Centro Andaluz de Biología Molecular y Medicina Regenerativa

Metabolism, Immunology and Cardiovascular risk

Main Research lines:

1-Regulation of LXR activity
        a-Impact of LXRalpha phosphorylation on cardiometabolic disease development
        b-LXR-modulated metabolism in human immune cells

2. Immunity & metabolism
        a-Interferon response factor 8 (IRF8)-LXR crosstalk: impact on atherosclerosis
        b-IFN signalling & and cholesterol metabolism in human monocytes
        c-Cholesterol and sex hormone crosstalk in human immune cells 

3. Understanding cardiovascular risk and lipid metabolism in autoimmune diseases:
        a-Mechanisms underlying increased cardiovascular risk in women with SLE
        b-Identification of multi-omic signatures 

4. Women & cardiovascular disease: Identification of multi-omic signatures
Identification of subclinical and pathological phenotypic groups for better stratification of patients for future pharmacological or nutritional interventions.

Background

Cardiovascular disease (CVD) remains the leading cause of mortality for women worldwide, including Spain, where 6% more women compared to men die of this disease. Despite this, women remain understudied, underdiagnosed and undertreated and they are significantly underrepresented in cardiometabolic trials. Cardiovascular risk factors, such as lipid and lipoprotein profiles, change substantially in women during their lifetime and immune responses can also present sex differences . The main pathology underlying ischemic CVD is atherosclerosis, a process resulting from dysregulation and build-up of lipids alongside inflammation and other immune responses in the vascular wall. 

Research focus

My group aims to understand how lipid metabolism affects systemic and intracellular metabolic and immune pathways and how that affects the development and severity of metabolic, cardiovascular and immune diseases.

We use a range of cell/molecular biology, genomic, lipidomic, metabolomic and computational approaches. These allows us to elucidate molecular mechanisms underlying disease and identify molecular and metabolic signatures that will help stratify patient groups to implement a precision medicine-based approach.

The overall goals are to a) uncover novel modes of crosstalk between lipid metabolism and immunity and b) to understand the regulation of lipid metabolism at the level of gene expression, mainly mediated by the Liver X Receptor-LXR and interferon response factors (IRFs) and C) investigate the interaction between lipid metabolism and sex hormone signalling in immune cells. We aim to understand how metabolic and immune pathways impact the progression of metabolic, cardiovascular and autoimmune diseases while elucidating these pathways particularly in women, who have been traditionally underrepresented in cardiometabolic studies. 

Recent publications:

Full list : https://scholar.google.com/citations?hl=en&user=NaCOKUMAAAAJ&view_op=list_works&sortby=pubdate


Cardiovascular risk/Lipid Metabolism in Autoimmunity

Robinson GA, Pineda-Torra I, Ciurtin C, Jury EC (2022). Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies. Journal of Clinical Investigation 132 (2). doi:10.1172/JCI148552    

Ciurtin C* Robinson GA, Pineda-Torra I, Jury EC (2022). Challenges in implementing cardiovascular risk scores for assessment of young people with childhood-onset autoimmune rheumatic conditions. Frontiers in Medicine 9. doi:10.3389/fmed.2022.814905 

Ciurtin C*, Robinson GA, Pineda-Torra I, Jury EC (2022) Comorbidity in young patients with juvenile systemic lupus erythematosus: how can we improve management? Clinical Rheumatology 41 (4), 961-964. doi: 10.1007/s10067-022-06093-3

Robinson GA*, Peng J*, Pineda-Torra I*, Ciurtin C*, Jury EC* (2022). Metabolomics Defines Complex Patterns of Dyslipidaemia in Juvenile-SLE Patients Associated with Inflammation and Potential Cardiovascular Disease Risk. Metabolites, 12 (1). doi: 10.3390/metabo12010003

Robinson GA, Pineda-Torra I, Ciurtin C, Jury EC* (2021). Predicting long-term cardiometabolic risk: Do childhood metabolomic signatures hold the key? eBioMedicine, 74. doi: 10.1016/j.ebiom.2021.103702 

Robinson GA*, Waddington KE, Coelewij L, Peng J, Naja M, Wincup C, Radziszewskab A, Peckham H, Isenberga DA, Ioannou Y, Ciurtin C*, Pineda-Torra I*, Jury EC* (2021). Increased apolipoprotein-B:A1 ratio predicts cardiometabolic risk in patients with juvenile onset SLE. eBioMedicine, 65. doi:10.1016/j.ebiom.2021.103243 

Coelewij L, Waddington KE, Robinson GA, Chocano E, McDonnell T, Farinha F, Peng J, Donnes P, Smith E, Croca S, Bakshi J, Griffin M, Nicolaides A, Rahman A, Jury EC*, Pineda-Torra I* (2021). Serum Metabolomic Signatures Can Predict Subclinical Atherosclerosis in Patients with Systemic Lupus Erythematosus. Arteriosclerosis, Thrombosis, and Vascular Biology, 41 (4), 1446-1458. doi:10.1161/ATVBAHA.120.315321

Robinson GA, Peng J, Donnes P, Coelewij L, Naja M, Radziszewska A, Wincup C, Peckham H, Isenberg DA, Ioannou Y, Pineda-Torra I, Ciurtin C, Jury EC* (2020). Disease-associated and patient-specific immune cell signatures in juvenile-onset systemic lupus erythematosus: patient stratification using a machine-learning approach. The Lancet Rheumatology, 2 (8), e485-e496. doi:10.1016/s2665-9913(20)30168-5

Waddington K, Papadaki A, Coelewij L, Adriani M, Donnes P, Nytrova P, Havrdova EK, Fogdell-Hahn A, Farrell R, Donnes P, Pineda-Torra I, Jury EC* (2020). Using serum metabolomics to predict development of neutralising anti-drug antibodies in multiple sclerosis patients treated with IFN beta. Frontiers in Immunology, 25, 852-853. doi:10.3389/fimmu.2020.01527

Liver X Receptors/Nuclear Receptors

Fan R*, Pineda-Torra I, Venteclef N (2021). Editorial: Nuclear Receptors and Coregulators in Metabolism and Immunity. Frontiers in Endocrinology, 12. doi:10.3389/fendo.2021.828635

 Waddington K E, Robinson G A, Rubio-Cuesta B, Chrifi-Alaoui E, Andreone S, Poon K-S, Ivanova I, Martin-Gutierrez L, Owen DM, Jury EC*, Pineda-Torra I* (2021). LXR directly regulates glycosphingolipid synthesis and affects human CD4+ T cell function. Proceedings of the National Academy of Sciences of USA, 118 (21). doi:10.1073/pnas.2017394118 

Thibaut R, Gage MC, Pineda-Torra I, Chabrier G, Venteclef N, Alzaid F* (2022). Liver macrophages and inflammation in physiology and physiopathology of non-alcoholic fatty liver disease. The Federation of European Biochemical Societies (FEBS) Journal, 289, 3024–3057 doi:10.1111/febs.15877         

Pineda-Torra I*, Siddique S, Waddington K E, Farrell R, Jury EC* (2021). Disrupted Lipid Metabolism in Multiple Sclerosis: A Role for Liver X Receptors? Frontiers in Endocrinology, 12, 639757. doi:10.3389/fendo.2021.639757 

Voisin M, Shrestha E, Rollet C, Nikain CA, Josefs T, Mahé M, Barrett TJ, Chang HR, Ruoff R, Schneider JA, Garabedian ML, Zoumadakis C, Yun C, Badwan B, Brown EJ, Mar AC, Schneider RJ, Goldberg IJ, Pineda-Torra I, Fisher EA*, Garabedian MJ* (2021). Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice. Communications Biology, 4 (1). doi:10.1038/s42003-021-01925-5

Voisin M, Gage MC, Becares N, Shrestha E, Fisher EA, Pineda-Torra I*, Garabedian MJ* (2020). LXRα phosphorylation in cardiometabolic disease: insight from mouse models. Endocrinology, 161(7). doi:10.1210/endocr/bqaa089

Becares N, Gage MC, Voisin M, Shrestha E, Martin-Gutierrez L, Liang N, Louie R, Pourcet B, Pello OM, Luong TV, Goñi S, Pichardo-Almarza C, Røberg-Larsen H, Diaz-Zuccarini V, Steffensen KR, O’Brien A, Garabedian MJ, Rombouts K, Treuter E, Pineda-Torra I* (2019). Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease. Cell Reports, 26 (4), 984-995.e6. doi:10.1016/j.celrep.2018.12.094 

Gage MC, Bécares N, Louie R, Waddington KE, Zhang Y, Tittanegro TH, Rodríguez-Lorenzo S, Jathanna A, Pourcet B, Pello OM, De la Rosa JV, Castrillo A, Pineda-Torra I* (2018). Disrupting LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation. Proceedings of the National Academy of Sciences of the United States of America, 115 (28), E6556-E6565. doi:10.1073/pnas.1721245115

Pourcet B, Gage MC, León TE, Waddington KE, Pello OM, Steffensen KR, Castrillo A, Valledor AF, Pineda-Torra I* (2016). The nuclear receptor LXR modulates interleukin-18 levels in macrophages through multiple mechanisms. Scientific Reports, 6. doi:10.1038/srep25481

Pourcet B, Feig JE, Vengrenyuk Y, Hobbs AJ, Kepka-Lenhart D, Garabedian MJ, Morris SM Jr, Fisher EA, Pineda-Torra I* (2011). LXRα regulates macrophage arginase 1 through PU.1 and interferon regulatory factor 8. Circulation Research, 109 (5), 492-501. doi:10.1161/CIRCRESAHA.111.241810


Sex Differences

Spitschan M*, Santhi N*, Ahluwalia A, Fischer D, Hunt L, Karp NA, Lévi F, Pineda-Torra I, Vidafar P, White R (2022). Science Forum: Sex differences and sex bias in human circadian and sleep physiology research. eLife, 11. doi:10.7554/ELIFE.65419

Robinson GA*, Peng J, Peckham H, Radziszewska A, Butler G, Pineda-Torra I*, Jury EC*, Ciurtin C* (2021). Sex hormones drive changes in lipoprotein metabolism. iScience, 24 (11). doi:10.1016/j.isci.2021.103257 


Group leader:
  • Ines Pineda Torra
Technicians:
  • Yolanda Aguilera García
  • Nuria Mellado-Damas Sanz