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Int. J. Mol. Sci. 2015, 16(9), 21056-21069; doi:10.3390/ijms160921056

Weekly Treatment of 2-Hydroxypropyl-β-cyclodextrin Improves Intracellular Cholesterol Levels in LDL Receptor Knockout Mice

1
Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht 6229ER, The Netherlands
2
Department of General Surgery, Maastricht University, Maastricht 6229ER, The Netherlands
3
Department of HPB and Liver Transplantation Surgery, Royal Free Hospital, University College London, London NW3 2PF, UK
4
Department of Molecular Cell Biology and Electron Microscopy, Maastricht University, Maastricht 6229ER, The Netherlands
5
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center (MUMC), Maastricht 6202AZ, The Netherlands
6
Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn D-53105, Germany
7
Institute of Innate Immunity, University Hospital, University of Bonn, Bonn D-53127, Germany
8
German Center for Neurodegenerative Diseases (DZNE), Bonn D-53127, Germany
9
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Amedeo Lonardo and Giovanni Targher
Received: 4 June 2015 / Revised: 19 August 2015 / Accepted: 20 August 2015 / Published: 2 September 2015
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)
View Full-Text   |   Download PDF [3600 KB, uploaded 2 September 2015]   |  

Abstract

Recently, the importance of lysosomes in the context of the metabolic syndrome has received increased attention. Increased lysosomal cholesterol storage and cholesterol crystallization inside macrophages have been linked to several metabolic diseases, such as atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Two-hydroxypropyl-β-cyclodextrin (HP-B-CD) is able to redirect lysosomal cholesterol to the cytoplasm in Niemann-Pick type C1 disease, a lysosomal storage disorder. We hypothesize that HP-B-CD ameliorates liver cholesterol and intracellular cholesterol levels inside Kupffer cells (KCs). Hyperlipidemic low-density lipoprotein receptor knockout (Ldlr−/−) mice were given weekly, subcutaneous injections with HP-B-CD or control PBS. In contrast to control injections, hyperlipidemic mice treated with HP-B-CD demonstrated a shift in intracellular cholesterol distribution towards cytoplasmic cholesteryl ester (CE) storage and a decrease in cholesterol crystallization inside KCs. Compared to untreated hyperlipidemic mice, the foamy KC appearance and liver cholesterol remained similar upon HP-B-CD administration, while hepatic campesterol and 7α-hydroxycholesterol levels were back increased. Thus, HP-B-CD could be a useful tool to improve intracellular cholesterol levels in the context of the metabolic syndrome, possibly through modulation of phyto- and oxysterols, and should be tested in the future. Additionally, these data underline the existence of a shared etiology between lysosomal storage diseases and NAFLD. View Full-Text
Keywords: NAFLD; metabolic syndrome; cyclodextrin; electron microscopy; lysosomes NAFLD; metabolic syndrome; cyclodextrin; electron microscopy; lysosomes
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Walenbergh, S.M.A.; Houben, T.; Hendrikx, T.; Jeurissen, M.L.J.; van Gorp, P.J.; Vaes, N.; Damink, S.W.M.O.; Verheyen, F.; Koek, G.H.; Lütjohann, D.; Grebe, A.; Latz, E.; Shiri-Sverdlov, R. Weekly Treatment of 2-Hydroxypropyl-β-cyclodextrin Improves Intracellular Cholesterol Levels in LDL Receptor Knockout Mice. Int. J. Mol. Sci. 2015, 16, 21056-21069.

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