Lipid signaling for novel diagnosis and treatment of diseases

Lipids represent a category of hydrophobic compounds primarily found enclosed in specific compartments, where they serve as a primary energy source for the body. Beyond their role as an energy source, lipids have diverse functions, including regulation (e.g., hormones and bile acid precursors) and serving as structural components in cells and organelles (e.g., phospholipids and cholesterol). This research group initially described lysosomal lipid accumulation in macrophages as a central pathological disease mechanism triggering inflammation in disorders related to metabolic syndrome (e.g. atherosclerosis and NAFLD). Subsequently, these findings were verified in diverse human populations, leading to the notion that circulating lysosomal enzymes are involved in metabolic disease processes. Additionally, uncovering this pathometabolic mechanism led to the identification of new diagnostic and therapeutic approaches in the aforementioned disorders as well as other, seemingly unrelated disorders, such as Niemann-Pick disease type C1 (a rare, genetic progressive disorder).

Due to the multifaceted roles of lipids and impact of previous findings in different fields, this research group has diversified its focus in metabolism in different directions. One research branch focuses on the role of lipids and lysosomal enzymes in the context of cancer with particular emphasis on targeted interventions to improve therapeutic outcome.

The other research branch, led by Tom Houben, PhD (assistant Prof.), explores the impact of lipids in neuropsychiatric disorders and specifically how disturbances in lipid metabolism influence the response to antidepressants.

The overarching goal of this research group is therefore to provide new diagnostic and therapeutic targets for a wide range of metabolic diseases by unravelling their pathometabolic basis. Through cooperation with public and private partners on both a national and international scale, this research group expedites the process of translating their laboratory discoveries into tangible products that can directly benefit patients.

• Van der Heijden AR, Houben T. Lipids in major depressive disorder: new kids on the block or old friends revisited? Front Psychiatry. 2023 Aug 17;14:1213011.
• Magro Dos Reis I, Houben T, Oligschläger Y, Bücken L, Steinbusch H, Cassiman D, Luetjohann D, Westerterp M, Prickaerts J, Plat J, Shiri-Sverdlov R. Dietary plant stanol ester supplementation reduces peripheral symptoms in a mouse model of Niemann-Pick type C1 disease. J Lipid Res. 2020 Apr 14.
• ​Ding L, Goossens GH, Oligschlaeger Y, Houben T, Blaak EE, Shiri-Sverdlov R. Plasma cathepsin D activity is negatively associated with hepatic insulin sensitivity in overweight and obese humans. Diabetologia. 2020 Feb;63(2):374-384.
• Bitorina AV, Oligschlaeger Y, Shiri-Sverdlov R, Theys J. Low profile high value target: The role of oxLDL in cancer. Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Dec;1864(12):15818.
• ​Houben T, Oligschlaeger Y, Bitorina AV, Hendrikx T, Walenbergh SMA, Lenders MH, Gijbels, ​MJJ, Verheyen F, Lütjohann D, Hofker MH, Binder CJ, Shiri-Sverdlov R. Blood-derived macrophages prone to accumulate lysosomal lipids trigger oxLDL-dependent murine hepatic inflammation. Sci Rep 2017 Oct2;7(1):12550.
• Hendrikx T, Watzenböck ML, Walenbergh SM, Amir S, Gruber S, Kozma MO, Grabsch HI, Koek GH, Pierik MJ, Staufer K, Trauner M, Kalhan SC, Jonkers D, Hofker MH, Binder CJ, Shiri-Sverdlov R; Low levels of IgM antibodies recognizing oxidation-specific epitopes are associated with human non-alcoholic fatty liver disease. BMC Med 2016 Jul22;14(1).
• Walenbergh SM, Houben T, Hendrikx T, Jeurissen ML, van Gorp PJ, Vreugdenhil AC, Adriaanse MP, Buurman WA, Hofker MH, Mosca A, Lindsey PJ, Alisi A, Liccardo D, Panera N, Koek GH, Nobili V, Shiri-Sverdlov R. Plasma cathepsin D levels: a novel tool to predict pediatric hepatic inflammation. Am J Gastroenterol 2015 Mar;110(3):462-70.
• Bieghs V, Hendrikx T, van Gorp PJ, Verheyen F, Guichot YD, Walenbergh SM, Jeurissen ML, Gijbels M, Rensen SS, Bast A, Plat J, Kalhan SC, Koek GH, Leitersdorf E, Hofker MH, Lütjohann D, Shiri-Sverdlov R; The cholesterol derivative 27-hydroxycholesterol reduces steatohepatitis in mice. Gastroenterology 2013 Jan;144(1):167-178.e1.
• Bieghs V, van Gorp PJ, Walenbergh SM, Gijbels MJ, Verheyen F, Buurman WA, Briles DE, Hofker MH, Binder CJ, Shiri-Sverdlov R; Specific immunization strategies against oxidized low-density lipoprotein: a novel way to reduce nonalcoholic steatohepatitis in mice. Hepatology 2012 Sep;56(3):894-903.
• Bieghs V, Wouters K, van Gorp PH, Gijbels MJ, de Winther MP, Binder CJ, Lütjohann D, Febbraio M, Moore KJ, van Bilsen M, Hofker MH, Shiri-Sverdlov R. Role of scavenger receptor A and CD36 in diet-induced non-alcoholic steatohepatits in hperlipidemic mice. Gastroenterology 2010 Jun;138(7):2477-86

2022      Ines dos Reis, Mind the gatekeeper: Key role of NPC1 protein and lysosomal cholesterol in metabolic diseases and therapeutical implications.
2021      Tulasi Yadati, Small Molecules, Big Consequences: Novel Therapeutic Approaches for Treating Chronic Inflammatory Diseases
2021      Lingling Ding, The entanglement of plasma Cathepsin D and metabolic disturbances: relevant insights in the metabolic syndrome 
2020      Albert Bitorina, Inconspicuous offender: Pathophysiological role of oxidized-low density lipoprotein in metabolic diseases
2018     Tom Houben, Lysosomes ‘in control’: where lipids meet inflammation in metabolic syndrome
2017     Jieyi Li, Macrophage stimulating protein (MSP) in the metabolic syndrome
2017     Mike Jeurissen, The entanglement of NASH and atherosclerosis: shared features of a macrophage-specific response
2016     Sofie Walenbergh, Storage solutions: novel ways for the detection and inhibition of non-alcoholic steatohepatitis
2015     Tim Hendrikx, Intracellular traffic jam: cholesterol accumulation as cause for chronic inflammatory diseases
2011     Veerle Bieghs, Kupffer cells in fatty liver disease: Does size really matter?
2008     Kristiaan Wouters, Non-alcoholic steatohepatits: second hit or strike out?

• Methods for the treatment of nonalcoholic steatohepatitis; Patent No. TEMP/E-1/47465/2017.
• Methods and compounds for the treatment of Niemann-Pick Disease Type C1.
• (patent number 330 EPP0; date filing: 27.03.2016, published as WO 2017/162806 A1) à continued to Europe and US à 17712159.7 (EU)
• Method for treating non-alcoholic steatohepatitis. (patent number 329 EPP0; date filing: 23.02.2016)
• Method for the treatment of lysosomal lipid storage diseases. (patent number EP13163419.8; date filing: 11.04.2013)
• ​Method for treating fatty liver diseases, in particular non-alcoholic steatohepatitis. (patent number WO 2012/019930 A1; date filing: 30.07.2011, international publication date: 16.02.2012)
• Method for diagnosing fatty liver diseases, in particular non-alcoholic steatohepatits. (patent number EP2418285 A1; date filing: 09.08.2010, international publication date: 15.02.2012). 
• Method for treating liver inflammation, fibrosis and non-alcoholic steatohepatitis. (patent number EP11155267.5; date filing: 21.02.2011)
• Phytosterols and phytostanols for the prevention of treatment of inflammation. (patent number 11191776.1-1216, date filing: 02.12.2011)
• Method for diagnosing of pediatric NASH (patent number EP14188909.7, date filing: 14.10.2014, WO 2016/059054)