Lipid Signaling and Homeostasis

The research group investigates the regulatory regimes that our cells employ to maintain their lipid balance and to integrate their lipid status with other vital functions such as cell signaling. The work employs molecular cell biology approaches to discover novel mechanisms that impact the comorbidities of obesity and fatty liver disease, the long-term aim being to discover new approaches for the prevention and treatment of these diseases.

The present main project involves obesity and its comorbidities. We have earlier investigated (i) the mechanisms underlying the insulin resistance and metabolic dysfunction of adipocytes, and (ii) intracellular membrane contact sites (MCSs), lipid homeostasis and signaling in primary endothelial cells (ECs). At present we focus on identifying defects in the communication of adipocytes and ECs in obese adipose tissue. We have optimized the isolation of ECs and mature adipocytes from human fat biopsies and established a trans-filter co-culture system to monitor the communication between the two cell types. We perform multiomics analyses of cells isolated from fat biopsies of either obese or normal weight subjects, and perform assays to discover defects in adipocyte-EC communication in obesity. The goal here is to discover new therapy targets that could be employed to promote adipose tissue functionality and to avoid the metabolic comorbidities of obesity.

In a more basic research project we investigate the functions of MCSs in the lipid homeostasis and signaling of endothelial cells. Here we have performed systems-wide analysis of the depletion of endoplasmic reticulum (ER)-Golgi contacts, or of inhibiting the lipid transporter protein OSBP (oxysterol-binding protein) at these sites, revealing a multitude of effects on lipid/sterol homeostasis, ER stress responses, and inflammatory gene expression. At the moment we focus on the function of the previously poorly studied OSBP family member ORP7 in the physiology of primary ECs. The ultimate aim of this work is to discover EC MCS functions that could be used as targets for the therapy of cardiometabolic diseases involving endothelial dysfunction. A further object of research in the group is the Golgi apparatus protein GOLM1/GP73, a suggested biomarker of liver diseases and several cancers. The function of this highly interesting component is investigated in cancerous and non-cancerous hepatocytes and cholangiocytes, the aim being to elucidate its potential as a putative therapy target for diseases of the liver. In addition, we also investigate the roles of lipid and calcium signaling in thyroid cancer.

Selected publications

Chaurasiya V, Pham DD, Harju J, Juuti A, Penttilä A, Goud ESK, Nguyen VD, Zhang B Perttunen S, Keskitalo S, Zhou Y, Pietiläinen KH, Nidhina Haridas1 PA, Olkkonen VM. Human visceral adipose tissue microvascular endothelial cell isolation and establishment of co-culture with white adipocytes to analyze cell-cell communication. Exp Cell Res. 2023 Oct 16:113819. doi: 10.1016/j.yexcr.2023.113819. Online ahead of print.

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. 2022. ORP5/8 and MIB/MICOS link ER-mitochondria and intramitochondrial contacts for non-vesicular transport of phosphatidylserine. Cell Rep. 40:111364.

Weber-Boyvat M, Kroll J, Trimbuch T, Olkkonen VM, Rosenmund C. 2022. The lipid transporter ORP2 regulates synaptic neurotransmitter release via two distinct mechanisms. Cell Rep 41:111882.

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. 2022. Insulin-inducible THRSP maintains mitochondrial function and regulates sphingolipid metabolism in human adipocytes. Mol. Med. 28:68.

Arora A, Kivelä AM, Wang L, Minkeviciene R, Taskinen JH, Zhang B, Koponen A, Sun J, Shirane M, Hotulainen P, Raiborg C, Olkkonen VM. 2022. Protrudin regulates FAK activation, endothelial cell migration and angiogenesis. Cell Mol Life Sci 79:220.

Takahashi K, Kanerva K, Vanharanta L, Almeida-Souza L, Lietha D, Olkkonen VM, Ikonen E. 2021. ORP2 couples LDL-cholesterol transport to FAK activation by endosomal cholesterol/PI(4,5)P2 exchange . EMBO J. 40:e106871.

Tikkanen E, Minicocci I, Hällfors J, Di Costanzo A, D’Erasmo L, Poggiogalle E, Donini LM, Würtz P. Jauhiainen M, Olkkonen VM, Arca M. 2019. Metabolomic signature of angiopoietin-like protein 3 deficiency in fasting and postprandial state, Arterioscler. Thromb. Vasc. Biol. 39:665-74.

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 75:4041-57.

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. 2016. ORP4L is essential for T-cell acute lymphoblastic leukemia (T-ALL) cell survival. Nat Commun. 7:12702.

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

External funding

Finnish Society of Sciences and Letters
Jane and Aatos Erkko Foundation
Medicinska undrstödsföreningen Liv och Hälsa r.f.
Magnus Ehrnrooth Foundation
Sigrid Jusélius Foundation