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

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.

Transcriptome Analysis Reveals Nonfoamy Rather Than Foamy Plaque Macrophages Are Proinflammatory in Atherosclerotic Murine Models

“…The number of foam cells and foamy MØs were markedly decreased in the APOE-AAV group compared with that in the control group (Online Figure VIII B). 2-Hydroxypropyl-ß-cyclodextrin (CD) has been reported to induce the plaque regression by removing cholesterol crystals 32–34 , lowering intracellular cholesterol levels in vivo 35 , and inducing MØ reprogramming and liver X receptor (LXR)-dependent atheroprotection 36 . Ldlr −/− mice with advanced atherosclerosis (WD for 25 weeks) were injected with CD (2 g/kg body weight) or PBS (vehicle control) for 8 weeks on a WD.…”

The Role of Tissue Macrophage-Mediated Inflammation on NAFLD Pathogenesis and Its Clinical Implications

“…The central role of KCs in the pathogenesis of NAFLD has been suggested by several studies in mouse models where the ablation of KCs determined the marked reduction of hepatic insulin resistance and inflammation in diet-induced steatosis [109, 110]. In experimental NASH, macrophages are characterized by the accumulation of large amounts of toxic lipids [99, 111] and cholesterol crystals [112]; fat-laden KCs exhibit a switch to a proinflammatory (M1) phenotype, which is reversible by inhibition of lipogenesis [99, 113]. Moreover, data obtained by different research groups showed that chemical depletion of KCs was able to prevent the release of proinflammatory cytokines and to alleviate liver damage [114].…”

Emerging evidence for beneficial macrophage functions in atherosclerosis and obesity-induced insulin resistance

“…In this way, atherosclerosis, obesity, and hepatosteatosis may all represent acquired lysosomal storage disorders [ 49 ]. Compounds that promote the mobilization of cholesterol crystals from the lysosome and into the cytoplasm (e.g., β -cyclodextrins) have been promoted as potential therapeutic compounds for these disorders [ 50 – 52 ]. This is in contrast to oleate and other unsaturated fatty acids that stimulate, but do not stall, flow through the autophagy pathway [ 34 ].…”