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Comparison of the hepatic effects of phenobarbital in chimeric mice containing either rat or human hepatocytes with humanized constitutive androstane receptor (CAR) and pregnane X receptor (PXR) mice (hCAR/hPXR mice) [chimeric humanized liver experiments]

ABSTRACT: Comparison of the hepatic effects of phenobarbital in chimeric mice containing either rat or human hepatocytes with humanized constitutive androstane receptor (CAR) and pregnane X receptor (PXR) mice (hCAR/hPXR mice) [chimeric humanized liver experiments]

PROVIDER: PRJNA627702 | ENA |

REPOSITORIES: ENA

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Comparison of the hepatic effects of phenobarbital in chimeric mice containing either rat or human hepatocytes with humanized constitutive androstane receptor (CAR) and pregnane X receptor (PXR) mice (hCAR/hPXR mice) [chimeric humanized liver experiments]

Project description:Using a chimeric mouse humanized liver model, we provided evidence that human hepatocytes are refractory to the mitogenic effects of rodent constitutive androstane receptor (CAR) activators. To evaluate the functional reliability of this model, the present study examined mitogenic responses to phenobarbital (PB) in chimeric mice transplanted with rat hepatocytes, since rats are responsive to CAR activators. Treatment with 1000 ppm PB for 7 days significantly increased replicative DNA synthesis (RDS) in rat hepatocytes of the chimeric mice, demonstrating that the transplanted hepatocyte model is functionally reliable for cell proliferation analysis. Treatment of humanized CAR and pregnane X receptor (PXR) mice (hCAR/hPXR mice) with 1000 ppm PB for 7 days significantly increased hepatocyte RDS together with increases in several mitogenic genes. Global gene expression analysis was performed with liver samples from this and from previous studies focusing on PB-induced Wnt/β-catenin signaling, and showed that altered genes in hCAR/hPXR mice clustered most closely with liver tumor samples from a diethylnitrosamine/PB initiation/promotion study than with wild type mice. However, different gene clusters were observed for chimeric mice with human hepatocytes for Wnt/ß-catenin signaling when compared to those of hCAR/hPXR mice, wild type mice and liver tumor samples. The results of this study demonstrate clear differences in the effects of PB on hepatocyte RDS and global gene expression between human hepatocytes of chimeric mice and hCAR/hPXR mice, suggesting that the chimeric mouse model is relevant to humans for studies on the hepatic effects of rodent CAR activators, whereas the hCAR/hPXR mouse is not.

2021-04-20 | GSE149228 | GEO

2021-04-20 | GSE149230 | GEO

2021-04-20 | GSE149229 | GEO

Project description:Comparison of the hepatic effects of phenobarbital in chimeric mice containing either rat or human hepatocytes with humanized constitutive androstane receptor (CAR) and pregnane X receptor (PXR) mice (hCAR/hPXR mice) [rat liver experiments]

| PRJNA627700 | ENA

| PRJNA627701 | ENA

Omics analyses of mouse constitutive androstane receptor (CAR) ligand TCPOBOP effects in humanized mice reveal off-target lipid metabolism disruption

Project description:In this study, we compared the metabolic effects of TCPOBOP using lipidomic, transcriptomic, and proteomic analyzes in wild-type and humanized CAR-PXR-CYP3A4/3A7 mice. In the humanized mouse model, human CAR retains its constitutive activity in metabolism regulation; however, it is not significantly activated by TCPOBOB. TCPOBOP elevated serum and liver levels of triglycerides and promoted hepatocyte hypertrophy in humanized CAR mice. Hepatic lipidomic analysis revealed a significant accumulation of triglycerides and downregulation of its metabolites in humanized CAR mice. RNA-seq analysis has shown gene expression changes mainly involved in lipid metabolic processes and in ppar, leptine, thyroid, and circadian clock pathways. In summary, we identify TCPOBOP as a lipid metabolism disruptor in humanized CAR mice

2022-01-31 | GSE186654 | GEO

Identifying Human Specific Adverse Outcome Pathways of Per- and Polyfluoroalkyl Substances Using Liver-Chimeric Humanized Mice

Project description:We investigated the effects of per- and polyfluroralkyl substance exposure on FRG liver-chimeric humanized mice on a C57Bl/6 background. These PFAS included PFOA, PFOS, and GenX. These mice were exposed to water ad libitum for 28 days to reach human relevant serum concentrations. We then performed RNA-Sequencing on isolated whole liver lysate to determine differentially expressed genes.

2023-07-14 | GSE208636 | GEO

Gene expression of human hepatocytes isolated from chimeric mice with humanized liver

Project description:Gene expression of human hepatocytes isolated from chimeric mice with humanized liver

| PRJNA641946 | ENA

Gene expression of human hepatocytes isolated from chimeric mice with humanized liver

Project description:Chimeric mice with humanized livers are considered a useful animal model for predicting human drug metabolism and toxicity. In this study, the characteristics of fresh h-hepatocytes (cFHHs, PXB-cells®) isolated from chimeric mice (PXB-mice®) were evaluated in vitro to confirm their utility for drug development. The cFHHs cultured at high density (2.13 × 10^5 cells/cm2) displayed stable production of human albumin and cytochrome P450 (CYP) 3A activities for at least 21 days. The mRNA expression levels of 10 of 13 CYPs, UDP-glucuronosyltransferase (UGP), and transporters were maintained at >10% of the levels of freshly isolated cFHHs after 21 days. From 7-days cultured cFHHs at high density, many bile canaliculi were observed between cFHHs, and the accumulation of multidrug resistance-associated protein (MRP2) and bile salt export pump (BSEP) substrates in these bile canaliculi was clearly inhibited by cyclosporin A. We used microarrays to elucidate global gene expressions underlying this higher hepatic functions of high density cultured cFHHs (PXB-cells). Microarray analysis revealed that high density cultured cFHHs maintained high expressions of some transcription factors (HNF4α, PXR, and FXR) perhaps involved in the high CYP, UGT and transporter gene expressions of cFHHs.

2020-08-07 | GSE153298 | GEO

Hepatic gene expression in various different lots of chimeric mice with highly humanized liver

Project description:In addition to immunodeficiency, host mice for chimeric mice with highly humanized liver should have hepatic malfunction in order to allow higher replacement rate of human hepatocytes in the liver. Urokinase-type plasminogen activator (uPA) whole gene transfer is often employed to achieve hepatic malfunction in the host mice. We have established uPA cDNA transfer that is far stable, as compared with traditional whole uPA gene transfer. Hepatic gene expression was quite similar between whole uPA gene transfer and uPA cDNA transfer after transplantation of the same lot of human hepatocyte (BD195),, as compared with the variation of gene expression after transplantation of different lots of human hepatocytes to host mice with whole uPA gene transfer.

2015-06-17 | GSE69936 | GEO

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