Weekly Treatment of 2-Hydroxypropyl-beta-cyclodextrin Improves Intracellular Cholesterol Levels in LDL Receptor Knockout Mice
AuthorsWalenbergh, Sofie M.A.
Jeurissen, Mike L.J.
van Gorp, Patrick J.
Olde Damink, Steven W.M.
Koek, Ger H.
UMass Chan AffiliationsDepartment of Medicine, Division of Infectious Diseases and Immunology
Cellular and Molecular Physiology
Digestive System Diseases
Endocrinology, Diabetes, and Metabolism
Nutritional and Metabolic Diseases
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AbstractRecently, 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-beta-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 7alpha-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.
SourceInt J Mol Sci. 2015 Sep 2;16(9):21056-69. doi: 10.3390/ijms160921056. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/39815
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© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
Except where otherwise noted, this item's license is described as <p>© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).</p>