Hepatocytes. We observe a 57fold enhance inside the RNA levels from the ratelimiting enzyme CYP7A1 in human hepatocytes in humanized mice as when compared with regular human hepatocytes. We speculate that this can be because of abnormal FGF signaling involving murine intestine and human liver cells. Consequently, FGF19 was administered (s.q) in single or repeated injections and human (h) CYP7A expression and bile acids production was examined. As expected, FGF19 injection was sensed by the human hepatocytes and led to a dramatic reduce in each hCYP7A expression and bile acid production within the animals, confirming the hypothesis that lack of FGF19 result in an increased hCYP7A expression and bile acid production. The constructive response in human hepatocytes to FGF19 administration confirms that the human hepatocytes inside the mouse liver respond to the species appropriate FGF using the anticipated outcome of suppression of CYP7A and bile acid production. This humanized FRG model offers a uniqueopportunity to examine human relevant modulation of bile acid production, in vivo. The bile acid concentration in gallbladder bile was decreased following injection of FGF19 in each repopulated and control mice. The concentration of DCA was reduce following injection of FGF19 in humanized mice whereas omega muricholic acid increased following administration in nontransplanted FRG mice. In repopulated mice injection of FGF19 results in repression in addition to a normalization of hCYP7A1. hCYP8B1 was also repressed whereas hCYP27A1 was not altered. However, hSHP expression didn’t boost following FGF19 injection, in fact it decreased. Holt et al. [27] recommended that FGF19 represses CYP7A1 via a SHP independent mechanism. We previously reported that treatment with bile acids or FGF19 substantially enhanced SHP protein stability in cultured human hepatocytes or mice in vivo [28]. For that reason, the role of SHP in the regulation of CYP7A1 by FGF19 remains unclear. Our research confirm prior studies that FGF19 down regulates mouse cyp7a1, in each handle mice and humanized mice [27].Price of 1-(oxolan-3-yl)ethan-1-one Interestingly, mouse Shp was down regulated by infusion of FGF19 in FRG controls, but not in repopulated FRG mice, however levels are currently low inside the repopulated mice and there was no additional down regulation by FGF19 injection.(4-(3-Hydroxypropyl)phenyl)boronic acid Data Sheet 1 doable explanation for this may be that human hepatocytes subjected to high levels of bile acids within the FRG mouse express and secrete FGF19 inside a paracrine manner and it has been suggested that human hepatocytes may contribute to the circulating FGF19 levels found in humans [29].PMID:33618025 Nevertheless, due to restricted amounts of serum accessible from these mice, analysis of circulating FGF19 levels could not be completed in the present research.ConclusionIn this report we demonstrate that FRG mice repopulated with main human hepatocytes display a serum lipoprotein profilePLOS 1 | www.plosone.orgLipoprotein Profiles in Mice with Humanized LiversFigure 3. Expression of human RNA. A, Expression of human CYP7A1 in humanized FRG mice (TxFRG) treated with FGF19 (TxFRGFGF19) in comparison to human handle. Statistics have been performed by a nonparametric KruskalWallis ANOVA. The general significance with the experiment was p,0.05. Expression of human CYP8B1 (B), CYP27A1(C), FXR (D) and SHP (E) in livers of humanized mice (TxFRG) treated with FGF19 (TxFRGFGF19). Human liver RNA was applied for reference (n = 9). doi:10.1371/journal.pone.0078550.gPLOS One | www.plosone.orgLipoprotein Profiles in Mice with Humani.
