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    • The small intestine is the only organ

    2021-05-10

    The small intestine is the only organ responsible for the L-Cysteinesulfinic acid australia of dietary and biliary cholesterol, leaving the unabsorbed cholesterol to be excreted in feces and together contributing to the body cholesterol homeostasis [13], [21], [33], [34]. Following intraluminal hydrolysis, free cholesterol is first incorporated into micelles and then transported across the ‘unstirred’ water layer to the brush border membrane of small intestine. This process has been demonstrated to be essential for the intestinal cholesterol absorption [15]. Thus, cholesterol micellarization assays have been developed and used, together with other methods, to study cholesterol absorption [35], particularly a product or compound that potentially disrupts cholesterol solubilisation in micelles [27]. It is well documented that plant stanols/sterols inhibit cholesterol absorption by interfering with cholesterol incorporation into micelles [13], [35], [36]. Therefore, in the present study we used plant stanols as a positive control to validate the cholesterol micellarization assay, which was further used to assess the effect of BBR. It was found that in the presence of BBR, the content of cholesterol in micelles was significantly decreased. This effect could be explained by the physical–chemical properties of BBR molecule. With both hydrophobic and hydrophilic binding sites, BBR can interact with the corresponding molecules of micelles. The bindings of BBR to hydrophobic and hydrophilic molecules of micelles lead to the formation of agglomerates and subsequently reduce the capacity of micelles to incorporate cholesterol [37], [38]. This property has in return been used in recent years to improve the bioavailability of BBR in mice and rats by mixing BBR in different emulsions or other similar solutions [39], [40]. Micellar size may affect the diffusion rate of micelles through the unstirred water layer and thus cholesterol absorption [41]. This potential effect was not measured in the present study. Once delivered to the epithelium of the small intestine, free cholesterol penetrates into the enterocytes from the apical side, esterified, and then secreted out from the basolateral side into the lymphatic system, further into the blood stream and ultimately delivered to the liver. The uptake of cholesterol by enterocyte is determined by the passive penetration and active transport, in addition to the availability of cholesterol to the brush border membrane as mentioned above. In the in vitro assay, disruption of cholesterol micellarization less likely occurred as micelles were not used, but instead cholesterol was dissolved in small quantity of ethanol and then mixed in the culture medium. In addition, there was not an unstirred water layer surrounding the cultured Caco-2 cells. The sterol transporters NPC1L1 and ABCG5/8 are not involved in the cholesterol-lowering effect of BBR in hamsters [5]. Thus, the reduction of cholesterol uptake in Caco-2 cells by BBR might be a result of interference with the passive penetration and/or the effect on other sterol transporters and proteins involved in the intraluminal cholesterol influx and efflux. Similar to the effect on micelles, the dual binding properties of BBR could interact with molecules on the enterocyte membranes, resulting in a change of cell membrane properties. This in turn reduced its permeability, leading to a decrease of cholesterol uptake. However, further experiments are warranted to determine how BBR affects cholesterol uptake in the enterocyte. Following uptake into the enterocyte, the re-esterification of free cholesterol becomes a key step because cholesterol is secreted out from the basolateral side in a form of esters [18]. This step is catalyzed by ACAT. Several studies have shown that inhibition of ACAT expression decreases cholesterol absorption and plasma cholesterol levels [18], [42]. In mammals, two ACAT genes have been identified, which are referred to ACAT1 and ACAT2 [18]. ACAT1 is a ubiquitous protein and functions in converting cellular cholesterol into cholesteryl ester in response to intracellular cholesterol abundance. ACAT2 is expressed only in hepatocytes and enterocytes and appears to provide cholesteryl esters for transport in lipoproteins. In line with their differential functions, the deletion of ACAT2 is consistently atheroprotective whereas deletion of ACAT1 is varyingly problematic [43], [44], [45]. BBR decreased ACAT2 protein expression while having no effect on ACAT1. Further experiments demonstrated that BBR decreased ACAT2 protein expression by downregulating its gene transcription. These results suggest that BBR might be an ACAT2 specific inhibitor in the enterocyte.