Membrane Biology
We aim to learn how major membrane and storage lipids, such as cholesterol and triacylglycerols, move in the intracellular milieu and how their compartmentalization in cells is controlled. We also want understand how changes in this balance lead to human diseases, and what can be done to improve the detection and treatment of such diseases.
Cholesterol is an essential constituent of mammalian cell membranes, where it dictates important biophysical properties of the bilayer and participates in lipid-protein interactions. Our group aims to understand how cholesterol is distributed and transported between subcellular organelles in human cells and how other lipids and lipid-interacting proteins influence this process. We are also interested in understanding how cholesterol is dynamically stored and released from major cellular storage sites, lipid droplets, to buffer membrane cholesterol content and control membrane dependent functions. Importantly, lipid droplets typically store both cholesteryl esters (CEs) and triacylglycerols (TAGs) as major neutral lipids. How these storage lipids are co-sequestered and metabolically co-regulated, is not well understood.
These basic questions are of fundamental importance for normal cellular functions and disturbances therein are associated with major human health threats, such as cardiovascular diseases and metabolic complications of obesity. We are currently investigating e.g. the mechanistic basis of excessive hepatic lipid storage associated with metabolic fatty liver disease and principles underlying the defective or inappropriate lipid deposition in human lipodystrophy syndromes.
We approach these questions by employing a variety of molecular cell biological, biochemical, biophysical, and advanced imaging approaches, in international collaborative efforts. We take advantage of both well-characterized cell lines and primary human cell and tissue materials. We also develop and employ novel imaging techniques to detect lipids as well as gene engineering tools to spatio-temporally control the behavior of lipid-handling proteins in the cellular and tissue context.
Selected publications
Sandhu J, Li S, Fairall L, Pfisterer SG, Weston TA, Gurnett JE, Xiao X, Vashi D, Ferrari A, Orozco JL, Kim J, Hartman CL, Strugatsky D, Lee SD, He C, Hong C, Jiang H, Bentolila LA, Gatta AT, Levine TP, Rajbhandari P, Sallam T, Ferng A, Lee R, Ford DA, Young SG, Ikonen E*, Schwabe JWR*, and Tontonoz P* (2018) Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells. Cell, 175: 1-16. * co-senior authors
Salo VT, Li S, Vihinen H, Hölttä-Vuori M, Szkalisity A, Horvath P, Belevich I, Peränen J, Thiele C, Somerharju P, Zhao H, Santinho A, Thiam AR*, Jokitalo E*, and Ikonen E* (2019) Seipin facilitates triglyceride flow to lipid droplet and counteracts droplet ripening via endoplasmic reticulum contact. Dev. Cell, 50: 478-493. *co-corresponding authors
Heybrock S, Kanerva K, Meng Y, Ing C, Liang A, Xiong ZJ, Weng X, Ah Kim Y, Collins R, Trimble W, Pomes R, Prive GG, Annaert W, Schwake M, Heeren J, Lullmann-Rauch R, Grinstein S*, Ikonen E*, Saftig P*, and Neculai D*. (2019) Lysosomal Integral Membrane Protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export. Nat. Commun., 10: 3521. *co-corresponding authors
Gungör B, Vanharanta L, Hölttä-Vuori M, Pirhonen J, Petersen NHT, Gramolelli S, Ojala PM, Kirkegaard T, and Ikonen E (2019) HSP70 induces Liver X receptor pathway activation and cholesterol reduction in vitro and in vivo. Mol. Metab., 28: 135-143.
Li S, Prasanna X, Salo VT, Vattulainen I, and Ikonen E (2019). An efficient auxin-inducible degron system with low basal degradation in human cells. Nat. Methods, 16: 866-869.
Prasanna X, Salo VT, Li S, Ven K, Vihinen H, Jokitalo E, Vattulainen I, and Ikonen E (2021) Seipin traps triacylglycerols to facilitate their nano-scale clustering in the endoplasmic reticulum membrane. PLoS Biol., 19: e3000998.
Takahashi K, Kanerva K, Vanharanta L, Almeida-Souza L, Lietha D, Olkkonen VM, and Ikonen E (2021) ORP2 couples LDL-cholesterol transport to FAK activation by endosomal cholesterol/PI(4,5)P2 exchange. EMBO J., 40: e106871.
Combot Y, Salo VT, Chadeuf G, Hölttä M, Ven K, Pulli I, Ducheix S, Pecqueur 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, Jokitalo E, Törnqvist K, Vigoureux C, Cariou B, Magre J, Larhlimi A, Ikonen E*, and Prieur X* (2022) Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes. Cell Rep., 38: 110213. *co-corresponding authors
Pirhonen J, Szkalisity A, Hagström J, Kim Y, Migh E, Kovacs M, Hölttä M, Peränen J, Seppänen J, Haglund C, Gil J, Rezeli M, Malm J, Horvath P, Marko-Varga Gy, Puolakkainen P, and Ikonen E (2022) Lipid metabolic reprogramming extends beyond histologic tumor demarcations in operable human pancreatic cancer. Cancer Res., 82: 3932-3949.
Dumesnil C, Vanharanta L, Prasanna X, Omrane M, Carpentier M, Enkavi G, Vattulainen I*, Ikonen E*, and Thiam AR* (2023) Cholesterol esters form supercooled lipid droplets whose nucleation is facilitated by triacylglycerols. Nat. Commun., 14: 915. *co-corresponding authors
External funding
Academy of Finland
EU MCSA
Fondation Leducq
Jane and Aatos Erkko Foundation
Sigrid Jusélius Foundation