Lipid Metabolism and Cardiometabolic Disease Group
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Head of Laboratory
Associate Professor Anna Calkin+61 3 8532 1140
Research Overview
One in three individuals has elevated blood lipid levels, putting them at increased risk of developing a range of conditions including diabetes and cardiovascular disease. The excess lipids can be deposited in tissues where they mediate a variety of pathological effects. In the liver they can promote the onset of insulin resistance and fatty liver disease; in the heart they can promote atherosclerotic lesion formation, damage the heart muscle and lead to a poorer prognosis after a heart attack. Therefore, we need unique strategies to identify novel regulators of lipid metabolism that have the potential to be targeted to treat these conditions.
The research program of the Lipid Metabolism and Cardiometabolic Disease laboratory takes a systems genetics approach, combining large scale ‘omics datasets from humans and genetic panels of mice with validation in cells and preclinical models, to unravel the mechanistic underpinnings of cardiometabolic disease. This allows us to identify novel therapeutic targets for the prevention of cardiometabolic disease.
The groups recent studies include the development of a world first multi-omics platform that combined cutting edge proteomics and lipidomics across genetically diverse preclinical models to interrogate hepatic lipid metabolism. This approach identified novel regulators and clinically relevant biomarkers of fatty liver disease, resulting in patents and collaborations with pharmaceutical companies.
Research focus
- Identification of novel biomarkers of fatty liver disease and progressive liver disease
- Identification and validation of novel regulators of hepatic lipid metabolism with therapeutic potential to treat fatty liver disease
- Identification of novel therapeutic targets strategies to attenuate coronary artery disease
- Modulation of cardiac metabolism to improve prognosis post-myocardial infarction
- Understanding of the importance of cholesterol in the regulation of hepatic glucose metabolism
Staff
Dr Adèle Richart - Senior Postdoctoral Scholar
Dr Yi Wang - Senior Postdoctoral Scholar
Dr Aowen Zhuang - Postdoctoral Scholar
Mr Michael Keating - Senior Research Assistant
Mr Kevin Liu - Research Assistant
Ms Yingying Liu - Research Assistant
Ms Medini Reddy - Research Assistant
Mr Tim Sikora - Research Assistant
Ms Christine Yang - Research Assistant
Mr Aaron Jurrjens - PhD Student
Ms Emily King - PhD Student
Ms Yvette Schooneveldt - PhD Student
Collaborators
Peter Tontonoz, Andrea Hevener, Jake Lusis, Tom Vallim, Elizabeth Tarling (University of California, Los Angeles; UCLA)
Joanne Curran, John Blangero (University of Texas Rio Grande Valley)
Adam Butterworth, Dirk Paul (University of Cambdrige)
Richard Lee (Ionis Pharmaceuticals)
Bronwyn Kingwell (CSL Limited)
Funding
Shine On Foundation (2020-2021)
CSL Commerical Contract (2019-2020)
NHMRC Project Grant (2015-2018)
National Heart Foundation Future Leader Fellow (2014-2018)
National Heart Foundation Overseas Fellowship (2009-2013)
NHMRC Peter Doherty Fellowship (2006-2009)
Research Outcomes
ORIGINAL MANUSCRIPTS
Climie RE, Wu JHY, CALKIN AC, Chapman N, Inglis SC, Mirabito Colafella KM, Picone DS, Tan JTM, Thomas E, Viola HM, Wise SG, Murphy AJ, Nelson MR, Nicholls SJ, Hool LC, Doyle K, Figtree GA, Marques FZ. Lack of strategic funding and long-term job security threaten to have profound effects on cardiovascular researcher retention in Australia. Heart, Lung Circulation (accepted August 2020)
Watson AMD, Gould EAM, Moody SC, Sivakumaran P, Sourris KC, Chow BSM, Köitka-Weber A, Allen TJ, Jandeleit-Dahm KAM, Cooper ME, CALKIN AC. Disparate effects of diabetes and lipids on experimental kidney disease. Frontiers in Physiology 2020;11:518
Ritchie SC, Liu Y, Lambert SA, Teo SM, Scepanovic P, Marten J, Zahid S, Chaffin M, Abraham G, Soranzo N, Burgess S, Drew BG, Kathiresan S, CALKIN AC, Khera AV, Danesh J, Butterworth AS, Inouye M. Integrative analysis of the plasma proteome. bioRxiv (posted 19/12/2019)
Lee SD, Priest C, Bjursell M, Gao, J, Arneson DV, Ahn IS, Diamante G, van Veen E, Massa M, CALKIN AC, Kim J, Andersén H, Porritt M, Carreras A, Ahnmark A, Seeliger F, Maxvall I, Eliasson P, Althage M, Åkerblad P, Lindén D, Cole TA, Lee R, Boyd H, Bohlooly-Y M, Correa S, Yang X, Tontonoz P, Hong C. IDOL regulates systemic energy balance through control of CNS VLDLR expression. Nature Metabolism 1(11):1089-1100
Bond ST, Kim J, CALKIN AC, Drew BG. The antioxidant moiety of MitoQ imparts minimal metabolic effects in adipose tissue of high fat fed mice. Front Physiol 2019;10:543
Parker BL*, CALKIN AC#*, Seldin MM*, Keating MF, Tarling EJ, Yang P, Moody SC, Liu Y, Zerenturk EJ, Needham EJ, Miller ML, Clifford BL, Morand P, Watt MJ, Meex RCR, Peng KY, Lee R, Jayawardana K, Pan C, Mellett NA, Weir JM, Lazarus R, Lusis AJ, Meikle PJ, James DE, de Aguiar Vallim TQ#, Drew BG#. An integrative systems genetic analysis of mammalian lipid metabolism. NATURE 2019;567(7747):187-193 *equal first & #co-corresponding author
Bond ST, Moody SC, Liu Y, Civelek M, Villanueva CJ, Gregorevic P, Kingwell BA, Hevener AL, Lusis AJ, Henstridge DC, CALKIN AC, Drew BG. The E3 ligase MARCH5 in a PPARγ target gene that regulates mitochondria and metabolism in adipocytes. Am J Physiol - Endocrinol Metab 2019;316(2):E293-E304
Ju L, McFadyen JD, Al-Daher S, Alwis I, Chen Y, Tønnesen LL, Maiocchi S, Coulter B, CALKIN AC, Felner EI, Cohen N, Yuan Y, Schoenwaelder SM, Cooper ME, Zhu C, Jackson SP. Compression force sensing regulates integrin αIIbβ3 adhesive function on diabetic platelets. Nature Communications 2018;9(1):1087
Gray SP, Di Marco E, Kennedy K, Chew P, Okabe J, El-Osta A, CALKIN AC, Biessen EA, Touyz RM, Cooper ME, Schmidt HH, Jandeleit-Dahm KA. Reactive Oxygen Species Can Provide Atheroprotection via NOX4-Dependent Inhibition of Inflammation and Vascular Remodeling. Arterioscler Thromb Vasc Biol 2016;36(2):295-307
Drew BG, Hamidi H, Zhou Z, Villanueva CJ, Krum SA, CALKIN AC, Parks BW, Ribas V, Kalajian NY, Phun J, Daraei P, Christofk HR, Hewitt SC, Korach KS, Tontonoz P, Lusis AJ, Slamon DJ, Hurvitz SA, Hevener AL. Estrogen Receptor (ER)α-regulated Lipocalin 2 Expression in Adipose Tissue Links Obesity with Breast Cancer Progression. J Biol Chem 2015;290(9):5566-81
CALKIN AC, Lee SD, Kim J, Van Stijn CM, Wu XH, Lusis AJ, Hong C, Tangirala RI, Tontonoz P. Transgenic expression of dominant-active IDOL in liver causes diet-induced hypercholesterolemia and atherosclerosis in mice. Circulation Research 2014;115(4):442-9
Watson AM, Olukman M, Koulis C, Tu Y, Samijono D, Yuen D, Lee C, Behm DJ, Cooper ME, Jandeleit-Dahm KA, CALKIN AC, Allen TJ. Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes. Diabetologia 2013;56(5):1155-65
Watson, A. M. Soro-Paavonen, A. Sheehy, K. Li, J. CALKIN, AC Koitka, A. Rajan, S. N. Brasacchio, D. Allen, T. J. Cooper, M. E., Thomas, M. C. Jandeleit-Dahm, KA. Delayed intervention with AGE inhibitors attenuates the progression of diabetes-accelerated atherosclerosis in diabetic apolipoprotein E knockout mice Diabetologia 2011;54;(3):681-9
CALKIN AC, Goult BT, Zhang L, Fairall L, Hong C, Schwabe JW, Tontonoz P. FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors. Proceedings of the National Academy of Science USA 2011;108(50):20107-12
Weissglas-Volkov D, CALKIN AC, Tusie-Luna T, Sinsheimer JS, Zelcer N, Riba L, Tino AM, Ordoñez-Sánchez ML, Cruz-Bautista I, Aguilar-Salinas CA, Tontonoz P, Pajukanta P. The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans. Journal of Clinical Investigation 2011;121(8):3062-71
Zhang L, Fairall L, Goult BT, CALKIN AC, Hong C, Millard CJ, Tontonoz P, Schwabe JW. The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor. Genes & Development 2011;25(12):1262-74
Soldatos G, Jandeleit-Dahm K, Thomson H, Formosa M, D'orsa K, CALKIN AC, Cooper ME, Ahimastos AA, Kingwell BA. Large artery biomechanics and diastolic dysfunction in patients with Type 2 diabetes. Diabetic Medicine 2011;28(1):54-60
Giunti S, CALKIN AC, Forbes JM, Allen TJ, Thomas MC, Cooper ME, Jandeleit-Dahm KA. The pleiotropic actions of rosuvastatin confer renal benefits in the diabetic Apo-E knockout mouse. American Journal of Physiology: Renal Physiology 2010;299(3):F528-35
Pham Y, Tu Y, Wu T, Allen TJ, CALKIN AC, Watson AM, Li J, Jandeleit-Dahm KA, Toh BH, Cao Z, Cooper ME, Chai Z. Cell division autoantigen 1 plays a profibrotic role by modulating downstream signalling of TGF-beta in a murine diabetic model of atherosclerosis. Diabetologia 2010;53(1):170-9
CALKIN AC, Drew BG, Ono A, Duffy SJ, Gordon MV, Schoenwaelder SM, Sviridov D, Cooper ME, Kingwell BA, Jackson SP. Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux. Circulation 2009;120(21):2095-104
Brasacchio D, Okabe J, Tikellis C, Balcerczyk A, George P, Baker EK, CALKIN AC, Brownlee M, Cooper ME, El-Osta A. Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes 2009;58(5):1229-1236
Soro-Paavonen, A, Watson, AM, Li J, Paavonen K, Koitka A, CALKIN AC, Barit, D, Coughlan, MT, Drew BG, Lancaster GI, Thomas M, Forbes JM, Nawroth PP, Bierhaus A, Cooper ME, Jandeleit-Dahm KA. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes Diabetes 2008;57(9):2461-9;
CALKIN AC, Giunti S, Sheehy KJ, Chew C, Boolell V, Rajaram YS, Cooper ME, Jandeleit-Dahm KA. The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in diabetic apolipoprotein E deficient mice via effects on advanced glycation, oxidative stress and inflammation. Diabetologia 2008;51(9) 1731-1740
Lewis P, Stefanovic N, Pete J, CALKIN AC, Giunti S, Thallas-Bonke V, Jandeleit-Dahm K, Allen TJ, Kola I, Cooper ME, deHaan JB. Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E-deficient mice. Circulation 2007;115(16):2178-2187
CALKIN AC, Allen TJ, Lassila M, Jandeleit-Dahm KA, Thomas MC. Increased atherosclerosis following treatment with a dual PPAR agonist in the ApoE knockout mouse. Atherosclerosis 2007;195(1):17-22
CALKIN AC, Giunti S, Cooper ME, Jandeleit-Dahm KA, Thomas MC, Allen TJ. PPAR α and γ agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse. Nephrology, Dialysis & Transplant 2006;21(9):2399-2405
CALKIN AC, Cooper ME, Jandeleit-Dahm KA, Allen TJ. Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation. Diabetologia 2006;49(4):766-774
CALKIN AC, Forbes JM, Smith CM, Lassila M, Cooper ME, Jandeleit-Dahm KA, Allen TJ. Rosiglitazone attenuates atherosclerosis in a model of insulin insufficiency independent of its metabolic effects. Arteriosclerosis, Thrombosis & Vascular Biology 2005;25(9):1903-1909
Lassila M, Jandeleit-Dahm KA, Seah KK, Smith CM, CALKIN AC, Allen TJ, Cooper ME. Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice. Journal of the American Society of Nephrology 2005;16(2):363-373
Lassila M, Seah KK, Allen TJ, Thallas V, Thomas MC, Candido R, Burns WC. Forbes JM, CALKIN AC, Cooper ME, Jandeleit-Dahm KA. Accelerated nephropathy in diabetic apolipoprotein E-knockout mice: role of advanced glycation end products. Journal of the American Society of Nephrology 2004;15(8):2125-2138
CALKIN AC, Sudhir K, Honisett S, Williams MRI, Dawood T, Komesaroff PA. Rapid potentiation of endothelium-dependent vasodilation by estradiol in postmenopausal women is mediated via cyclooxygenase 2. Journal of Clinical Endocrinology & Metabolism 2002;87(11):5072-5075
INVITED REVIEWS / EDITORIALS / BOOK CHAPTERS
Magliano DJ, Macefield VG, Ellis AM, CALKIN AC. Addressing Gender Equity in Senior Leadership Roles in Translational Science. ACS Pharmacology & Translation Science; 2020;3(4):773-779
Keating MK, CALKIN AC. The CCC COMManDs control of LDL Cholesterol Levels. Circulation Research 2018;122(12):1629-1631
Westein E, Hoefer T, CALKIN AC. Thrombosis in Diabetes: A Shear Flow Effect? Clinical Sci (London). 2017;131(12):1245-1260
Ritchie RH, Zerenturk EJ, Prakoso D, CALKIN AC. Lipid Metabolism and its Implications for Type I Diabetes-Associated Cardiomyopathy. J Mol Endocrinol. 2017;59(4):R225-R240
Zerenturk EJ, CALKIN AC. The use of L-sIDOL Transgenic Mice as a Murine Model to Study Hypercholesterolaemia and Atherosclerosis. In: Brown A.J., Gelissen I.C. (ed) Methods in Molecular Biology: Cholesterol Homeostasis, Springer, New York. 2017;1583:65-72
CALKIN AC. Novel Regulation of Lipid Metabolism. Impact 2017;8:37-39
CALKIN AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR Nat Rev Mol Cell Biol 2012;14;13(4):213-24;
CALKIN AC, Tontonoz P. Genome-wide association studies identify new targets in cardiovascular disease (Editorial). Sci Transl Med 2010;2(48):48ps46
CALKIN AC, Tontonoz P. Liver x receptor signaling pathways and atherosclerosis. Arteriosclerosis Thrombosis and Vascular Biology 2010;30(8):1513-8
Jandeleit-Dahm KA, CALKIN A, Tikellis C, Thomas M. Direct anti-atherosclerotic effects of PPAR agonists. Current Opinion in Lipidology 2009;20(1):24-29
CALKIN AC, Thomas MC. PPAR agonists and Cardiovascular Disease in Diabetes. PPAR Research 2008:245410
Jackson SP, CALKIN AC. The clot thickens – Oxidized lipids and thrombosis (Editorial). Nature Medicine 2007;13(9):1015-1016
CALKIN AC, Jandeleit-Dahm KA, Sebokova E, Allen TJ, Mizraki J, Cooper ME, Tikellis C. PPARs and Diabetes-Associated Atherosclerosis. Current Pharmaceutical Design 2007;13(26):2736-41
Drew BG, CALKIN AC Drug Evaluation: K-111, an insulin sensitising peroxisome proliferator-activated receptor alpha agonist. Current Opinion in Investigational Drugs 2007;8(4):324-330
Drew BG, CALKIN AC (2007) K-111 Evaluation. Investigational Drugs Database www.IDdb3.com
Gordon MV, CALKIN AC. Vildagliptin: A Viewpoint by Michelle V Gordon and Anna C Calkin. Drugs 2006;66(15):2002
CALKIN AC, Allen TJ. Diabetes-mellitus associated atherosclerosis: mechanisms involved and potential for pharmacological intervention. American Journal of Cardiovascular Disease 2006;6(1):15-40
CALKIN AC (2006) The PPARα agonist, Gemfibrozil, Attenuates Diabetes-Associated Atherosclerosis Independent of Effects on the Lipid Profile. Commentary for the International Atherosclerosis Society www.athero.org
CALKIN AC, Thomas MC, Cooper ME. MK-767. Kyorin/Banyu/Merck. Current Opinion in Investigational Drugs 2003;4(4):444-448
Research Publications
Parker BL*, CALKIN AC#*, Seldin MM*, Keating MF, Tarling EJ, Yang P, Moody SC, Liu Y, Zerenturk EJ, Needham EJ, Miller ML, Clifford BL, Morand P, Watt MJ, Meex RCR, Peng KY, Lee R, Jayawardana K, Pan C, Mellett NA, Weir JM, Lazarus R, Lusis AJ, Meikle PJ, James DE, de Aguiar Vallim TQ#, Drew BG#. An integrative systems genetic analysis of mammalian lipid metabolism. Nature 2019;567(7747):187-193 *equal first & #co-corresponding author
Magliano DJ, Macefield VG, Ellis AM, CALKIN AC. Addressing Gender Equity in Senior Leadership Roles in Translational Science. ACS Pharmacology & Translation Science; 2020;3(4):773-779
Ritchie RH, Zerenturk EJ, Prakoso D, CALKIN AC. Lipid Metabolism and its Implications for Type I Diabetes-Associated Cardiomyopathy. J Mol Endocrinol. 2017;59(4):R225-R240
CALKIN AC, Lee SD, Kim J, Van Stijn CM, Wu XH, Lusis AJ, Hong C, Tangirala RI, Tontonoz P. Transgenic expression of dominant-active IDOL in liver causes diet-induced hypercholesterolemia and atherosclerosis in mice. Circulation Research 2014;115(4):442-9
CALKIN AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR Nat Rev Mol Cell Biol 2012;14;13(4):213-24
CALKIN AC, Goult BT, Zhang L, Fairall L, Hong C, Schwabe JW, Tontonoz P. FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors. Proceedings of the National Academy of Science USA 2011;108(50):20107-12
Weissglas-Volkov D, CALKIN AC, Tusie-Luna T, Sinsheimer JS, Zelcer N, Riba L, Tino AM, Ordoñez-Sánchez ML, Cruz-Bautista I, Aguilar-Salinas CA, Tontonoz P, Pajukanta P. The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans. Journal of Clinical Investigation 2011;121(8):3062-71