Inflammatory & Metabolic Signaling in the Pathogenesis of Atherosclerosis
Atherosclerosis is characterized by a complex interaction of vascular and immune cells, different tissues and organs, and triggered by hypercholesterolemia and other risk factors. Our research team is interested to discover and describe molecular and metabolic processes that are involved in the development of atheromatous plaques. We are studying different transcriptional regulators and their effects on atherosclerosis development and progression. These transcriptional regulators play an important role in the regulation of gene expression under physiological and pathological conditions by connecting chromatin-modifying enzymes, coregulators and transcription factors, and are involved in various processes affecting atherosclerosis development and progression. Together with our collaborators we combine different genetic, biochemical and metabolic methods in model systems and human samples to explore this fascinating biomedical topic.
Sokrates Stein – Research Group Leader, PhD
Sara Oppi – PhD Student, MSc
Stefanie Nusser-Stein – Postdoctoral fellow, PhD
Selection of previous work
LRH-1 in RCT and atherosclerosis
Liver receptor homolog 1 (LRH-1) is a nuclear receptor that is highly expressed in enterohepatic tissues and different metabolic processes, including lipid metabolism and hepatic glucose sensing (Stein & Schoonjans, Curr Opin Cell Biol 2015). During a postdoctoral stage at the laboratory of Prof. Kristina Schoonjans at the EPFL in Lausanne, we demonstrated that atherosclerosis-prone mice carrying a mutation that abolishes the SUMOylation of the nuclear receptor are significantly protected from atherosclerosis development (Stein et al., Cell Metabolism 2014). The mechanism underlying this atheroprotection involves a local increase of reverse cholesterol transport in the liver and is secondary to a compromised interaction of the non-SUMOylatable form of LRH-1 with the co-repressor PROX1 (Stein et al., Cell Metabolism 2014). This study highlights that a single posttranslational modification of a specific residue of a transcriptional regulator is sufficient to modulate the function of the protein and the corresponding cellular and metabolic processes, which consequently can affect the development of a complex chronic disease, such as atherosclerosis.
Protective roles of SIRT1 in athero-thrombosis
SIRT1 is the best characterized member of the class III (histone) deacetylases (HDAC), and its role has been implicated in various molecular and physiological processes. During my PhD graduation with Prof. Christian Matter at the University of Zurich, we showed that SIRT1 exerts atheroprotective functions in macrophages and vascular endothelial cells. Using genetic loss- and gain-of-function approaches, we demonstrated that SIRT1 reduces the expression of Lox-1 via suppression of NF-κB signaling in macrophages (Stein et al., Eur Heart J 2010). Bone-marrow transplantations demonstrated that macrophage-derived SIRT1 is sufficient to decrease atherogenesis. In two further studies, we showed that suppression of NF-κB signaling by SIRT1 in endothelial cells diminishes the expression of pro-inflammatory adhesion molecules, thereby preventing endothelial activation (Stein et al., Aging 2010) and reducing the expression of tissue factor, a key factor in the activation of the coagulation cascade during arteriothrombosis (Breitenstein et al., Cardiovasc Res 2011). Taken together, our data suggested that SIRT1 prevents atherosclerosis in early and advanced stages (Stein & Matter, Cell Cycle 2011).
Stein S, Lemos V, Xu P, Demagny H, Wang X, Ryu D, Jimenez V, Bosch F, Luscher TF, Oosterveer MH, et al. (2017). Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease. J Clin Invest 127, 583-592.
Item F, Wueest S, Lemos V, Stein S, Lucchini FC, Denzler R, Fisser MC, Challa TD, Pirinen E, Kim Y, et al. (2017). Fas cell surface death receptor controls hepatic lipid metabolism by regulating mitochondrial function. Nat Commun 8, 480.
Gariani K, Ryu D, Menzies KJ, Yi HS, Stein S, Zhang H, Perino A, Lemos V, Katsyuba E, Jha P, et al. (2017). Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease. J Hepatol 66, 132-141.
Xu P, Oosterveer MH, Stein S, Demagny H, Ryu D, Moullan N, Wang X, Can E, Zamboni N, Comment A, et al. (2016). LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer. Genes Dev 30, 1255-1260.
Stein S, and Matter CM (2016). CardioPulse - Translational research in cardiovascular disease. Eur Heart J 37, 1088-1095.
Stein S, and Schoonjans K (2015). Molecular basis for the regulation of the nuclear receptor LRH-1. Curr Opin Cell Biol 33, 26-34.
Lefevre L, Authier H, Stein S, Majorel C, Couderc B, Dardenne C, Eddine MA, Meunier E, Bernad J, Valentin A, et al. (2015). LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARgamma ligand synthesis. Nat Commun 6, 6801.
Ryu D, Jo YS, Lo Sasso G, Stein S, Zhang H, Perino A, Lee JU, Zeviani M, Romand R, Hottiger MO, et al. (2014). A SIRT7-Dependent Acetylation Switch of GABPbeta1 Controls Mitochondrial Function. Cell Metab 20, 856-869.
Stein S, Oosterveer MH, Mataki C, Xu P, Lemos V, Havinga R, Dittner C, Ryu D, Menzies KJ, Wang X, et al. (2014). SUMOylation-Dependent LRH-1/PROX1 Interaction Promotes Atherosclerosis by Decreasing Hepatic Reverse Cholesterol Transport. Cell Metab 20, 603-613.
Perino A, Pols TW, Nomura M, Stein S, Pellicciari R, and Schoonjans K (2014). TGR5 reduces macrophage migration through mTOR-induced C/EBPbeta differential translation. J Clin Invest 124, 5424-5436.
Besler C, Heinrich K, Rohrer L, Doerries C, Riwanto M, Shih DM, Chroni A, Yonekawa K, Stein S, Schaefer N, et al. (2011). Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 121, 2693-2708.
Stein S, and Matter CM (2011). Protective roles of SIRT1 in atherosclerosis. Cell Cycle 10, 640-647.
Breitenstein A, Stein S, Holy EW, Camici GG, Lohmann C, Akhmedov A, Spescha R, Elliott PJ, Westphal CH, Matter CM, et al. (2011). Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells. Cardiovasc Res 89, 464-472.
Stein S, Lohmann C, Schafer N, Hofmann J, Rohrer L, Besler C, Rothgiesser KM, Becher B, Hottiger MO, Boren J, et al. (2010a). SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis. Eur Heart J 31, 2301-2309.
Stein S, Schafer N, Breitenstein A, Besler C, Winnik S, Lohmann C, Heinrich K, Brokopp CE, Handschin C, Landmesser U, et al. (2010b). SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/- mice. Aging (Albany NY) 2, 353-360.
Kania G, Blyszczuk P, Stein S, Valaperti A, Germano D, Dirnhofer S, Hunziker L, Matter CM, and Eriksson U (2009). Heart-infiltrating prominin-1+/CD133+ progenitor cells represent the cellular source of transforming growth factor beta-mediated cardiac fibrosis in experimental autoimmune myocarditis. Circ Res 105, 462-470.