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Research Groups

CELLULAR NEUROCIENCE | NEURONAL SIGNALING | CARDIOVASCULAR RESEARCH | METABOLISM | LIPID SIGNALING AND HOMEOSTASIS | ENDOCRINOLOGY | CELLULAR PHYSIOLOGY | TARGETED GENE-EXPRESSION ANALYSIS | MEMBRANE BIOLOGY | TELOMERE RESEARCH

 


LIPID SIGNALING AND HOMEOSTASIS

Group Members

Vesa Olkkonen, Ph.D., Professor, Head
Matti Jauhiainen, Ph.D., Docent, Senior scientist 
P.A. Nidhina Haridas, Ph.D.
Amita Arora, Ph.D. 
Henriikka Kentala, M.Sc. 
Hanna Ruhanen, M.Sc.
Annika Koponen, M.Sc.
Maria Ahonen, B.Sc.
Jari Metso, M.Sc., Biologist
Riikka Kosonen, M.Sc., Research assistant
Eeva Jääskeläinen, Laboratory technician


The research group investigates new regulatory mechanisms that our cells employ to maintain their lipid balance and to integrate their lipid status with other vital functions such as vesicle transport and cell signaling. The work aims at the identification and characterization of novel molecular pathways that impact the development of cardiovascular and metabolic diseases, 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 votal cellular funcitons 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 ac 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 their interaction partners in the control of cellular lipid metabolism, signaling and in the development of cardiometabolic diseases. To reach our goals we employ a spectrum of methods from biochemistry and molecular cell biology approaches to laboratory animal models.




A second major focus in the group is the control of lipoprotein metabolism, which plays a central role in the development of metabolic diseases and their cardiovascular complications. 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. The factors under study include both proteins such as Angiopoietin-like proteins 3, 4 and 8 (ANGPTL3, -4 and -8), transmembrane 6 superfamily member 2 (TM6SF2), and microRNAs. 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 respiration. 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.


Contact info

Vesa Olkkonen, Ph.D., Professor
E-mail: vesa.olkkonen@helsinki.fi
Tel: +358 2941 25705


Selected publications

Olkkonen VM, Sinisalo J, Jauhiainen M. New medications targeting triglyceride-rich lipoproteins: Can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk? Atherosclerosis. 2018; 272:27-32. 

Kentala H, Koponen A, Kivelä AM, Andrews R, Li C, Zhou Y, Olkkonen VM. Analysis of ORP2-knockout hepatocytes uncovers a novel function in actin cytoskeletal regulation. FASEB J. 2018; 32:1281-1295.

Mysore R, Ortega FJ, Latorre J, Ahonen M, Savolainen-Peltonen H, Fischer-Posovszky P, Wabitsch M, Olkkonen VM, Fernández-Real JM, Nidhina Haridas PA. MicroRNA-221-3p regulates Angiopoietin-like 8 (ANGPTL8) expression in adipocytes. J Clin Endocrinol Metab. 2017 Aug 30. doi: 10.1210/jc.2017-00453. [Epub ahead of print]

Tikka A, Metso J, Jauhiainen M. ANGPTL3 serum concentration and rare genetic variants in Finnish population. Scand J Clin Lab Invest. 2017; 77:601-609. 

Ruhanen H, Nidhina Haridas PA, Eskelinen EL, Eriksson O, Olkkonen VM, Käkelä R. Depletion of TM6SF2 disturbs membrane lipid composition and dynamics in HuH7 hepatoma cells. Biochim. Biophys. Acta. 2017; 1862:676-685.

Minicocci I, Tikka A, Poggiogalle E, Metso J, Montali A, Ceci F, Labbadia G, Fontana M, Di Costanzo A, Maranghi M, Rosano A, Ehnholm C, Donini LM, Jauhiainen M, Arca M. Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism. J Lipid Res. 2016; 57:1097-107.

Negi P, Lövgren J, Malmi P, Sirkka N, Metso J, Huovinen T, Brockmann EC, Pettersson K, Jauhiainen M, Lamminmäki U. Identification and analysis of anti-HDL scFv-antibodies obtained from phage display based synthetic antibody library. Clin Biochem. 2016; 49:472-479.

Laurila PP, Soronen J, Kooijman S, Forsström S,  Boon MR, Surakka I, Kaiharju E, Coomans CP, Van Den Berg SAA,  Autio A,  Sarin AP, Kettunen J, Tikkanen E, Manninen T, Metso J,  Silvennoinen R, Merikanto K, Perttilä J, Mäkelä A, Isomi A, Ruuth M, Tuomainen AM, Tikka A,  bin Ramadan O, Seppälä I, Lehtimäki T, Eriksson J, Havulinna A, Jula A, Karhunen PJ, Salomaa V, Perola M, Lee-Rueckert M, Ehnholm C, Van Eck M, Roivainen A, Taskinen MR, Peltonen L, Mervaala E, Jalanko A, Hohtola E, Olkkonen VM, Ripatti S, Kovanen PT, Rensen PCN, Suomalainen A, M Jauhiainen. USF1 Links Energy Expenditure with Plasma Lipid Metabolism and Cardiometabolic Health. Science Transl Med 2016; 8:323ra13.

Zhong W, Yi Q, Xu B, Li S, Wang T, Liu F, Zhu B, Hoffmann PR, Ji G, Lei P, Li G, Li J, Li J, Olkkonen VM, Yan D. ORP4L is essential for T-cell acute lymphoblastic leukemia (T-ALL) cell survival. Nat. Commun. 2016; 7:12702.

Motazacker MM, Pirhonen J, van Capelleveen JC, Weber-Boyvat M, Kuivenhoven JA, Shah S, Hovingh GK, Metso J, Li S, Ikonen E, Jauhiainen M, Dallinga-Thie GM, Olkkonen VM. A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity. Atherosclerosis. 2016; 249:140-7.

Weber-Boyvat M, Chernov KG, Aro N, Wohlfahrt G, Olkkonen VM, Jäntti J. The Sec1/Munc18 Protein Groove Plays a Conserved Role in Interaction with Sec9p/SNAP-25. Traffic. 2016; 17:131-53.

Mysore R, Zhou Y, Sädevirta S, Savolainen-Peltonen H, P.A. Haridas N, Soronen J, Leivonen M, Sarin A-P, Fischer-Posovszky P, Wabitsch M, Yki-Järvinen H, Olkkonen VM. MicroRNA-192* impairs adipocyte triglyceride storage. Biochim. Biophys. Acta. 2015; 1861:342-51.

Nidhina Haridas PA, Soronen J, Sädevirta S, Mysore R, Quagliarini F, Pasternack A, Metso J, Perttilä J, Leivonen M, Smas CM, Fischer-Posovszky P, Wabitsch M, Ehnholm C, Ritvos O, Jauhiainen M, Olkkonen VM, Yki-Järvinen H. Regulation of Angiopoietin-Like Proteins (ANGPTLs) 3 and 8 by Insulin. J Clin Endocrinol Metab. 2015; 100:E1299-307.

Weber-Boyvat M, Kentala H, Peränen J, Olkkonen VM. Ligand-dependent localization and function of ORP-VAP complexes at membrane contact sites. Cell Mol Life Sci. 2014; 72:1967-87.

Ruhanen H, Perttilä J, Hölttä-Vuori M, Zhou Y, Yki-Järvinen H, Ikonen E, Käkelä R, Olkkonen VM. PNPLA3 mediates hepatocyte triacylglycerol remodeling. J Lipid Res. 2014; 55:739-46.

Vogel A, Scheidt HA, Feller SE, Metso J, Badeau RM, Tikkanen MJ, Wähälä K, Jauhiainen M, Huster D. The orientation and dynamics of estradiol and estradiol oleate in lipid membranes and HDL disc models. Biophys J. 2014; 107:114-25.

Olkkonen, V.M. and Li, S. Oxysterol-binding proteins: Sterol and phosphoinositide sensors coordinating transport, signaling and metabolism. Prog. Lipid Res. 2013; 52:529-38.

Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Öörni K, Metso J, Minicocci I, Ciociola E, Ceci F, Montali A, Arca M, Ehnholm C, Jauhiainen M. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1706-13.

Nissilä E, Ohsaki Y, Weber-Boyvat M, Perttilä J, Ikonen E, Olkkonen VM. ORP10, a cholesterol binding protein associated with microtubules, regulates apolipoprotein B-100 secretion. Biochim Biophys Acta. 2012; 1821:1472-84.

Biedzka-Sarek M, Metso J, Kateifides A, Meri T, Jokiranta TS, Muszyński A, Radziejewska-Lebrecht J, Zannis V, Skurnik M, Jauhiainen M. Apolipoprotein A-I exerts bactericidal activity against Yersinia enterocolitica serotype O:3. J Biol Chem. 2011; 286:38211-9.

Robciuc MR, Naukkarinen J, Ortega-Alonso A, Tyynismaa H, Raivio T, Rissanen A, Kaprio J, Ehnholm C, Jauhiainen M, Pietiläinen KH. Serum angiopoietin-like 4 protein levels and expression in adipose tissue are inversely correlated with obesity in monozygotic twins. J Lipid Res. 2011; 52:1575-82.

Yetukuri L, Söderlund S, Koivuniemi A, Seppänen-Laakso T, Niemelä PS, Hyvönen M, Taskinen MR, Vattulainen I, Jauhiainen M, Oresic M. Composition and lipid spatial distribution of HDL particles in subjects with low and high HDL-cholesterol. J Lipid Res. 2010; 51:2341-51.

Perttilä J, Merikanto K, Naukkarinen J, Surakka I, Martin NW, Tanhuanpää K, Grimard V, Taskinen MR, Thiele C, Salomaa V, Jula A, Perola M, Virtanen I, Peltonen L, Olkkonen VM. OSBPL10, a novel candidate gene for high triglyceride trait in dyslipidemic Finnish subjects, regulates cellular lipid metabolism. J Mol Med (Berl). 2009 Aug;87(8):825-35.

Hynynen R, Suchanek M, Spandl J, Bäck N, Thiele C, Olkkonen VM. OSBP-related protein 2 is a sterol receptor on lipid droplets that regulates the metabolism of neutral lipids. J Lipid Res. 2009 Jul;50(7):1305-15.

Lehto M, Mäyränpää MI, Pellinen T, Ihalmo P, Lehtonen S, Kovanen PT, Groop PH, Ivaska J, Olkkonen VM. The R-Ras interaction partner ORP3 regulates cell adhesion. J Cell Sci. 2008; 121:695-705.

Yan D, Mäyränpää MI, Wong J, Perttilä J, Lehto M, Jauhiainen M, Kovanen PT, Ehnholm C, Brown AJ, Olkkonen VM . OSBP-related protein 8 (ORP8) suppresses ABCA1 expression and cholesterol efflux from macrophages. J Biol Chem. 2008; 283:332-40.

Johansson M, Rocha N, Zwart W, Jordens I, Janssen L, Kuijl C, Olkkonen VM, Neefjes J. Activation of endosomal dynein motors by stepwise assembly of Rab7-RILP-p150Glued, ORP1L, and the receptor betalll spectrin. J Cell Biol. 2007; 176:459-71.

Yan D, Lehto M, Rasilainen L, Metso J, Ehnholm C, Ylä-Herttuala S, Jauhiainen M, Olkkonen VM. Oxysterol binding protein induces upregulation of SREBP-1c and enhances hepatic lipogenesis. Arterioscler Thromb Vasc Biol. 2007; 27:1108-14.

Suchanek M, Hynynen R, Wohlfahrt G, Lehto M, Johansson M, Saarinen H, Radzikowska A, Thiele C, Olkkonen VM. The mammalian oxysterol-binding protein-related proteins (ORPs) bind 25-hydroxycholesterol in an evolutionarily conserved pocket. Biochem J. 2007; 405:473-80.

Vikstedt R, Metso J, Hakala J, Olkkonen VM, Ehnholm C, Jauhiainen M. Cholesterol efflux from macrophage foam cells is enhanced by active phospholipid transfer protein through generation of two types of acceptor particles. Biochemistry. 2007; 46:11979-86.

Van Eck M, Ye D, Hildebrand RB, Kar Kruijt J, de Haan W, Hoekstra M, Rensen PC, Ehnholm C, Jauhiainen M, Van Berkel TJ. Important role for bone marrow-derived cholesteryl ester transfer protein in lipoprotein cholesterol redistribution and atherosclerotic lesion development in LDL receptor knockout mice. Circ Res. 2007; 100:678-85.

Yan D, Jauhiainen M, Hildebrand RB, Willems van Dijk K, Van Berkel TJ, Ehnholm C, Van Eck M, Olkkonen VM. Expression of human OSBP-related protein 1L in macrophages enhances atherosclerotic lesion development in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2007; 27:1618-24.

Lehto M, Laitinen S, Chinetti G, Johansson M, Ehnholm C, Staels B, Ikonen E, Olkkonen VM. The OSBP-related protein family in humans. J Lipid Res. 2001; 42:1203-13.


 

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