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  • In BBR was reported to increase

    2019-09-10

    In 2004, BBR was reported to increase LDL receptor (LDLR) gene expression by stabilizing LDLR mRNA [4]. Following this report, the same groups conducted additional studies predominantly in HepG2 cells, with similar effects being observed [8], [11], [12], [4]. In addition to LDLR-mediated LDL cholesterol clearance in the liver, several other mechanisms are involved in cholesterol homeostasis, including cholesterol absorption, cholesterol biosynthesis, cholesterol secretion, bile acid synthesis and secretion. Nevertheless, the effects of BBR on these processes have not been reported. Amongst these metabolic pathways, cholesterol b catenin inhibitor plays a very important role [13], [14]. It is well-known that cholesterol absorption is collectively controlled by multiple factors or processes in the small intestine. These factors include cholesterol micellarization in the intestinal lumen [15], the expression of sterol transporters [5], [16], [17], cholesterol uptake, and the expression and activity of enzymes that catalyze the esterification of free cholesterol in the enterocytes [18]. Cholesterol micellarization determines the amount of cholesterol that can be transported across the ‘unstirred’ water layer to the apical side of enterocytes for absorption [15]. Cholesterol is then taken up by the enterocytes. Apart from the passive penetration, cholesterol uptake by enterocyte also involves the active transport through sterol transporters such as Niemann-Pick C1 Like 1 (NPC1L1) [19] and ATP-binding cassette, subfamily G, member 5 (ABCG5) and 8 (ABCG8) [20], [21]. The expression of these transporters, together with passive penetration, mediates the dynamic flux of cholesterol at the apical side membrane of the enterocytes and thus the net amount of cholesterol that is taken up by the enterocytes. Prior to absorption, cholesterol esters of dietary and biliary sources are hydrolyzed to free cholesterol, which is the predominant form being absorbed into the enterocytes. Nevertheless, after entering the enterocytes free cholesterol needs to be converted back to esters because cholesterol is secreted out predominantly as ester form from the basolateral side membrane of enterocytes into the lymphatics and then the general circulation, and ultimately to be delivered to the liver. This step is catalyzed by acetyl-coenzyme A cholesterol acyltransferase (ACAT), primarily the ACAT2 isoform [18], [22]. Our previous study showed that BBR lowered blood cholesterol through a mechanism that is independent of the expression of sterol transporters NPC1L1, ABCG5, and ABCG8 [5]. Therefore, in the present study we investigated the mechanism of action of BBR on cholesterol metabolism in diet-induced hypercholesterolemic rats with a primary focus on the intestinal absorption and further on cholesterol micellization prior to absorption and the apical side uptake and basolateral side secretion of the enterocytes during the absorption.
    Materials and Methods
    Results
    Discussion Rats have a low cholesterol absorption rate compared to humans. Thus, the inclusion of cholic acid in a cholesterol diet has been widely used to improve cholesterol absorption and induce hypercholesterolemia in rats for studying human cholesterol metabolism [29], [30], [31]. In agreement with these previous reports, rats fed the diet without cholic acid had a very low cholesterol absorption rate, approximately 16%. When 0.5% cholic acid was added to the diet, cholesterol absorption rate was increased to about 60%, becoming close to that in humans and hamsters [13], [26]. More importantly, the cholesterol profiles of rats without supplementation of cholic acid were quite different from that of humans and by contrast became similar when cholic acid was provided [13]. Using this rat model, we demonstrated that BBR significantly inhibited the intestinal cholesterol absorption, leading to the large decreases of plasma total and nonHDL cholesterol levels. An indirect support has been provided by a recent study showing that BBR promoted the excretion of neutral sterols [32]. Strong correlations between cholesterol absorption rates and plasma total or nonHDL cholesterol levels provide further support that BBR lowered blood cholesterol levels through inhibiting the intestinal absorption. This is another mechanism that is distinct from the previously reported enhancement of LDLR-mediated liver LDL-C clearance [4].