LIPID SIGNALING AND HOMEOSTASIS
Vesa Olkkonen, Ph.D., Professor, Head
Kid Törnquist, Ph.D., Professor
Matti Jauhiainen, Ph.D., Docent, Adjunct professor
P.A. Nidhina Haridas, Ph.D.
Muhammad Yasir Asghar, Ph.D.
Amita Arora, Ph.D.
Annika Koponen, M.Sc.
Taru Lassila, M.Sc.
Maria Ahonen, M.Sc.
Meghana Nagaraj, M.Sc.
Juuso Taskinen, B.Engin., M.Sc.
Riikka Kosonen, M.Sc., Research assistant
The research group investigates new regulatory mechanisms that our cells employ to maintain their lipid balance and how the transport and metabolism of lipid species modify cellular functions dysregulated in common disease. The work aims at the identification and characterization of novel molecular pathways that impact the development of cardiovascular and metabolic diseases as well as cancers, the long-term aim being to find new approaches for the prevention and treatment of these diseases.
A major project of the group deals with the mechanisms that the cell uses to sense its lipid status and to relay this information to regulate (i) the inter-organelle transport of lipids, (ii) signaling events that control vital cellular functions such as energy metabolism, motility and proliferation. An emerging key concept we are highly interested in are membrane contact sites (MCSs), zones of close apposition between organelle limiting membranes. Such contacts are found between virtually every organelle type, the most prominent ones being those between the endoplasmic reticulum (ER) and mitochondria, Golgi apparatus, endosomes, the plasma membrane or lipid droplets. The MCSs act as high-specificity and capacity platforms for the inter-organelle transport of lipids or calcium ions and signaling events. We identified in 2001 a family of 12 human genes that encode oxysterol-binding protein homologues, ORPs (also known as OSBPL proteins), cytoplasmic lipid binding/transfer proteins liganded by cholesterol, oxysterols, and/or glycerophospholipids. Several of these proteins are known to execute their functions at distinct MCSs. Our work focuses on the elucidation of the function of these proteins and other MCS components in the control of cellular lipid metabolism, signaling and in the development of cardiometabolic diseases, the main cell type studied in this project being endothelial cells. Another key target of study is the dysfunction of white adipocytes in metabolic disease. Here we focus on molecular factors, both proteins and microRNAs the dysregulation of which is envisioned to contribute to obesity, adipose tissue insulin resistance and the precipitation of metabolic disease. To reach our goals we employ a spectrum of methods from biochemistry and molecular cell biology to laboratory animal models and multi-omics approaches.
A second major focus in the group is the control of lipoprotein metabolism, which plays a central role in the development of cardiometabolic diseases. We concentrate on functional analysis of factors that regulate or mediate the production of triglyceride (TG)-rich lipoproteins by the liver, the distribution of TG fatty acids among different tissues, hepatic fat accumulation, and adipose tissue factors that regulate the lipid storage and metabolism in adipocytes as well as the communication between fat tissue and the liver. In addition, we study atherosclerotic lesions and how blood-derived monocytes differentiate into phenotypically distinct macrophage subpopulations, and further into cholesterol-filled foam cells under a complex milieu of cytokines. Moreover, our work involves the putative use of antibodies against high-density lipoproteins (HDL) as cardiovascular biomarkers and the function of HDL as modulators of muscle cell especially how HDL subpopulations regulate mitochondrial function. Factors are studied both on protein and mRNA expression levels. Detailed understanding of the function of such factors adds insight into the mechanisms of metabolic regulation and provides tools for the development of new therapeutic approaches.
The group is also interested in investigating the importance of calcium and lipid signaling in mainly human tumor-derived thyroid cancer cells. Of special interest has been the importance of stromal interacting molecule 1 (STIM1) and Orai1, two important proteins regulating intracellular calcium storage and signaling, and the TRPC1 cation channels. All these proteins regulating calcium entry into the cells are major regulators of e.g. cancer cell migration, invasion, and proliferation. Furthermore, the effect of the interactions between calcium signaling and the sphingomyelin metabolite sphingosine 1-phosphate (S1P) on the regulation of thyroid cancer cell migration and invasion, and signaling pathways coupled to these events, are of interest.
Vesa Olkkonen, Ph.D., Professor
Kid Törnquist, Ph.D., Professor
Ahonen M, Asghar MA, Parviainen S, Liebisch G, Höring M, Leidenius M, Fischer-Posovszky P, Wabitsch M, Mikkola TS, Törnquist K, Savolainen-Peltonen H, Haridas PAN, Olkkonen VM. 2020. Human adipocyte differentiation and composition of disease-relevant lipids are regulated by miR-221-3p. Biochim Biophys Acta Mol Cell Biol Lipids, Oct 16:158841.
Koponen A, Pan G, Kivelä AM, Ralko A, Taskinen J, Arora A, Kosonen R, Kari OK, Ndika J, Ikonen E, Cho W, Yan D, Olkkonen VM. 2020. ORP2, a cholesterol transporter, regulates angiogenic signaling in endothelial cells. FASEB J 34:14671-94.
Ruhanen H, Haridas PAN, Minicocci I, Taskinen JH, Palmas F, di Costanzo A, D’Erasmo L, Metso J, Partanen J, Dalli J, Zhou Y, Arca M, Jauhiainen M, Käkelä R, Olkkonen VM. 2020. ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins. Biochim Biophys Acta Mol Cell Biol Lipids 1865:158679.
Kentala H, Koponen A, Vihinen H, Pirhonen J, Liebisch G, Pataj Z, Kivelä A, Li S, Karhinen L, Jääskeläinen E, Andrews R, Meriläinen L, Matysik S, Ikonen E, Zhou Y, Jokitalo E, Olkkonen VM. 2018. OSBP-related protein-2 (ORP2): A novel Akt effector that controls cellular energy metabolism. Cell Mol Life Sci 75:4041-4057.
Kentala H, Koponen A, Kivelä A, Andrews R, Li C, You Z, Olkkonen VM.2018. Analysis of ORP2 knock-out hepatocytes uncovers a novel function in actin cytoskeletal regulation. FASEB J 32:1281-1295.
Cedó L, Metso J, Santos D, García-León A, Plana N, Sabate-Soler S, Rotllan N, Rivas-Urbina A, Méndez-Lara KA, Tondo M, Girona J, Julve J, Pallarès V, Benitez-Amaro A, Llorente-Cortes V, Pérez A, Gómez-Coronado D, Ruotsalainen AK, Levonen AL, Sanchez-Quesada JL, Masana L, Kovanen PT, Jauhiainen M, Lee-Rueckert M, Blanco-Vaca F, Escolà-Gil JC. 2020. LDL receptor regulates the reverse transport of macrophage-derived unesterified cholesterol via concerted action of the HDL-LDL axis: Insight from mouse models. Circ Res 127:778-792.
Hoekstra M, van der Sluis RJ, Hildebrand RB, Lammers B, Zhao Y, Praticò D, van Berkel TJC, Rensen PCN, Kooijman S, Jauhiainen M, van Eck M. 2020. Disruption of Phospholipid Transfer Protein-Mediated High-Density Lipoprotein Maturation Reduces Scavenger Receptor BI Deficiency-Driven Atherosclerosis Susceptibility Despite Unexpected Metabolic Complications. Arterioscler Thromb Vasc Biol. 40:611-623.
Ruhanen H, Haridas PAN, Jauhiainen M, Olkkonen VM. 2020. Angiopoietin-like protein 3, an emerging cardiometabolic therapy target with systemic and cell-autonomous functions. Biochim Biophys Acta Mol Cell Biol Lipids 1865:158791
Negi P, Heikkilä T, Tallgren T, Malmi P, Lund J, Sinisalo J, Metso J, Jauhiainen M, Pettersson K, Lamminmäki U, Lövgren J. 2021. Three two-site apoA-I immunoassays using phage expressed detector antibodies – Preliminary clinical evaluation with cardiac patients. J Pharm Biomed Anal 194:113772
Cedó L, Plana N, Metso J, Lee-Rueckert M, Sanchez-Quesada JL, Kovanen PT, Jauhiainen M, Masana L, Escolà-Gil JC, Blanco-Vaca F. 2018. Altered HDL Remodeling and Functionality in Familial Hypercholesterolemia. J Am Coll Cardiol 71:466-468.
Niemelä E*, Desai D*, Niemi R, Özliseli E, Doroszka M, Kemppainen K, Sahlgren C, Törnquist K, Eriksson JE, Rosenholm J. 2020. Fingolimod (FTY720) and methotrexate (MTX) multidrug carrying nanoparticles enables targeted induction of cell death and immobilization of invasive thyroid cancer cells. (*equal contribution). Eur J Pharm Biopharm 148: 1-9.
Asghar MY, Törnquist K. 2020. TRPC channels as modulators of migration and invasion. Int J Mol Sci 21, 1739; doi:10.3390/ijms21051739.
Pada AK, Desai D, Sun K, Govardhanam NP, TörnquistK, Zhang J, Rosenholm JM. 2019. Comparison of polydopamine-coated mesoporous silica nanorods and spheres for the delivery of hydrophilic and hydrophobic anticancer drugs. Int J Mol Sci, 20, 3408; doi:10.3390/ijms20143408.
Pulli I, Löf C, Blom T, Ashgar MY, Lassila T, Nyström JH, Toivola DM, Kemppainen K, Bäck N, Dufour E, Cooper HM, Sanz A, Parys J, Törnquist K. 2019. Sphingosine kinase overexpression induces mitofusin-2 fragmentation and alters mitochondrial matrix Ca2+ handling in HeLa cells. Biochem Biophys Acta Mol Cell Res 1866:1475-1486.