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.

LingguizhuganDecoction Protects against High-Fat-Diet-Induced Nonalcoholic Fatty Liver Disease by Alleviating Oxidative Stress and Activating Cholesterol Secretion

“…ABCG5 and ABCG8 are two half-transporters that dimerize to create a cholesterol transporter, and their activation promotes the excretion of hepatic cholesterol [ 42 ]. In addition, NCEH1 , ABCG5 , and ABCG8 are reported to be drug targets of pioglitazone [ 43 ] and ezetimibe [ 42 ] in the therapy of human gallbladder cholesterolosis and HFD-induced fatty liver.…”

High density lipoprotein as a therapeutic target: Focus on its functionality

“…On the contrary, in another study, PPAR-γ stimulation by pioglitazone reduced ABCA1 expression in macrophages (Jiang and Li, 2017). In another study, pioglitazone stimulated cholesterol efflux and ABCA1 expression in gallbladder epithelial cells (Wang et al, 2015). In summary, the effect of pioglitazone on cholesterol efflux would depend on the type of cell and pathway involved.…”

Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment

“…Thiazolidinediones are probably the most well-known and widely used PPARg agonists, due to their antidiabetic properties. Thiazolidinediones, including pioglitazone, ciglitazone, and rosiglitazone, enhanced LXRa expression, which subsequently induced ABCA1 protein expression and cholesterol efflux toward apoA-I in vitro (Chawla et al, 2001;Chinetti et al, 2001;Claudel et al, 2001;Cabrero et al, 2003;Li et al, , 2015Llaverias et al, 2006;Panzenboeck et al, 2006;Nakaya et al, 2007;Lee et al, 2008;Tanabe et al, 2008;Ogata et al, 2009;Cocks et al, 2010;Ozasa et al, 2011;Wang et al, 2014bWang et al, , 2015bJiang and Li, 2017) (Table 2). Contradictory to these results with pioglitazone in THP-1 macrophages and J774 macrophages, an attenuated or unaffected ABCA1 expression was found in peritoneal macrophages isolated from 15PGJ2-, troglitazone-, and pioglitazonetreated C57BL/6 mice, and in the liver of pioglitazonetreated LDLR 2/2 C57BL/6 mice (Ruan et al, 2003;Ogata et al, 2009;Ozasa et al, 2011;Zhao et al, 2015;Jiang and Li, 2017;Silva et al, 2018).…”