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

International Journal of Molecular Sciences

Sofie M. A. Walenbergh⁴  Tom Houben⁴  Tim Hendrikx⁴  Mike L. J. Jeurissen⁴  Patrick J. van Gorp⁴  Nathalie Vaes⁴  Steven W. M. Olde Damink¹  Fons Verheyen²  Ger H. Koek⁶  Dieter Lütjohann³  Alena Grebe⁵  Eicke Latz⁵  Ronit Shiri-Sverdlov⁴  Amedeo Lonardo⁷ 

[1] Department of General Surgery, Maastricht University, Maastricht 6229ER, The Netherlands; E-Mail:;Department of Molecular Cell Biology and Electron Microscopy, Maastricht University, Maastricht 6229ER, The Netherlands; E-Mail:;Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn D-53105, Germany; E-Mail:;Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht 6229ER, The Netherlands; E-Mails:;Institute of Innate Immunity, University Hospital, University of Bonn, Bonn D-53127, Germany; E-Mails:;Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center (MUMC), Maastricht 6202AZ, The Netherlands; E-Mail:Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht 6229ER, The Netherlands;

关键词: NAFLD;    metabolic syndrome;    cyclodextrin;    electron microscopy;    lysosomes;   

DOI  :  10.3390/ijms160921056

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.