LABORATORY OF PHARMACOLOGY

Nuclear Receptors controlling Energy Metabolism as Targets of Drug Action

From initially studying the molecular mechanism of action of hypolipidemic drugs, our interest has expanded to the study of RXR heterodimeric (PPAR, FXR, LXR, etc.) receptors and other nuclear receptors participating in the control of energy metabolism, mainly in hepatic, adipose, skeletal muscle and heart tissues, and macrophages. We focus on atherosclerosis-related pathologies (Metabolic Syndrome, Diabetes, Dyslipidemia, etc) and their control by drugs acting, directly or indirectly, on nuclear receptors (fibrates, statins, thiazolidinediones, etc.).

• . Experimental models of Metabolic Syndrome: the fructose-fed rat and senescence-related models in rodents. Molecular basis and drug activity.
• Molecular basis of insulin resistance in skeletal muscle and modulation by drugs.
• Molecular basis of cardiac hypertrophy: Role of PPARs and inflammation-related Transcription Factors.
• Macrophage Pharmacogenomics in Humans: Gene expression changes induced by disease (Familial Combined Hyperlipemia) and drug-therapy (statins, fibrates).

• Experimental models of dyslipemia, diabetes, etc.
• Experimental Pharmacology on Nuclear Receptors
• Mammalian cell culture
• Experimental Pharmacology on Hypolipidemic drugs and drugs acting on Nuclear Receptors

• Age as a resistance factor to the hypolipidemic effect of fibrates and statins (MEC SAF2004-03045) (Dr. JC Laguna)
• Study of the association atorvastatin-amlodipin in the prevention of cardiac hypertrophy in an animal model of aortic abdominal constriction (Pfizer Laboratories Spain, Estudio Dual-IIG-11) (Drs. JC Laguna and M Vázquez-Carrera)
• Inflammation, obesity and type 2 diabetes mellitus. Study of the effects of lipid mediators to NF-kB activity. Fundación Ramón Areces. 2004. (Dr. M. Vázquez-Carrera).
• HIV infection and atherosclerosis. Influence of atorvastatin treatment. Spanish Arteriosclerosis Society. 2005 (Dr. M. Alegret).
• Development of animal models for inflammatory/autoimmune diseases and search for biomarkers. CENIT Project (PalauFarma and Drs. JC Laguna and M Vázquez)
• Inflammation, diabetes and cardiac hypertrophy. An study of the effects of drugs inhibiting NFkB in cellular and animal models of insulin resistance and cardiac hypertrophy (SAF2006-01475) (Dr. M. Vázquez).
• Molecular bases for fructose-induced changes in metabolism and its reversion by statins. (FIS PI060247) (Dr. M. Alegret)

• 1: Coll T, Jove M, Rodriguez-Calvo R, Eyre E, Palomer X, Sanchez RM, Merlos M, Laguna JC, Vazquez-Carrera M. Palmitate-mediated downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1alpha in skeletal muscle cells involves MEK1/2 and nuclear factor-kappaB activation. Diabetes. 2006 Oct;55(10):2779-87.
• 2: Rodriguez-Calvo R, Jove M, Coll T, Camins A, Sanchez RM, Alegret M, Merlos M, Pallas M, Laguna JC, Vazquez-Carrera M. PGC-1beta down-regulation is associated with reduced ERRalpha activity and MCAD expression in skeletal muscle of senescence-accelerated mice. J Gerontol A Biol Sci Med Sci. 2006 Aug;61(8):773-80.
• 3: Sanguino E, Roglans N, Rodriguez-Calvo R, Alegret M, Sanchez RM, Vazquez-Carrera M, Laguna JC. Ageing introduces a complex pattern of changes in several rat brain transcription factors depending on gender and anatomical localization. Exp Gerontol. 2006 Apr;41(4):372-9
• 4: Planavila A, Rodriguez-Calvo R, de Arriba AF, Sanchez RM, Laguna JC, Merlos M, Vazquez-Carrera M. Inhibition of cardiac hypertrophy by triflusal (4-trifluoromethyl derivative of salicylate) and its active metabolite. Mol Pharmacol. 2006 Apr;69(4):1174-81.
• 5: Llaverias G, Rebollo A, Pou J, Vazquez-Carrera M, Sanchez RM, Laguna JC, Alegret M. Effects of rosiglitazone and atorvastatin on the expression of genes that control cholesterol homeostasis in differentiating monocytes. Biochem Pharmacol. 2006 Feb 28;71(5):605-14.
• 6: Cabrero A, Cubero M, Llaverias G, Alegret M, Sanchez R, Laguna JC, Vazquez-Carrera M. Leptin down-regulates peroxisome proliferator-activated receptor gamma (PPAR-gamma) mRNA levels in primary human monocyte-derived macrophages. Mol Cell Biochem. 2005 Jul;275(1-2):173-9.
• 7: Ribas V, Palomer X, Roglans N, Rotllan N, Fievet C, Tailleux A, Julve J, Laguna JC, Blanco-Vaca F, Escola-Gil JC. Paradoxical exacerbation of combined hyperlipidemia in human apolipoprotein A-II transgenic mice treated with fenofibrate. Biochim Biophys Acta. 2005 Dec 15;1737(2-3):130-7.
• 8: Jove M, Planavila A, Sanchez RM, Merlos M, Laguna JC, Vazquez-Carrera M. Palmitate induces tumor necrosis factor-alpha expression in C2C12 skeletal muscle cells by a mechanism involving protein kinase C and nuclear factor-kappaB activation. Endocrinology. 2006 Jan;147(1):552-61.
• 9: Planavila A, Sanchez RM, Merlos M, Laguna JC, Vazquez-Carrera M. Atorvastatin prevents peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) downregulation in lipopolysaccharide-stimulated H9c2 cells. Biochim Biophys Acta. 2005 Sep 15;1736(2):120-7.
• 10: Llaverias G, Lacasa D, Vazquez-Carrera M, Sanchez RM, Laguna JC, Alegret M. Cholesterol regulation of genes involved in sterol trafficking in human THP-1 macrophages. Mol Cell Biochem. 2005 May;273(1-2):185-91.
• 11: Sanguino E, Roglans N, Alegret M, Sanchez RM, Vazquez-Carrera M, Laguna JC. Different response of senescent female Sprague-Dawley rats to gemfibrozil and rosiglitazone administration. Exp Gerontol. 2005 Jul;40(7):588-98.
• 12: Sanguino E, Roglans N, Alegret M, Sanchez RM, Vazquez-Carrera M, Laguna JC. Atorvastatin reverses age-related reduction in rat hepatic PPARalpha and HNF-4. Br J Pharmacol. 2005 Aug;145(7):853-61.
• 13: Jove M, Laguna JC, Vazquez-Carrera M. Agonist-induced activation releases peroxisome proliferator-activated receptor beta/delta from its inhibition by palmitate-induced nuclear factor-kappaB in skeletal muscle cells. Biochim Biophys Acta. 2005 May 1;1734(1):52-61.
• 14: Jove M, Planavila A, Laguna JC, Vazquez-Carrera M. Palmitate-induced interleukin 6 production is mediated by protein kinase C and nuclear-factor kappaB activation and leads to glucose transporter 4 down-regulation in skeletal muscle cells. Endocrinology. 2005 Jul;146(7):3087-95.
• 15: Planavila A, Alegret M, Sanchez RM, Rodriguez-Calvo R, Laguna JC, Vazquez-Carrera M. Increased Akt protein expression is associated with decreased ceramide content in skeletal muscle of troglitazone-treated mice. Biochem Pharmacol. 2005 Apr 15;69(8):1195-204.
• 16: Vinals M, Bermudez I, Llaverias G, Alegret M, Sanchez RM, Vazquez-Carrera M, Laguna JC. Aspirin increases CD36, SR-BI, and ABCA1 expression in human THP-1 macrophages. Cardiovasc Res. 2005 Apr 1;66(1):141-9.
• 17: Planavila A, Laguna JC, Vazquez-Carrera M. Nuclear factor-kappaB activation leads to down-regulation of fatty acid oxidation during cardiac hypertrophy. J Biol Chem. 2005 Apr 29;280(17):17464-71.
• 18: Planavila A, Rodriguez-Calvo R, Jove M, Michalik L, Wahli W, Laguna JC, Vazquez-Carrera M. Peroxisome proliferator-activated receptor beta/delta activation inhibits hypertrophy in neonatal rat cardiomyocytes. Cardiovasc Res. 2005 Mar 1;65(4):832-41.
• 19: Planavila A, Laguna JC, Vazquez-Carrera M. Atorvastatin improves peroxisome proliferator-activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-kappa B activation. Biochim Biophys Acta. 2005 Feb 21;1687(1-3):76-83.
• 20: Sanguino E, Bejarano R, Alegret M, Sanchez RM, Vazquez-Carrera M, Laguna JC. Sexual dimorphism in lipid metabolic phenotype associated with old age in Sprague-Dawley rats. Exp Gerontol. 2004 Sep;39(9):1295-306.
• 21: Sanguino E, Roglans N, Alegret M, Sanchez RM, Vazquez-Carrera M, Laguna JC. Prevention of age-related changes in rat cortex transcription factor activator protein-1 by hypolipidemic drugs. Biochem Pharmacol. 2004 Oct 1;68(7):1411-21.
• 22: Llaverias G, Vazquez-Carrera M, Sanchez RM, Noe V, Ciudad CJ, Laguna JC, Alegret M. Rosiglitazone upregulates caveolin-1 expression in THP-1 cells through a PPAR-dependent mechanism. J Lipid Res. 2004 Nov;45(11):2015-24.
• 23: Llaverias G, Lacasa D, Vinals M, Vazquez-Carrera M, Sanchez RM, Laguna JC, Alegret M. Reduction of intracellular cholesterol accumulation in THP-1 macrophages by a combination of rosiglitazone and atorvastatin. Biochem Pharmacol. 2004 Jul 1;68(1):155-63.
• 24: Llaverias G, Noe V, Penuelas S, Vazquez-Carrera M, Sanchez RM, Laguna JC, Ciudad CJ, Alegret M. Atorvastatin reduces CD68, FABP4, and HBP expression in oxLDL-treated human macrophages. Biochem Biophys Res Commun. 2004 May 21;318(1):265-74.
• 25: Roglans N, Vazquez-Carrera M, Alegret M, Novell F, Zambon D, Ros E, Laguna JC, Sanchez RM. Fibrates modify the expression of key factors involved in bile-acid synthesis and biliary-lipid secretion in gallstone patients. Eur J Clin Pharmacol. 2004 Feb;59(12):855-61.
• 26: Sanguino E, Ramon M, Michalik L, Wahli W, Alegret M, Sanchez RM, Vazquez-Carrera M, Laguna JC. Lack of hypotriglyceridemic effect of gemfibrozil as a consequence of age-related changes in rat liver PPARalpha. Biochem Pharmacol. 2004 Jan 1;67(1):157-66.
• 27: Jove M, Salla J, Planavila A, Cabrero A, Michalik L, Wahli W, Laguna JC, Vazquez-Carrera M. Impaired expression of NADH dehydrogenase subunit 1 and PPARgamma coactivator-1in skeletal muscle of ZDF rats: restoration by troglitazone. J Lipid Res. 2004 Jan;45(1):113-23.

5. Defended Doctoral Projects (last three years)

• 1. Identification of new factors related to the development of insulin resistance, by Dr. Mireia Jové Godino (2005). Project Director: Dr. M Vázquez-Carrera
• 2. Possible pharmacological targets for the treatment of insulin resistance and cardiac hypertrophy, by Dr. Anna Planavila Porta (2005). Project Director: Dr. M Vázquez-Carrera
• 3. Pharmacological modulation of cholesterol content and cholesterol transport-related genes in macrophages, by Dr. Gemma Llaverias Pijoan (2004). Project Director: Dr. Marta Alegret/Carles Ciudad
• 4. Metabolic changes induced by age: Modification in the expression of PPAR? and pharmacological responses, by Dr. Elena Sanguino López (2004). Project Director: Dr. Joan Carles Laguna

6. Current collaborations 

• Dr. Emili Ros, Lipid Clinics, Hospital Clínico, Barcelona, Spain
• Dr. Carles Ciudad, Biochemistry Laboratory, School of Pharmacy, University of Barcelona, Spain
• Dr. Walter Whali, Center for Integrative Genomics, University of Lausanne, Switzerland
• Dr. Francesc Blanco-Vaca, Lipid Clínics, Hospital de Sant Pau, Barcelona, Spain

8. Group members

Dr. Joan Carles Laguna (Professor), jclagunae@ub.edu . Dr. Marta Alegret (Assistant Professor), alegret@ub.edu . Dr. Rosa María Sánchez (Assistant Professor), rmsanchez@ub.edu . Dr. Manuel Vázquez-Carrera (Assistant Professor), mvazquezcarrera@ub.edu . Dr. Manuel Merlos (Associate Professor), pharm-merlos@uriach.com . Dr. Núria Roglans (Associate Professor), roglans@ub.edu . Dr. Xavier Palomar (Postdoctoral fellow) XPalomer@santpau.es . Teresa Coll (Predoctoral fellow) . Elena Eyre (Predoctoral fellow) . María Victoria Peña (Predoctoral fellow) . Jordi Pou (Predoctoral fellow) . Alba Rebollo (Predoctoral fellow) . Ricardo Rodríguez (Predoctoral fellow) . Lucía Serrano (Predoctoral fellow) . Laia Vilà (Predoctoral fellow)