Tion represses CD36 expression, remains to become investigated. Recent reports recommend that FXR activation reduces CD36 expression within the murine liver and in macrophages [32,33]. Besides activating gene expression, FXR can also directly act as a transcriptional repressor. For example, hepatic lipase and apoA-I, which are both relevant to HDL metabolism, are repressed by FXR [34,35]. When SR-BI levels had been strongly reduced in HepG2 cells, there was still considerable residual HDL cell association apparent (examine Figs. 4 and six). Other receptors for instance the low affinity binding web page below the handle of F1-ATPase/P2Y13 also as CD36 could possibly account for this residual activity. In line, SR-BI does not appear to be the significant factor determining hepatic HDL endocytosis [6,10]. In contrast, SR-BI may be the key receptor mediating selective lipid uptake from HDL. Our final results show that SR-BI expression is unaltered immediately after FXR activation (Fig. six). Current research report that FXR activates SR-BI expression [24,25,36]. Nevertheless, it was also discovered that FXR activation represses SR-BI by a mechanism comparable for the repression for Cyp7a1 [26].The motives for these discrepancies stay unknown. As a result of unaltered SR-BI expression after CDCA or GW4064 therapy in our experiments, cholesteryl-ester uptake from HDL was unchanged. This resulted in a rise of calculated selective uptake, due to the fact HDL particle association was decreased (Fig. 6). Altogether, our data have implications for the connection involving HDL endocytosis and selective uptake. When HDL uptake in HepG2 cells was decreased either by extracellular or transcriptional mechanisms, no concomitant reduction in cholesteryl-ester uptake was observed. In contrast, selective CE uptake seemed to be differentially regulated. HDL endocytic trafficking is accompanied by lipid exchange [5,37]. Furthermore, pharmacological interference with HDL endocytosis resulted in induced flux of HDL cholesterol from the p38 MAPK Inhibitor manufacturer plasma towards the liver and enhanced biliary cholesterol secretion [38]. Nevertheless, HDL endocytosis is no prerequisite for selective lipid uptake: liposomes containing purified SR-BI take up CE efficiently [39]. Furthermore, distinctive experimental approaches to block HDL endocytosis don’t affect selective uptake [40,41]. Consistently, our data presented right here suggest that HDL endocytosis and selective CE uptake are usually not necessarily linked with every other. Indeed, in-vivo research recommend that bile acids boost selective lipid uptake, thereby enhancing the clearance of HDL cholesterol in the plasma. Bile acid feeding lowers HDL cholesterol in mice [42]. Regularly, GW4064 administration decreases HDL cholesterol in mice [36] as well as the synthetic FXR agonist PX 20606 decreased plasma HDL levels in cynomolgus monkeys [43]. In contrast, FXR knockout mice have improved HDL cholesterol levels [23]. Taken collectively, our final results indicate that bile acids lessen HDL endocytosis by transcriptional and CDK1 drug non-transcriptional mechanisms. Nevertheless, reduced HDL endocytosis just isn’t accompanied by reduced cholesteryl-ester transfer.AcknowledgmentsWe thank Dr. Michael Trauner and Dr. Monika Strobl for helpful scientific discussion. We’re grateful to Jelena Brankovic for excellent technical help.Author ContributionsConceived and designed the experiments: CR HS. Performed the experiments: CR KE SF. Analyzed the data: CR KE SF HS. Wrote the paper: CR SF HS.
Int. J. Mol. Sci. 2013, 14, 21647-21659; doi:ten.3390/ijmsOPEN ACCESSInternational Jo.