title: Pioglitazone reduces lipid droplets in cholesterolosis of the gallbladder by increasing ABCA1 and NCEH1 expression.
abstract: As a cholesterol-induced metabolic disease, cholesterolosis of the gallbladder is often resected clinically, which could lead to many complications. The histopathology of cholesterolosis is due to excessive lipid droplet accumulation in epithelial and subcutaneous tissues. The main components of lipid droplets are cholesterol esters (CEs). Removal of CEs from gallbladder epithelial cells (GBECs) is very important for maintaining intracellular cholesterol homeostasis and for treating cholesterol-related diseases. In this study, pioglitazone was used to reduce intracellular CEs. To further elucidate the mechanism, cholesterolosis GBECs were treated with pioglitazone, 22-(R)-hydroxycholesterol (a liver X receptor α (LXRα) agonist), or peroxisome proliferator-activated receptor gamma (PPARγ) siRNA. Western blotting for PPARγ, LXRα, ATP-binding cassette transporter A1 (ABCA1), and neutral cholesteryl ester hydrolase 1 (NCEH1) was performed. At length, cholesterol efflux to apoA-I was measured, and oil red O staining was used to visualize lipid droplet variations in cells. In conclusion, we observed that pioglitazone increased ABCA1 expression in an LXR-dependent manner and NCEH1 expression in an LXRα-independent manner, which mobilized CE hydrolysis and cholesterol efflux to reduce lipid droplet content in cholesterolosis GBECs. Our data provide a plausible alternative to human gallbladder cholesterolosis.
authors.affiliation: Department of General Surgery, Institute for Minimally Invasive Surgery, Zhongda Hospital Southeast University, Medical School of Southeast University, 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu, China, wjm730222@163.com.
authors.forename: Jing-Min
authors.initials: JM
authors.lastname: Wang
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Yu-Yan
authors.initials: YY
authors.lastname: Tan
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Zhen-Ling
authors.initials: ZL
authors.lastname: Ji
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005704:Gallbladder / Q000187:drug effects / Q000378:metabolism; D005705:Gallbladder Diseases / Q000188:drug therapy*; D006801:Humans; D066292:Lipid Droplets / Q000187:drug effects*; D052439:Lipid Metabolism Disorders / Q000188:drug therapy*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D000077205:Pioglitazone; D002787:Sterol Esterase; D045162:Thiazolidinediones / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D045162:Thiazolidinediones; D002265:Carboxylic Ester Hydrolases; C515677:NCEH1 protein, human; D002787:Sterol Esterase; D000077205:Pioglitazone