Molecular pathology and therapy in heterogenic and polygenic diseases
Antonio Zorzano
Principal Investigator
Professor (Biochemistry and Molecular Biology Dept. - UB)
Office Tel : +34 93 403 71 97
Lab Tel : +34 93 403 47 01- +34 93 403 71 99-
+34 93 4037198
e-mail : antonio.zorzano
irbbarcelona.org
Background
It has been estimated that between 200 million and 300 million people worldwide will meet World Health Organization diagnostic criteria for diabetes mellitus by the end of this decade. This epidemic of predominantly type 2 diabetes has been mediated largely by our shift toward a more sedentary lifestyle, which predisposes us to obesity and insulin resistance. Individuals affected by this disease may also exhibit an array of associated undesirable effects such as hypertension, dyslipidemia, and hypercoagulability, which lead to morbidity and mortality from atherosclerotic vascular disease. The co-existence of several of these disorders with insulin resistance constitutes the metabolic syndrome. In Western society, metabolic syndrome diseases are growing at epidemic rates and currently affect about 20% of the general population and over 40% of people over 60 years of age. Recent epidemiological and biological data indicate that the etiology of these diseases may share unexpected and common genetic and biochemical mechanisms. A major step towards understanding the metabolic syndrome is the identification of susceptibility genes, which may lead to the acquisition of additional therapeutic targets for future drug design.
Research Interests
We aim to determine the molecular mechanisms involved in the development of insulin resistance and, in particular, to identify novel obesity and type 2 diabetes susceptibility genes.
This general objective is structured into three levels:
- Identification of genes responsible for the development of insulin resistance associated with obesity or type 2 diabetes, with special emphasis on those genes implicated in novel mechanisms involving mitochondrial processes (i.e., mitochondrial dynamics), encoding proteins involved in the regulation of nuclear gene expression, or encoding proteins involved in novel signalling events.
- Analysis of the molecular mechanisms involved in the regulation of glucose transport in muscle and adipose cells and in the development of lipotoxicity.
- Identification of novel targets and development of new compounds for the treatment of the metabolic syndrome.
Research Lines
Our research group is organized around 3 research lines:
1. Identification of genes responsible for the development of insulin resistance, obesity or type 2 diabetes.
Our laboratory has reported the implication of the bi-functional protein SSAO/VAP-1 (semicarbazide-sensitive amine oxidase/vascular adhesion protein-1) in the regulation of glucose transport in adipose cells. Manipulation of SSAO activity reverses insulin resistance and hyperglycemia in diabetic rats. Furthermore, SSAO/VAP-1 is cleaved from the plasma membrane in response to factors such as TNFα, and the soluble resultant form (soluble SSAO) is released to the circulation. In keeping with this, the plasma concentration of soluble SSAO increases in insulin resistant states. On the basis of these data, at present we are studying the functional role of SSAO/VAP1 in knock-out mice and the specific role of the soluble form of SSAO and its relationship with insulin resistance. We have identified a nuclear gene that encodes the mitochondrial protein mitofusin-2 (Mfn2).
We have demonstrated that Mfn2 regulates mitochondrial fusion as well as mitochondrial metabolism. In addition, we have also shown that Mfn2 gene expression is repressed in skeletal muscle of obese or type 2 diabetic subjects. All these findings indicate that Mfn2 may be involved in the pathophysiology of obesity and type 2 diabetes. We are currently examining the possible role of of Mfn2 in the development of traits of the metabolic syndrome in humans and also the specific mechanisms by which Mfn2 regulates mitochondrial metabolism.
Furthermore, we have identified several genes that encode nuclear proteins with altered expression in obesity and/or type 2 diabetes. Our current research addresses the functional role of these genes and their possible implication as susceptibility factors for type 2 diabetes or in the development of the metabolic syndrome.
2. Analysis of the molecular mechanisms involved in the regulation of glucose transport in muscle and adipose cells and in the development of lipotoxicity.
We address the delineation of intracellular signalling mechanisms that cause the rapid translocation of GLUT4 glucose transporters from an intracellular localization to the cell surface as well as the molecular machinery that causes cell lipotoxicity. In this regard, our research activities explore the signalling pathways involved in the metabolic effects of muscle contraction and specifically in the mechanisms implicated in GLUT4 recruitment to the cell surface. In addition, and on the basis of the recent observations that caveolin-1 and caveolae are involved in integrity and function of the lipid droplet and in binding, transport, and storage of fatty acids and insulin action, we aim to define the role of caveolin-1/caveolae in the mechanisms by which the adipocyte efficiently packages and stores TAG in distinct adipose depots. These studies may reveal the underlying causes of obesity- or lipodystrophy-associated lipotoxicity.
3. Identification of novel targets and development of new compounds for the treatment of the metabolic syndrome.
We have demonstrated that the use of SSAO/VAP-1 substrates and low doses of vanadate potently stimulate glucose transport in adipocytes. In addition, the in vivo administration of these compounds exerts an anti-diabetic action in animal models of diabetes. On the basis of these studies, and in collaboration with Fernando Albericio (IRB Barcelona) and Miriam Royo (PCB), we have generated a novel class of compounds, namely arylalkylamine vanadium salts, which, when administered orally or subcutaneously, also show very potent anti-diabetic activity in animals. We are currently studying the toxicological and pharmacological properties of this class of compounds, and their possible application in the treatment of traits of the metabolic syndrome.
Funding
This group receives financial support from the following sources:
- Generalitat de Catalunya (Government of Catalonia)
- Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (Spanish National Institute of Health)
- Ministerio de Educación y Ciencia (Spanish Ministry of Science & Education)
More info
Molecular pathology and therapy in heterogenic and polygenic diseases
Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis
Parra V, Eisner V, Chiong M, Criollo A, Moraga F, Garcia A, Härtel S, Jaimovich E, Zorzano A, Hidalgo C and Lavandero S
Cardiovasc Res, 77 (2), 387-397 (2008º)
The structure of human 4F2hc ectodomain provides a model for homodimerization and electrostatic interaction with plasma membrane
Fort J, de la Ballina LR, Burghardt HE, Ferrer-Costa C, Turnay J, Ferrer-Orta C, Usón I, Zorzano A, Fernández-Recio J, Orozco M, Lizarbe MA, Fita I and Palacín M
J Biol Chem, 282 (43), 31444-31452 (2007)
Identification of a novel modulator of thyroid hormone receptor-mediated action
Bernhard G. Baumgartner, Meritxell Orpinell, Jordi Duran, Vicent Ribas, Hans E. Burghardt, Daniel Bach, Ana Victoria Villar, José C. Paz, Meritxell González, Marta Camps, Josep Oriola, Francisca Rivera, Manuel Palacín and Antonio Zorzano
PLoS ONE, 2 (11), 1183 (2007)
Understanding the mechanism of action of the novel SSAO substrate (C7NH10)6(V10O28).2H2O, a prodrug of peroxovanadate insulin mimetics
Yraola F, García-Vicente S, Marti L, Albericio F, Zorzano A and Royo M
Chem Biol Drug Des, 69 (6), 423-428 (2007)
Oral insulin-mimetic compounds that act independently of insulin
Garcia-Vicente S, Yraola F, Marti L, González-Muñoz E, García-Barrado MJ, Canto C, Abella A, Bour S, Artuch R, Sierra C, Brandi N, Carpene C, Moratinos J, Camps M, Palacín M, Testar X, Guma A, Albericio F, Royo M, Mian A and Zorzano A
Diabetes, 56 (2), 486 (2007)
Neuregulins increase mitochondrial oxidative capacity and insulin sensitivity in skeletal muscle cells
Canto C, Pich S, Paz JC, Sanches R, Martinez V, Orpinell M, Palacin M, Zorzano A and Guma A
Diabetes, 56 (9), 2185 (2007)
Functional and structural characterization of the first prokaryotic member of the L-amino acid transporter (LAT) family: a model for APC transporters
Reig N, del Rio C, Casagrande F, Ratera M, Gelpi JL, Torrents D, Henderson PJ, Xie H, Baldwin SA, Zorzano A, Fotiadis D and Palacin M
J Biol Chem, 282 (18), 13270 (2007)
Myotonia-related mutations in the distal C-terminus of ClC-1 and ClC-0 chloride channels affect the structure of a poly-proline helix
Macias MJ, Teijido O, Zifarelli G, Martin P, Ramirez-Espain X, Zorzano A, Palacin M, Pusch M and Estevez R
Biochem J, 403, 79-87 (2007)
Voltage-dependent anion channel (VDAC) participates in amyloid beta-induced toxicity and interacts with plasma membrane estrogen receptor alpha in septal and hippocampal neurons
Marin R, Ramirez CM, Gonzalez M, Gonzalez-Munoz E, Zorzano A, Camps M, Alonso R and Diaz M
Mol Membr Biol, 24 (2), 148-160 (2007)
Expression patterns of MLC1 protein in the central and peripheral nervous systems
Teijido O, Casaroli-Marano R, Kharkovets T, Aguado F, Zorzano A, Palacín M, Soriano E, Martínez A and Estévez R
Neurobiol Dis, 26 (3), 532-545 (2007)
Adipogenesis-related increase of semicarbazide-sensitive amine oxidase and monoamine oxidase in human adipocytes
Bour S, Daviaud D, Gres S, Lefort C, Prevot D, Zorzano A, Wabitsch M, Saulnier-Blache JS, Valet P and Carpene C
Biochimie, 89 (8), 916-925 (2007)
Role of Myotonic Dystrophy Protein Kinase (DMPK) in Glucose Homeostasis and Muscle Insulin Action
Llagostera E, Catalucci D, Marti L, Liesa M, Camps M, Ciaraldi TP, Kondo R, Reddy S, Dillmann WH, Palacin M, Zorzano A, Ruiz-Lozano P, Gomis R and Kaliman P
PLoS ONE, 2 (11), e1134 (2007)
Voltage-dependent Na(+) channel phenotype changes in myoblasts. Consequences for cardiac repair.
Martínez-Mármol R, David M, Sanches R, Roura-Ferrer M, Villalonga N, Sorianello E, Webb SM, Zorzano A, Gumà A, Valenzuela C and Felipe A
Cardiovasc Res, 76 (3), 430-441 (2007)
Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2
Soriano FX, Liesa M, Bach D, Chan DC, Palacin M and Zorzano A
Diabetes, 55 (6), 1783-1791 (2006)
Granulocyte-macrophage colony-stimulating factor increases L-arginine transport through the induction of CAT2 in bone marrow-derived macrophages
Martin L, Comalada M, Marti L, Closs EI, Macleod CL, Martin Del Rio R, Zorzano A, Modolell M, Celada A, Palacin M and Bertran J
Am J Physiol Cell Physiol, 290 (5), C1364-1372 (2006)
The genetics of heteromeric amino acid transporters
Palacin M, Nunes V, Font-Llitjos M, Jimenez-Vidal M, Fort J, Gasol E, Pineda M, Feliubadalo L, Chillaron J and Zorzano A
Physiology (Bethesda), 20, 112-124 (2005)
Identification of LAT4, a novel amino acid transporter with system L activity
Bodoy S, Martin L, Zorzano A, Palacin M, Estevez R and Bertran J
J Biol Chem, 280 (12), 12002-12011 (2005)
Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6
Bach D, Naon D, Pich S, Soriano FX, Rieusset J, Vega N, Laville M, Guillet C, Boirie Y, Wallberg- Henriksson H, Manco M, Calvani M, Castagneto M, Palacín M, Mingrone G, Zierath JR, Vidal H and Zorzano A
Diabetes, 54 (9), 2685-2693 (2005)
Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?
Mingrone G, Manco M., Calvani M, Castagneto M, Naon D and Zorzano A
Diabetologia, 48 (10), 2108-2114 (2005)
Mitofusins 1/2 and ERRalpha expression are increased in human skeletal muscle after physical exercise
Cartoni R, Leger B, Hock MB, Praz M, Crettenand A, Pich S, Ziltener JL, Luthi F, Deriaz O, Zorzano A, Gobelet C, Kralli A and Russell AP
J Physiol, 567 (Pt 1), 349-358 (2005)
The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system
Pich S, Bach D, Briones P, Liesa M, Camps M, Testar X, Palacín M and Zorzano A
Human Mol Genet, 14 (11), 1405-1415 (2005)
Identification and functional characterization of a novel low affinity aromatic-preferring amino acid transporter (arpAT) One of the few proteins silenced during primate evolution
Fernandez E, Torrents D, Zorzano A, Palacin M and Chillaron J
J Biol Chem, 280 (19), 19364-19372 (2005)
Intracellular signalling mechanisms involved in insulin action
Zorzano A
In “The Metabolic Syndrome at the beginning of the XXIst Century. A genetic and molecular approach”, 15-42 (2005)
Phenylephrine requires the TATA box to activate transcription of GLUT1 in neonatal rat cardiac myocytes
Santalucia T, Sánchez-Feutrie M, Felkin LE, Bhavsar PK, Barton PJR, Zorzano A, Yacoub MH and Brand NJ
J Mol Cell Cardiol, 38 (4), 677-684 (2005)
Mechanisms regulating GLUT4 glucose transporter expression and glucose transport in skeletal muscle
Zorzano A, Palacín M and Gumà A
Acta Physiol Scand, 183 (1), 43-58 (2005)
Myotonic dystrophy protein kinase (DMPK) phosphorylates phospholamban and regulates calcium uptake in cardiomyocyte sarcoplasmic reticulum
Kaliman P, Catalucci D, Lam JT, Kondo R, Gutierrez JC, Reddy S, Palacin M, Zorzano A, Chien KR and Ruiz-Lozano P
J Biol Chem., 280 (9), 8016-8021 (2005)
Adipocytes release a soluble form of VAP-1/SSAO by a metalloprotease-dependent process and in a regulated manner
Abella A, Garcia-Vicente S, Viguerie N, Ros-Baro A, Camps M, Palacin M, Zorzano A and Marti L
Diabetologia, 47 (3), 429-438 (2004)
Exploring the binding mode of semicarbazide-sensitive amine oxidase/VAP-1: identification of novel substrates with insulin-like activity
Marti L, Abella A, De La Cruz X, Garcia-Vicente S, Unzeta M, Carpene C, Palacin M, Testar X, Orozco M and Zorzano A
J Med Chem, 47 (20), 4865-4874 (2004)
A novel muscle DNA-binding activity in the GLUT1 promoter
Sanchez-Feutrie M, Santalucia T, Fandos C, Noe V, Vinals F, Brand NJ, Ciudad CJ, Palacin M and Zorzano A
Cell Mol Life Sci, 61 (6), 709-720 (2004)
The amino acid transporter asc-1 is not involved in cystinuria
Pineda M, Font M, Bassi MT, Manzoni M, Borsani G, Marigo V, Fernandez E, Rio RM, Purroy J, Zorzano A, Nunes V and Palacin M
Kidney Int, 66 (4), 1453-1464 (2004)
Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts
Teijido O, Martinez A, Pusch M, Zorzano A, Soriano E, Del Rio JA, Palacin M and Estevez R
Hum Mol Genet, 13 (21), 2581-2594 (2004)
Membrane topology of system xc- light subunit reveals a re-entrant loop with substrate-restricted accessibility
Gasol E, Jiménez-Vidal M, Chillarón J, Zorzano A and Palacín M
J Biol Chem, 279 (30), 31228-31236 (2004)
Alteration of amine oxidase activity in the adipose tissue of obese subjects
Visentin V, Prevot D, De Saint Front VD, Morin-Cussac N, Thalamas C, Galitzky J, Valet P, Zorzano A and Carpene C
Obes Res, 12 (3), 547-555 (2004)
Semicarbazide-sensitive amine oxidase overexpression has dual consequences: insulin mimicry and diabetes-like complications
Stolen CM, Madanat R, Marti L, Kari S, Yegutkin GG, Sariola H, Zorzano A and Jalkanen S
FASEB J, 18 (16), 702-704 (2004)
Regulation of cardiac long-chain fatty acid and glucose uptake by translocation of substrate transporters
Luiken JJ, Coort SL, Koonen DP, Van Der Horst DJ, Bonen A, Zorzano A and Glatz JF
Pflugers Arch, 448 (1), 1-15 (2004)
Thiol modification of cysteine 327 in the eighth transmembrane domain of the light subunit xCT of the heteromeric cystine/glutamate antiporter suggests close proximity to the substrate binding site/permeation pathway
Jimenez-Vidal M, Gasol E, Zorzano A, Nunes V, Palacin M and Chillaron J
J Biol Chem, 279 (12), 11214-11221 (2004)
Neuregulin signaling on glucose transport in muscle cells
Cantó C, Suárez E, Lizcano J, Griñó E, Shepherd P, Fryer L, Carling D, Bertran J, Palacin M, Zorzano A and Gumà A
J Biol Chem, 279 (13), 12260-12268 (2004)
Cystinuria-specific rBAT(R365W) mutation reveals two translocation pathways in the amino acid transporter rBAT-b0,+AT
Pineda M, Wagner CA, Broer A, Stehberger PA, Kaltenbach S, Gelpi JL, Martin Del Rio R, Zorzano A, Palacin M, Lang F and Broer S
Biochem J, 377 (Pt 3), 665-674 (2004)
Identification of a novel proliferation-dependent C-rich element that mediates inhibition of the rat GLUT1 promoter
Sánchez-Feutrie M, Viñals F, Palacín M and Zorzano A
Gene, 322, 47-55 (2003)
Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis
Feliubadalo L, Arbones ML, Manas S, Chillaron J, Visa J, Rodes M, Rousaud F, Zorzano A, Palacin M and Nunes V
Hum Mol Genet, 12 (17), 2097-2108 (2003)
Voltage-dependent K+ channel beta subunits in muscle: differential regulation during postnatal development and myogenesis
Grande M, Suarez E, Vicente R, Canto C, Coma M, Tamkun MM, Zorzano A, Guma A and Felipe A
J Cell Physiol, 195 (2), 187-193 (2003)
Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity
Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, Rabasa-Lhoret R, Wallberg-Henriksson H, Laville M, Palacín M, Vidal H, Rivera F, Brand M, Zorzano A
J Biol Chem, 278 (19), 17190-17197 (2003)
Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 activity exerts an antidiabetic action in Goto-Kakizaki rats
Abella A, Marti L, Camps M, Claret M, Fernández-Alvarez J, Gomis R, Gumà A, Viguerie N, Carpéné C, Palacín M, Testar X and Zorzano A
Diabetes, 52 (4), 1004-1013 (2003)
Intracellular signals involved in the effects of insulin-like growth factors and neuregulins on myofibre formation
Zorzano A, Kaliman P, Gumà A and Palacín M
Cell Signal, 15 (2), 141-149 (2003)
Semicarbazide-sensitive amine oxidase activity exerts insulin-like effects on glucose metabolism and insulin-signaling pathways in adipose cells
Zorzano A, Abella A, Marti L, Carpéné C, Palacín M and Testar X
Biochim Biophys Acta, 1647 (1-2), 3-9 (2003)
Differential regulation of the muscle-specific GLUT4 enhancer in regenerating and adult skeletal muscle
Moreno H, Serrano AL, Santalucia T, Guma A, Canto C, Brand NJ, Palacin M, Schiaffino S and Zorzano A
J Biol Chem, 278 (42), 40557-40564 (2003)
Basolateral LAT-2 has a major role in the transepithelial flux of L-cystine in the renal proximal tubule cell line OK
Fernandez E, Torrents D, Chillaron J, Martin Del Rio R, Zorzano A and Palacin M
J Am Soc Nephrol, 14 (4), 837-847 (2003)
