scholarly journals Synthesis of multi-lactose-appended β-cyclodextrin and its cholesterol-lowering effects in Niemann–Pick type C disease-like HepG2 cells

2017 ◽  
Vol 13 ◽  
pp. 10-18 ◽  
Author(s):  
Keiichi Motoyama ◽  
Rena Nishiyama ◽  
Yuki Maeda ◽  
Taishi Higashi ◽  
Yoichi Ishitsuka ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
High Dose ◽  
Unesterified Cholesterol ◽  
Peanut Lectin ◽  
Cholesterol Lowering ◽  
Cholesterol Levels ◽  
Type C ◽  
Intracellular Cholesterol ◽  
Niemann Pick ◽  
Very High

Niemann–Pick type C (NPC) disease, characterized by intracellular accumulation of unesterified cholesterol and other lipids owing to defects in two proteins NPC1 and NPC2, causes neurodegeneration and other fatal neurovisceral symptoms. Currently, treatment of NPC involves the use of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). HP-β-CD is effective in the treatment of hepatosplenomegaly in NPC disease, albeit at a very high dose. One of the methods to reduce the required dose of HP-β-CD for treatment of NPC is to actively targeting hepatocytes with β-cyclodextrin (β-CD). The aim of the present study was to synthesize a novel multi-lactose-appended β-CD (multi-Lac-β-CD) and to evaluate its cholesterol-lowering effect in U18666A-treated HepG2 (NPC-like HepG2) cells. Further, the study aimed at delivering β-CD to hepatocytes via cholesterol-accumulated HepG2 cells, and indicated that the newly synthesized multi-Lac-β-CD had an average degree of substitution of lactose (DSL) of 5.6. This newly synthesized multi-Lac-β-CD was found to significantly decrease the concentration of intracellular cholesterol with negligible cytotoxicity as compared to HP-β-CD. An increased internalization of TRITC-multi-Lac-β-CD (DSL 5.6) as compared to TRITC-HP-β-CD was observed in NPC-like HepG2 cells. Further, the dissociation constant of peanut lectin with multi-Lac-β-CD (DSL5.6) was found to be extremely low (2.5 × 10−8 M). These results indicate that multi-Lac-β-CD (DSL5.6) diminished intracellular cholesterol levels in NPC-like HepG2 cells via asialoglycoprotein receptor (ASGPR)-mediated endocytosis.

scholarly journals Cholesterol lowering effects of mono-lactose-appended β-cyclodextrin in Niemann–Pick type C disease-like HepG2 cells

2015 ◽  
Vol 11 ◽  
pp. 2079-2086 ◽  
Author(s):  
Keiichi Motoyama ◽  
Yumi Hirai ◽  
Rena Nishiyama ◽  
Yuki Maeda ◽  
Taishi Higashi ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Cholesterol Content ◽  
High Dose ◽  
Dependent Manner ◽  
Lysosomal Storage ◽  
Concentration Dependent Manner ◽  
Cholesterol Lowering ◽  
Type C ◽  
Intracellular Cholesterol ◽  
Niemann Pick

The Niemann–Pick type C disease (NPC) is one of inherited lysosomal storage disorders, emerges the accumulation of unesterified cholesterol in endolysosomes. Currently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) has been applied for the treatment of NPC. HP-β-CyD improved hepatosplenomegaly in NPC patients, however, a high dose of HP-β-CyD was necessary. Therefore, the decrease in dose by actively targeted-β-CyD to hepatocytes is expected. In the present study, to deliver β-CyD selectively to hepatocytes, we newly fabricated mono-lactose-appended β-CyD (Lac-β-CyD) and evaluated its cholesterol lowering effects in NPC-like HepG2 cells, cholesterol accumulated HepG2 cells induced by treatment with U18666A. Lac-β-CyD (degree of substitution of lactose (DSL) 1) significantly decreased the intracellular cholesterol content in a concentration-dependent manner. TRITC-Lac-β-CyD was associated with NPC-like HepG2 cells higher than TRITC-β-CyD. In addition, TRITC-Lac-β-CyD was partially localized with endolysosomes after endocytosis. Thus, Lac-β-CyD entered NPC-like HepG2 cells via asialoglycoprotein receptor (ASGPR)-mediated endocytosis and decreased the accumulation of intracellular cholesterol in NPC-like HepG2 cells. These results suggest that Lac-β-CyD may have the potential as a drug for the treatment of hepatosplenomegaly in NPC disease.

scholarly journals Quantitative Comparison of the Efficacy of Various Compounds in Lowering Intracellular Cholesterol Levels in Niemann-Pick Type C Fibroblasts

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e48561 ◽  
Author(s):  
Zachary T. Wehrmann ◽  
Tyler W. Hulett ◽  
Kara L. Huegel ◽  
Kevin T. Vaughan ◽  
Olaf Wiest ◽  
...  
Keyword(s):  
Quantitative Comparison ◽  
Cholesterol Levels ◽  
Type C ◽  
Intracellular Cholesterol ◽  
Niemann Pick

scholarly journals Defining the Cholesterol Lowering Mechanism of Bergamot (Citrus bergamia) Extract in HepG2 and Caco-2 Cells

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3156
Author(s):  
Yunying Huang ◽  
Restituto Tocmo ◽  
Mirielle C. Nauman ◽  
Monica A. Haughan ◽  
Jeremy J. Johnson
Keyword(s):  
Hepg2 Cells ◽  
Southern Italy ◽  
Citrus Fruit ◽  
Fruit Extract ◽  
Cholesterol Lowering ◽  
Cholesterol Levels ◽  
Niemann Pick ◽  
Kinase Phosphorylation ◽  
Lowering Activity ◽  
Citrus Bergamia

Bergamot, a Mediterranean citrus fruit native to southern Italy, has been reported to have cholesterol-lowering properties; however, the mechanism of action is not well understood. Due to structural similarities with 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors, it has been proposed that the phenolic compounds in bergamot may also inhibit HMGCR. Statins are widely used for their cholesterol-lowering properties; however, they are not universally well tolerated, suggesting there is a need to identify novel cholesterol-lowering strategies. In the present study, we investigated bergamot fruit extract (BFE) and its principal components (neoeriocitrin, naringin, neohesperidin, melitidin, and brutieridin) for their ability to regulate cholesterol levels in HepG2 and Caco-2 cells. BFE at increasing concentrations decreased the levels of total and free cholesterol in HepG2 cells. BFE and its constituents did not directly inhibit HMGCR activity. However, BFE and neohesperidin decreased HMGCR levels in HepG2 cells, suggesting that neohesperidin and BFE may downregulate HMGCR expression. An increase in AMP-kinase phosphorylation was observed in BFE and neohesperidin-treated cells. In Caco-2 cells, brutieridin exhibited a significant reduction in cholesterol uptake and decreased the level of Niemann-Pick C1 Like 1, an important cholesterol transporter. Taken together, our data suggest that the cholesterol-lowering activity of bergamot is distinct from statins. We hypothesize that BFE and its principal constituents lower cholesterol by inhibiting cholesterol synthesis and absorption.

scholarly journals Vorinostat, a Histone Deacetylase Inhibitor, as a Candidate Therapy to Treat Liver Pathology in a Niemann-Pick type C Disease Mouse Model

2021 ◽  
Author(s):  
◽  
Natalie Hammond
Keyword(s):  
Clinical Trial ◽  
Liver Disease ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Therapeutic Efficacy ◽  
Premature Death ◽  
Unesterified Cholesterol ◽  
Deacetylase Inhibitor ◽  
Type C ◽  
Niemann Pick

<p>Niemann-Pick type C (NPC) disease is a rare neuro-visceral, lysosomal storage disorder for which no effective therapy yet exists. A recessive mutation in the late endosomal/lysosomal cholesterol transport genes NPC1 (95%) or NPC2 (5%) are the causative factors which leads to an accumulation of unesterified cholesterol and sphingolipids in the late endosome/lysosome. It is a build-up of these lipids that, in the majority of cases, ultimately leads to premature death prior to adolescence. In recent years, an imbalance of histone acetylation in a yeast model of NPC disease and subsequently an increased expression of histone deacetylase genes in NPC patient fibroblasts relative to healthy controls was discovered. This led to the finding that Vorinostat (suberoylanilide hydroxamic acid (SAHA); Zolinza®) a histone deacetylase inhibitor (HDACi) drug, rescued unesterified cholesterol accumulation in NPC patient fibroblasts. From these findings in NPC patient fibroblasts, a Phase I clinical trial testing the efficacy of orally-administered Vorinostat in adult NPC disease patients commenced in 2014; however, the therapeutic efficacy of Vorinostat in a whole animal model of NPC disease has not been investigated and is thus unknown. In this thesis, the therapeutic efficacy of intra-peritoneal administered 150 mg/kg Vorinostat in the Npc1nmf164 mouse was explored. This internationally approved HDACi reduced liver disease by decreasing lipid accumulation without increasing expression of NPC1; however, the treatment did not delay weight loss, onset of ataxia and premature death, possibly due to insufficient concentrations penetrating through the blood brain barrier. Transcriptome analysis suggested Vorinostat improved liver disease in a pleiotropic manner, not surprising given the epigenetic nature of HDACi at the gene expression level. Overall, the results herein are of particular importance to the current clinical trial where the therapeutic efficacy is being investigated without any knowledge of efficacy in an animal of NPC disease.</p>

scholarly journals Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives

2021 ◽  
Vol 22 (16) ◽  
pp. 8858
Author(s):  
Antonietta Bernardo ◽  
Chiara De Nuccio ◽  
Sergio Visentin ◽  
Alberto Martire ◽  
Luisa Minghetti ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Autophagic Flux ◽  
Unesterified Cholesterol ◽  
A2a Adenosine Receptor ◽  
Disease Mechanisms ◽  
Mitochondrial Functions ◽  
Type C ◽  
Niemann Pick ◽  
Cellular Compartments ◽  
The Brain

Niemann–Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, NPC1 and NPC2, coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane. The first trait of NPC is the accumulation of unesterified cholesterol and other lipids, like sphingosine and glycosphingolipids, in the late endosomal and lysosomal compartments, which causes the blockade of autophagic flux and the impairment of mitochondrial functions. In the brain, the main consequences of NPC are cerebellar neurodegeneration, neuroinflammation, and myelin defects. This review will focus on myelin defects and the pivotal importance of cholesterol for myelination and will offer an overview of the molecular targets and the pharmacological strategies so far proposed, or an object of clinical trials for NPC. Finally, it will summarize recent data on a new and promising pharmacological perspective involving A2A adenosine receptor stimulation in genetic and pharmacological NPC dysmyelination models.

scholarly journals In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease

Nanomaterials ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 802 ◽  
Author(s):  
Yuki Maeda ◽  
Keiichi Motoyama ◽  
Rena Nishiyama ◽  
Taishi Higashi ◽  
Risako Onodera ◽  
...  
Keyword(s):  
Free Cholesterol ◽  
Subcutaneous Administration ◽  
Safety Evaluation ◽  
Autosomal Recessive Disorder ◽  
Liver Cells ◽  
High Dose ◽  
Efficacy And Safety ◽  
Type C ◽  
Niemann Pick

Niemann-Pick type C disease (NPC) is a fatal, autosomal recessive disorder, which causes excessive accumulation of free cholesterol in endolysosomes, resulting in progressive hepatomegaly and neurodegeneration. Currently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) is used at a high dose for the treatment of NPC, risking lung toxicity and hearing loss during treatment. One method to reduce the required dose of HP-β-CyD for the treatment of hepatomegaly is to actively deliver β-cyclodextrin (β-CyD) to hepatocytes. Previously, we synthesized lactosyl-β-CyD (Lac-β-CyD) and demonstrated that it lowers cholesterol in NPC model liver cells. In the present study, we studied the efficacy and safety of Lac-β-CyD treatment of hepatomegaly in Npc1−/− mice. After subcutaneous administration, Lac-β-CyD accumulated in the liver and reduced hepatomegaly with greater efficacy than HP-β-CyD. In addition, subcutaneous administration of a very high dose of Lac-β-CyD was less toxic to the lungs than HP-β-CyD. Notably, the accumulation of intracellular free cholesterol in endolysosomes of NPC-like liver cells was significantly lower after administration of Lac-β-CyD than after treatment with HP-β-CyD. In conclusion, these results suggest that Lac-β-CyD is a candidate for the effective treatment of hepatomegaly in NPC.

scholarly journals Niemann-Pick Type C Disease and Intracellular Cholesterol Trafficking

2005 ◽  
Vol 280 (22) ◽  
pp. 20917-20920 ◽  
Author(s):  
Ta-Yuan Chang ◽  
Patrick C. Reid ◽  
Shigeki Sugii ◽  
Nobutaka Ohgami ◽  
Jonathan C. Cruz ◽  
...  
Keyword(s):  
Cholesterol Trafficking ◽  
Type C ◽  
Intracellular Cholesterol ◽  
Niemann Pick

scholarly journals ACAT1-associated Late Endosomes/Lysosomes Significantly Improve Impaired Intracellular Cholesterol Metabolism and the Survival of Niemann-Pick Type C Mice

2014 ◽  
Vol 47 (2) ◽  
pp. 35-43 ◽  
Author(s):  
Masashi Kamikawa ◽  
XiaoFeng Lei ◽  
Yukio Fujiwara ◽  
Kazuchika Nishitsuji ◽  
Hiroshi Mizuta ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Late Endosomes ◽  
Type C ◽  
Intracellular Cholesterol ◽  
Niemann Pick
Sign in / Sign up

Export Citation Format

Share Document