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.
Highlights
Bisphenol A (BPA), an commonly exposed environmental chemicals in humans, has been shown to have a hypercholesterolemic effect with molecular mechanism not clear
Absorption of cholesterol in Caco-2 cells was mediated by Niemann-Pick C1-like 1 (NPC1L1) Because the cholesterol absorption in intestine was mediated by NPC1L1 and ezetimibe is a specific inhibitor for NPC1L1, we first examined whether the Caco-2 cells express NPC1L1 and whether cholesterol absorption in Caco-2 cells under the experimental conditions was related to the functions of NPC1L1
BPA promoted cholesterol absorption in Caco-2 cells We addressed a question whether BPA can promote cholesterol absorption
Summary
Bisphenol A (BPA), an commonly exposed environmental chemicals in humans, has been shown to have a hypercholesterolemic effect with molecular mechanism not clear. 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. The absorption of cholesterol from the intestine is an important determinant of plasma cholesterol levels [3], those individuals with high absorption rates are hypercholesterolemic and generally have an increased number of cardiovascular events [4]. Cholesterol absorption in intestine is a multi-step process and this process is mediated by a specific membrane protein named Niemann-Pick C1-like 1 (NPC1L1) protein [6], which can be inhibited by ezetimibe [7]. NPC1L1 has been recently identified as a novel target gene of sterol regulatory element binding protein-2 (SREBP-2) [9]. There are two putative sterol regulatory elements in the human NPC1L1 promoter and they are essential for mediating the effects of cholesterol on promoter activity [9]
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