Inhibition of rat hepatocyte proliferation by transforming growth factor beta and glucagon is associated with inhibition of ERK2 and p70 S6 kinase. Hepatology 1999, 29(5), 1418-1424.
• Aiston S, Agius L. Leptin enhances glycogen storage in hepatocytes by inhibition of phosphorylase and exerts an additive effect with insulin. Diabetes 1999, 48(1), 15-20.
• Agius L. The role of glucokinase translocation in the hepatocyte in the control of glucose metabolism. In: FASEB Journal. 1999, Federation of American Societies for Experimental Biology.
• W. Lowes, M. Walker, K. Alberti and L. Agius. Hexokinase isoenzymes in normal and cirrhotic human liver: suppression of glucokinase in cirrhosis. Biochimica Et Biophysica Acta-General Subjects 1998, 1379, 134-142.
• G. H. Thoresen, T. K. Guren, D. Sandnes, M. Peak, L. Agius and T. Christoffersen. Response to transforming growth factor or (TGF alpha) and epidermal growth factor (EGF) in hepatocytes: Lower EGF receptor affinity of TGF alpha is associated with more sustained activation of p42/p44 mitogen-activated protein kinase and greater efficacy in stimulation of DNA synthesis. Journal of Cellular Physiology 1998, 175, 10-18.
• L. Agius. The physiological role of glucokinase binding and translocation in hepatocytes. Advances in Enzyme Regulation, Vol 38 1998, 38, 303-331.
• L. Agius. Involvement of glucokinase translocation in the mechanism by which resorcinol inhibits glycolysis in hepatocytes. Biochemical Journal 1997, 325, 667-673.
• L. Agius, M. Peak, C. B. Newgard, A. M. GomezFoix and J. J. Guinovart. Evidence for a role of glucose-induced translocation of glucokinase in the control of hepatic glycogen synthesis. Journal of Biological Chemistry 1996, 271, 30479-30486.
• L. Agius. Substrate modulation at aldolase B binding in hepatocytes. Biochemical Journal 1996, 315, 651-658.
• Agius L. The hepatocyte cytoskeleton. Biochemical, physiological, and pathological aspects. In: John E. Hesketh and Ian F. Pryme, ed. Cytoskeleton in Specialized Tissues and in Pathological States. London: JAI Press, 1996, pp.71-106.