Metabolic syndrome and vascular risk

GROUP INFORMATION

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common chronic liver disease worldwide with a diverse histopathological spectrum ranging from simple steatosis without significant inflammation to steatohepatitis (NASH) with various stages of fibrosis, and finally cirrhosis and hepatocellular carcinoma. It is well documented that NAFLD occurs more frequently in obese people and diabetics and is currently considered to be the hepatic manifestation of metabolic syndrome. Although the molecular mechanisms involved in the pathogenesis of NAFLD and its progression to NASH are not fully defined, most research indicates that insulin resistance plays an important role in the origin of NAFLD. Since NASH is becoming one of the most frequent causes of cirrhosis and liver transplantation in developed countries, it is crucial to identify populations at risk of NASH in order to prioritise diagnosis and therapeutic interventions in patients at risk of liver disease progression.

Our group will be pursuing three fundamental lines of research over the next five years.

  1. Revealing the molecular mechanisms involved in the pathogenesis of NASH by searching for potential therapeutic targets. We are exploring the role of autophagy in the development of NASH. We recently showed that autophage flow is altered in hepatocytes from NASH patients and in mouse NASH models and therefore we propose investigating in the near future whether therapies aimed at restoring autophage flow might prevent or attenuate NASH progression. We are also addressing the role of intermittent hypoxia in the pathogenesis of NAFLD by analysing the expression levels of hypoxia-1 and -2 induced factors in biopsies of NASH patients and in mouse models of NASH, as well as the impact of hypoxia on the mitochondrial function of human hepatocytes under experimental conditions of lipid overload.
  2. Identification of markers that can be used for non-invasive diagnosis of NASH. We have shown that genetic variants of SLC2A1 are associated with NAFLD and that the circulating level of soluble CD36 is an independent factor associated with advanced steatosis in NAFLD, but not in patients with chronic hepatitis C virus (HCV) infection. More recently we have published that the combination of ultrasound and the HOMA index is useful for the non-invasive diagnosis of patients with NASH. We are currently looking for multiplex-based ELISA diagnostic techniques that use proteins relevant to chronic liver disease.
  3. Impact of new direct-acting antivirals on carbohydrate and lipid metabolism in patients with chronic hepatitis C virus infection treated with these highly effective antiviral drugs: Implications for cardiovascular morbidity and mortality. It is well established that chronic HCV infection is associated with insulin resistance and type 2 diabetes mellitus, along with alterations in lipid metabolism. The discovery of new direct-acting antiviral agents represents a great advance in the treatment of HCV infection. Among them, sofosbuvir and other new antivirals combined with ribavirin have significantly improved sustained viral response in HCV infection. Very little is known, however, about the effects on metabolic profiles of carbohydrates and lipids in patients treated with these new agents, and their possible mechanisms of action. On this basis, we would like to determine the effects of sofosbuvir and other direct-acting antivirals on HCV-induced metabolic complications, such as insulin resistance, hyperglycaemia and dyslipidaemia. In addition, we will analyse the impact of sofosbuvir therapy and other related agents on metabolic disturbances induced by autophage flow deficiency in HCV infection. In summary, we believe that our lines of research could in the near future clarify key issues for NAFLD pathogenesis and therapy, as well as those of other chronic liver diseases, and for non-invasive NASH diagnosis.
Team members
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Group leader:

Carmelo García Monzón

Hospital Universitario Santa Cristina

  Other team members:

  • Raffaele Carraro Casieri. Hospital Universitario La Princesa.
  • Alfonso Jaime Casado Collado. Universidad Autónoma de Madrid.
  • Elvira del Pozo Maroto. Hospital Universitario Santa Cristina.
  • Javier Rodríguez de Cía. Hospital Universitario Santa Cristina.
  • Alicia Sáez Sáez. Hospital Universitario Santa Cristina.
  • Isabel Trijueque García. Hospital Universitario Santa Cristina.
  • Rodolfo Javier Vargas Castrillón. Hospital Universitario Santa Cristina.

González Rodríguez, Águeda. Impacto de las Proteínas Morfogenéticas Óseas en la progresión del hígado graso no alcohólico. PI16/00823. ISCIII. 2017-2019.

Non-alcoholic fatty liver (NAFL) is the main cause of chronic liver disease in the western world. Early diagnosis and treatment of hepatic steatosis is important in preventing its development into more serious states of liver disease.

This grant is funded by the 2013-2016 Spanish Science, Technology and Innovation Research Plan and the ISCIII – Subdirectorate General for Evaluation and Promotion of Research – and co-financed by the European Regional Development Fund, Operational Programme Smart Growth 2014-2020 according to Regulation (EU) no. 1303/2013.

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González Rodríguez, Águeda. Identificación de nuevos biomarcadores para el diagnóstico no invasivo de la enfermedad del hígado graso no alcohólico. Fundación Francisco Cobos. 2016-2017.

García Monzón, Carmelo. Papel de la hipoxia intermitente del síndrome de apnea-hipopnea obstructiva del sueño en la patogenia del hígado graso no alcohólico. PI13/01299. ISCIII. 2014-2016.

García Monzón, Carmelo. Identificación y evaluación de biomarcadores relacionados con la hipoxia para el diagnóstico no invasivo de la enfermedad hepática grasa no alcohólica y del daño vascular asociado. PI17/00535. ISCIII. 2018-2020.

The aim of the project is to determine the prevalence of non-alcoholic fatty liver disease and cardiovascular disease in patients with sleep apnoea-hypopnoea syndrome.

This grant is funded by the 2013-2016 Spanish Science, Technology and Innovation Research Plan and the ISCIII – Subdirectorate General for Evaluation and Promotion of Research – and co-financed by the European Regional Development Fund, Operational Programme Smart Growth 2014-2020 according to Regulation (EU) no. 1303/2013.

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Garcia-Monzon, Carmelo, Lo Iacono, Oreste, Mayoral, Rafael, Gonzalez-Rodriguez, Agueda, Miquilena-Colina, Maria E., Lozano-Rodriguez, Tamara, Garcia-Pozo, Leonor, Vargas-Castrillon, Javier, Casado, Marta, Bosca, Lisardo, Valverde, Angela M., Martin-Sanz, Paloma. Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C. J Hepatol 2011. 54: 142-152. FI: 9.264(Q1). PMID: 20888662. DOI: 10.1016/j.jhep.2010.06.021.

Eugenia Miquilena-Colina, Maria, Lima-Cabello, Elena, Sanchez-Campos, Sonia, Victoria Garcia-Mediavilla, Maria, Fernandez-Bermejo, Miguel, Lozano-Rodriguez, Tamara, Vargas-Castrillon, Javier, Buque, Xabier, Ochoa, Begona, Aspichueta, Patricia, Gonzalez-Gallego, Javier, Garcia-Monzon, Carmelo. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut 2011. 60: 1394-1402. FI: 10.111(Q1). PMID: 21270117. DOI: 10.1136/gut.2010.222844.

Vescovo T, Romagnoli A, Perdomo AB, Corazzari M, Ciccosanti F, Alonzi T, Nardacci R, Ippolito G, Tripodi M, Garcia-Monzon C, Lo Iacono O, Piacentini M, Fimia GM. Autophagy Protects Cells From HCV-Induced Defects in Lipid Metabolism. Gastroenterology 2012. 142: 644-339. FI: 12.821(Q1). PMID: 22155365. DOI: 10.1053/j.gastro.2011.11.033.

Vazquez-Chantada M, Gonzalez-Lahera A, Martinez-Arranz I, Garcia-Monzon C, Regueiro MM, Garcia-Rodriguez JL, Schlangen KA, Mendibil I, Rodriguez-Ezpeleta N, Lozano JJ, Banasik K, Justesen JM, Joergensen T, Witte DR, Lauritzen T, Hansen T, Pedersen O, Veyrie N, Clement K, Tordjman J, Tran A, Le Marchand-Brustel Y, Buque X, Aspichueta P, Echevarria-Uraga JJ, Martin-Duce A, Caballeria J, Gual P, Castro A, Mato JM, Martinez-Chantar ML, Aransay AM. Solute Carrier Family 2 Member 1 Is Involved in the Development of Nonalcoholic Fatty Liver Disease. Hepatology 2013. 57: 505-514. FI: 11.190(Q1). PMID: 22961556. DOI: 10.1002/hep.26052.

 González-Rodríguez A, Mayoral R, Agra N, Valdecantos MP, Pardo V, Miquilena-Colina ME, Vargas-Castrillón J, Lo Iacono O, Corazzari M, Fimia GM, Piacentini M, Muntané J, Boscá L, García-Monzón C, Martín-Sanz P, Valverde ÁM. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis. 2014. FI: 5.014(Q2). PMID: 24743734. DOI: 10.1038/cddis.2014.162.