Bisphenol A promotes cholesterol absorption in Caco-2 cells by up-regulation of NPC1L1 expression

Abstract

BackgroundBisphenol A (BPA), an commonly exposed environmental chemicals in humans, has been shown to have a hypercholesterolemic effect with molecular mechanism not clear. Since intestinal cholesterol absorption plays a major role in maintaining total body cholesterol homeostasis, the present study is to investigate whether BPA affects cholesterol absorption in the intestinal Caco-2 cells. Methods: The Caco-2 cells were pretreated with BPA at different concentrations for 24 h and then incubated with radioactive micellar cholesterol for 2 h. The absorption of radioactive cholesterol was quantified by liquid scintillation. The expression of Niemann-Pick C1-like 1 (NPC1L1) and sterol regulatory element binding protein-2 (SREBP-2) was analyzed by Western blot and qPCR.ResultsWe found that confluent Caco-2 cells expressed NPC1L1, and the absorption of cholesterol in the cells was inhibited by ezetimibe, a specific inhibitor of NPC1L1. We then pretreated the cells with 0.1–10 nM BPA for 24 h and found that BPA at 1 and 10 nM doses promoted cholesterol absorption. In addition, we found that the BPA-induced promotion of cholesterol absorption was associated with significant increase in the levels of NPC1L1 protein and NPC1L1 mRNA. Moreover, the stimulatory effects of BPA on cholesterol absorption and NPC1L1 expression could be prevented by blockade of the SREBP-2 pathway.ConclusionsThis study provides the first evidence that BPA promotes cholesterol absorption in the intestinal cells and the stimulatory effect of BPA is mediated, at least in part, by SREBP-2-NPC1L1 signaling pathway.

Broccoli Florets Supplementation Improves Insulin Sensitivity and Alters Gut Microbiome Population—A Steatosis Mice Model Induced by High-Fat Diet

“…Although not tested, several explanations may account for this phenomenon, including that HFD consumption induced increased hepatic TG clearance and/or decreased hepatic TG export. Similarly, increased HDL blood levels, following the consumption of an HFD, was also previously observed ( 29 , 30 ). Nevertheless, HDL levels are not indicators reliable for functionality of this lipoprotein nor the individual atherogenic risk ( 31 ).…”

Hydroxycinnamic acid derivatives effect on hypercholesterolemia, comparison with ezetimibe: Permeability assays and FTIR spectroscopy on Caco-2 ​cell line

“…For instance, cholesterol absorption in intestine is a multi-step process mediated by specific membrane proteins. The reduction in the permeation of cholesterol can be associated with the regulation of mRNA levels of Niemann-Pick Like 1 protein (NPC1L1) that promotes the transport of cholesterol inside the cells as well as ATP-binding cassette (ABC) proteins such as ABCG5 and ABCG8 which are cholesterol efflux transporters ( Brown and Yu, 2009 ; Feng et al., 2017 ; Jia et al., 2011 ).…”

“…Thus, transporter proteins expression and their activity is regulated by transcriptional as well as post-transcriptional mechanisms. For instance, it is known that EZ, drug used to treat hypercholesterolemia, inhibits Niemann-Pick C1-like 1 (NPC1L1) and mediates cellular cholesterol uptake ( Feng et al., 2017 ; Nakano et al., 2020 ). Furthermore, in the intestine, Liver X Receptors LXRs limits cholesterol absorption by downregulating NPC1L1 ( Duval et al., 2006 ).…”

Current Aspect of Bisphenol A Toxicology and Its Health Effects

“…It has been reported that BPA enhances hepatic cholesterol biosynthesis via increased expression of sterol regulatory element-binding protein 2, which is a key regulator in cholesterol biosynthesis. BPA also promotes cholesterol absorption in the intestinal cells [50,56]. Recent epidemiological and animal studies have suggested that BPA is involved in the development of obesity, type 2 diabetes, and cardiovascular diseases.…”