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.
Zydrune Polianskyte-Prause, Ph.D.
Maria Ahonen Mehmeti, M.Sc.
Vaishali Chaurasiya, M.Sc.
Taru Knuutila, M.Sc.
Meghana Nagaraj, M.Sc.
Juuso Taskinen, B.Engin., M.Sc.
Elizaveta Boiko, M.Sc. student (shared student with Cellular Neuroscience group)
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 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 and hepatocytes 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. A new key topic of study are defects in the communication of white adipocytes with endothelial cells in obese adipose tissue, and the role of these defects in the metabolic comorbidities of obesity. To reach our goals we employ a spectrum of methods from biochemistry and molecular cell biology to laboratory animal models and multi-omics approaches.
Another study area 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-derived 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 and functionally distinct macrophage subpopulations, and further into cholesterol-filled foam cells under a complex milieu of cytokines. Moreover, our work involves the putative, diagnostic use of antibodies against high-density lipoproteins (HDL) as cardiovascular biomarkers and the function of HDL as modulators of muscle cell function especially how HDL subpopulations regulate mitochondrial function. These 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, calcium signaling regulates the transcription factors TRβ1 and Runx2 in thyroid cancer cells. 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
Takahashi K, Kanerva K, Vanharanta L, Almeida-Souza L, Lietha D, Olkkonen VM, Ikonen E. ORP2 couples LDL-cholesterol transport to FAK activation by endosomal cholesterol/PI(4,5)P2 exchange. EMBO J. 2021; 40:e106871.
Stromal interaction molecule 1 (STIM1) knock down attenuates invasion and proliferation and enhances the expression of thyroid-specific proteins in human follicular thyroid cancer cells. Asghar MY, Lassila T, Paatero I, Nguyen VD, Kronqvist P, Zhang J, Slita A, Löf C, Zhou Y, Rosenholm J, Törnquist K. Cell Mol Life Sci. 2021; 78:5827-5846.
Arora A, Kivelä AM, Wang L, Minkeviciene R, Taskinen JH, Zhang B, Koponen A, Sun J, Shirane M, Zhou Y, Hotulainen P, Raiborg C, Olkkonen VM. Protrudin regulates FAK activation, endothelial cell migration and angiogenesis. Cell Mol Life Sci. 2022; 79:220.
Taskinen JH, Ruhanen H, Matysik S, Käkelä R, Olkkonen VM. Global effects of pharmacologic inhibition of OSBP in human umbilical vein endothelial cells. Steroids. 2022; 185:109053.
Suppression of calcium entry modulates the expression of TRβ1 and Runx2 in thyroid cancer cells, two transcription factors that regulate invasion, proliferation and thyroid-specific protein levels. Asghar MY, Knuutinen T, Holm E, Nordström T, Nguyen VD, Zhou Y, and Törnquist K. Cancers. 2022; 14:5838.
Ahonen MA, Höring M, Nguyen VD, Qadri S, Taskinen JH, Nagaraj M, Wabitsch M, Fischer-Posovszky P, Zhou Y, Liebisch G, Haridas PAN, Yki-Järvinen H, Olkkonen VM. Insulin-inducible THRSP maintains mitochondrial function and regulates sphingolipid metabolism in human adipocytes. Mol Med. 2022; 28:68.
Nagaraj M, Höring M, Ahonen MA, Nguyen VD, Zhou Y, Vihinen H, Jokitalo E, Liebisch G, Nidhina Haridas PA, Olkkonen VM. GOLM1 depletion modifies cellular sphingolipid metabolism and adversely affects cell growth. J Lipid Res. 2022; 63:100259.
Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes. Combot Y, Salo VT, Chadeuf G, Hölttä M, Ven K, Pulli I, Duchex S, Pecquer C, Renoult O, Lak B, Li S, Karhinen L, Belevich I, Le May C, Rieusset J, Le Lay S, Croyal M, Tayeb KS, Vihinen H, Jikitalo E, Törnquist K, Vigouroux C, Cariou B, Magre J, Lrhlimi A, Ionen E, Prieur X. Cell Rep. 2022; 38:110213.
Zhong W, Lin W, Yang Y, Chen D, Cao X, Xu M, Pan G, Chen H, Zheng J, Feng X, Yang LH, Lai C, Olkkonen VM, Xu J, Cui S, Yan D. An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis. Nat Commun. 2022; 13:4390.
Monteiro-Cardoso VF, Rochin L, Arora A, Houcine A, Jääskeläinen E, Kivelä AM, Sauvanet C, Le Bars R, Marien E, Dehairs J, Neveu J, El Khallouki N, Santonico E, Swinnen JV, Tareste D, Olkkonen VM, Giordano F. ORP5/8 and MIB/MICOS link ER-mitochondria and intra-mitochondrial contacts for non-vesicular transport of phosphatidylserine. Cell Rep. 2022; 40:111364.
Radulovic M, Wenzel EM, Gilani S, Holland LK, Lystad AH, Phuyal S, Olkkonen VM, Brech A, Jäättelä M, Maeda K, Raiborg C, Stenmark H. Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair. EMBO J. 2022; 41:e112677.
Weber-Boyvat M, Kroll J, Trimbuch T, Olkkonen VM, Rosenmund C. The lipid transporter ORP2 regulates synaptic neurotransmitter release via two distinct mechanisms. Cell Rep. 2022; 41:111882.