CELLULAR NEUROCIENCE | NEURONAL SIGNALING | CARDIOVASCULAR RESEARCH | METABOLISM | LIPID SIGNALING AND HOMEOSTASIS | ENDOCRINOLOGY | CELLULAR PHYSIOLOGY | TARGETED GENE-EXPRESSION ANALYSIS | MEMBRANE BIOLOGY | TELOMERE RESEARCH
Elina Ikonen, M.D. Dr.Med.Sci., Academy Professor (Director), Head
Tomas Blom, Ph.D., Academy Research Fellow
Riku Fagerlund, Ph.D.
Maarit Hölttä-Vuori, Ph.D.
Kristiina Kanerva, Ph.D.
Shiqian Li, Ph.D.
Maarit Neuvonen, Ph.D.
Simon Pfisterer, Ph.D.
Sanjeev Ranjan, Ph.D.
Boris Vassilev, M.Sc.
Juho Pirhonen, medical student
Veijo Salo, medical student
Lauri Vanharanta, medical student
Anna Uro, laboratory technician
Our group aims to understand how cholesterol functions in the cellular context, both under physiological conditions and in human diseases. To this end, we also develop novel imaging techniques to analyze cholesterol and other lipids in cells. Cholesterol is an essential component of cell membranes, where it dictates important biophysical properties of the bilayer and participates in lipid-protein interactions. These aspects are important for understanding the mechanisms that underlie the adverse effects of cholesterol. Besides cardiovascular diseases, disturbances in cholesterol metabolism are implicated e.g., in several neurodegenerative diseases.
Figure. The principle of third-harmonic generation (THG) microscopy for labelfree imaging of cellular lipid storage. Left: Both linearly polarized (LP) and circularly polarized (CP) light can be used to generate signals from lipid droplets. Right: Representative images of single cells with either triacylglycerol or cholesteryl ester deposition. Cholesteryl ester storage generates a more pronounced THG signal, with individual lipid droplets visualized. Courtesy of Dr. Godofredo Bautista, Tampere University of Technology (for details see Bautista et al., Biophys
Cholesterol metabolism and Alzheimer’s disease (AD) are connected, but the molecular mechanisms involved are not well understood. Amyloid precursor protein (APP) undergoes amyloidogenic processing (beta-cleavage), that predisposes a patient to AD, in a cholesterol-dependent manner. Moreover, increasing evidence suggests that APP itself regulates cholesterol metabolism. We have recently discovered a new link between APP and cholesterol that is relevant both physiologically and in AD: APP regulates the key transcription factor of cholesterol metabolism, sterol-regulatory element binding protein 2 (SREBP2) via its secretory ectodomain fragments. This regulation can be either positive or negative, depending on APP non-amyloidogenic vs. amyloidogenic (alpha vs. beta) processing. The physiologically dominant, APPs-alpha fragment stimulates SREBP2, leading to enhanced cholesterol synthesis and LDL receptor levels. In contrast, APP secretory beta fragment suppresses SREBP2 signaling. In line with this finding, in familial AD patients with increased beta-cleavage, serum cholesterol synthesis markers were decreased and fibroblast LDL-receptor levels were reduced (Wang et al., 2014).
Cells can store excess lipids in cellular lipid droplets. The major storage lipids inside lipid droplets are cholesteryl esters (CE) and triacylglycerols (TAG). Lipid droplets can be visualized in cells without exogenous labels by non-linear imaging techniques. In collaboration with physicists, we have recently discovered that one such technique, polarized third-harmonic generation (THG) microscopy, can differentiate between native TAGand CE-enriched lipid droplets in mammalian cells. This distinction is based on the differential ordering of the two lipid classes (Bautista, Pfisterer et al., 2014). The degree of lipid ordering is thought to play an important role in the mobility and enzymatic processing of lipids in lipid droplets This technique may, in the future, be useful for differentiating lipid storage types in a label-free fashion.
Elina Ikonen, M.D., Dr.Med.Sci., Professor
Tel: +358 2941 25277
Bautista G, Pfisterer SG, Huttunen MJ, Ranjan S, Kanerva K, Ikonen E, Kauranen M. Polarized THG microscopy identifies compositionally different lipid droplets in mammalian cells. Biophys J. 2014; 107:2230–6.
Brown AJ, Ikonen E, Olkkonen VM. Cholesterol precursors: more than mere markers of biosynthesis. Curr Opin Lipidol. 2014; 25(2):133–9.
Neuvonen M, Manna M, Mokkila S, Javanainen M, Rog T, Liu Z, Bittman R, Vattulainen I, Ikonen E. Enzymatic oxidation of cholesterol: properties and functional effects of cholestenone in cell membranes. PLoS One. 2014; 9:e103743.
Ruhanen H, Perttilä J, Hölttä-Vuori M, Zhou Y, Yki-Järvinen H, Ikonen E, Käkelä R, Olkkonen VM. PNPLA3 mediates hepatocyte triacylglycerol remodelling. J Lipid Res. 2014; 55:739–46.
Wang W, Mutka AL, Zmrzljak UP, Rozman D, Tanila H, Gylling H, Remes AM, Huttunen HJ, Ikonen E. Amyloid precursor protein alpha- and beta-cleaved ectodomains exert opposing control of cholesterol homeostasis via SREBP2. FASEB J. 2014; 28:849–60.
Hölttä-Vuori M, Salo VT, Ohsaki Y, Suster ML, Ikonen E. Alleviation of seipinopathy-related ER stress by triglyceride storage. Hum Mol Genet 2013; 22:1157–66.
Ikonen E, Olkkonen VM. Nobelin palkinto solunsisäisen kalvoliikenteen tutkijoille. PALKINNOT. Duodecim 2013; 129:75–76.
Kanerva K, Uronen L-R, Blom T, Li S, Bittman R, Lappalainen P, Peränen J, Raposo G, Ikonen E. LDL cholesterol recycles to the plasma membrane via a Rab8a-myosin5b-actin-dependent membrane transport route. Developmental Cell 2013; 27:1–14.
Pietiäinen V, Vassilev B, Blom T, Wang W, Nelson J, Bittman R, Bäck N, Zelcer N, Ikonen E. NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation. J Cell Sci 2013; 126:3961–71.
Siljamäki E, Rintanen N, Kirsi M, Upla P, Wang W, Karjalainen M, Ikonen E, Marjomäki V. Cholesterol dependence of collagen and echovirus 1 trafficking along the novel α2β1 integrin internalization pathway. PLoS One 2013; 8:e55465.
Zerenturk EJ, Sharpe LJ, Ikonen E, Brown AJ. Desmosterol and DHCR24: Unexpected new directions for a terminal step in cholesterol synthesis. Prog Lipid Res 2013; 52:666–680.
Wang W, Mutka A-L, Prosenc Zmrzljak U, Rozman D, Tanila H, Gylling H, Remes AM, Huttunen HJ, Ikonen E. Amyloid precursor protein alpha- and beta-cleaved ectodomains exert opposing control of cholesterol homeostasis via SREBP2. FASEB J. Epub 2013 Nov 18.
Blom T, Li Z, Bittman R, Somerharju P, Ikonen E. Tracking Sphingosine Metabolism and Transport in Sphingolipidoses: NPC1 Deficiency as a Test Case. Traffic 2012; 13:1234-43.
Jansen M, Wang W, Greco D, Bellenchi GC, di Porzio U, Brown AJ, Ikonen E. What dictates the accumulation of desmosterol in the developing brain? FASEB J 2012; Epub Dec 10.
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; 1821:1472-1484.
Wang F, Vihma V, Badeau M, Savolainen-Peltonen H, Leidenius M, Mikkola T, Turpeinen U, H.m.l.inen E, Ikonen E, W.h.l. K, Fledenius C, Jauhiainen M, and Tikkanen MJ. Fatty acyl esterification and deesterification of 17-beta-estradiol in human breast subcutaneous adipose tissue. J Clin Endocrinol Metab 2012; 97: 3349-3356.