Quantification of Lipoprotein Uptake in Vivo Using Magnetic Particle Imaging and Spectroscopy

Abstract

Lipids are a major source of energy for most tissues, and lipid uptake and storage is therefore crucial for energy homeostasis. So far, quantification of lipid uptake in vivo has primarily relied on radioactive isotope labeling, exposing human subjects or experimental animals to ionizing radiation. Here, we describe the quantification of in vivo uptake of chylomicrons, the primary carriers of dietary lipids, in metabolically active tissues using magnetic particle imaging (MPI) and magnetic particle spectroscopy (MPS). We show that loading artificial chylomicrons (ACM) with iron oxide nanoparticles (IONPs) enables rapid and highly sensitive post hoc detection of lipid uptake in situ using MPS. Importantly, by utilizing highly magnetic Zn-doped iron oxide nanoparticles (ZnMNPs), we generated ACM with MPI tracer properties superseding the current gold-standard, Resovist®, enabling quantification of lipid uptake from whole-animal scans. We focused on brown adipose tissue (BAT), which dissipates heat and can consume a large part of nutrient lipids, as a model for tightly regulated and inducible lipid uptake. High BAT activity in humans correlates with leanness and improved cardiometabolic health. However, the lack of non-radioactive imaging techniques is an important hurdle for the development of BAT-centered therapies for metabolic diseases such as obesity and type 2 diabetes. Comparison of MPI measurements with iron quantification by inductively coupled plasma mass spectrometry (ICP-MS) revealed that MPI rivals the performance of this highly sensitive technique. Our results represent radioactivity-free quantification of lipid uptake in metabolically active tissues like BAT. KEYWORDS magnetic particle imaging, brown adipose tissue, BAT, chylomicron, TRL, magnetic particle spectroscopy, lipid uptake Adipose tissues are the major sites of lipid storage. There are two major types of adipose tissue, white adipose tissue (WAT) and BAT. 1 BAT is an organ that is capable of converting chemical energy into heat by mitochondrial uncoupling. 2,3 Since the discovery of metabolically active BAT in adult humans in 2007/9, 4-8 it has been the subject of intense research due to the possibility of exploiting its thermogenic properties for combating obesity, diabetes, dyslipidemia, and cardiovascular disease. [9][10][11] During the process of thermogenesis in BAT, there is a dramatic increase in the demand for energy substrates and ca. 50-75% of the food-derived lipids and glucose, respectively, are taken up by activated BAT. [12][13][14][15][16] Consequently, quantification of lipid uptake in BAT is a highly valuable tool both to measure BAT activity, as well as to develop ways to measure lipid transport and storage. Additionally, safe and non-invasive measurements of BAT activity in humans would be an important prerequisite for the development of antiobesity drugs.Lipoprotein particles are composed of triglycerides, phospholipids, and cholesterol, and are associated with apolipoproteins (ApoA, ApoB, ApoC, and ApoE), which confer fu...

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