Changes in Bile Acid Concentrations in Chimeric Mice Transplanted with Different Replacement Indexes of Human Hepatocytes

Fujino, Chieri; Sanoh, Seigo; Tamura, Yuka; Ishida, Yuji; Tateno, Chise; Ohta, Shigeru; Kotake, Yaichiro

doi:10.1248/bpbreports.2.2_29

Cited by 2 publications

(4 citation statements)

References 24 publications

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“…Notably, an expanded bile acid pool size, increased liver/body weight ratio, and enlarged gall bladder were observed in chimeric mice, which were also true in the chimeric uPA/SCID mice (Birkenfeld & Shulman, 2014). Fujino et al (2019) also demonstrated a RI‐dependent increase of bile acid content in plasma. The dramatic expansion of bile acid pool in chimeric mice was believed to be partially caused by miscommunication between FGF15 (analog of FGF19 in human) secreted by mouse intestine and FGFR4 on human hepatocytes, which caused a failed inhibition of CYP7A1 expression, the rate‐limiting enzyme in the classical bile acid synthesis pathway, in human hepatocytes of the chimeric liver (Chow et al, 2017; Ellis et al, 2013).…”

Section: Basis For the Application Of Lhm In Metabolic Disordersmentioning

confidence: 92%

“…Tateno et al, 2013). Analysis of bile acid from the bile duct or gall bladder in LHM revealed the presence of human bile acids in the FRG (Ellis et al, 2013), FRGN (Chow et al, 2017), and uPA/SCID (Fujino et al, 2019) systems suggesting a functional bile acid system in LHM.…”

Section: Bile Duct Systemmentioning

confidence: 97%

“…In uPA‐SCID chimeric livers, bile canaliculi are observed between human hepatocytes and, in a rare condition, between human and mouse hepatocytes (Meuleman et al, 2005; C. Tateno et al, 2013). Analysis of bile acid from the bile duct or gall bladder in LHM revealed the presence of human bile acids in the FRG (Ellis et al, 2013), FRGN (Chow et al, 2017), and uPA/SCID (Fujino et al, 2019) systems suggesting a functional bile acid system in LHM.…”

Section: Basis For the Application Of Lhm In Metabolic Disordersmentioning

confidence: 99%

“…Human hepatocytes can also be isolated and purified for ex vivo studies evaluating novel therapies instead of expensive primate models preclinically (Lisowski et al, 2014;Paulk et al, 2018;Pekrun et al, 2019;Westhaus et al, 2020). They are also widely used in some liver-specific infectious diseases such as viral hepatitis and malaria (Allweiss et al, 2016;van de Garde et al, 2017;Giersch et al, 2014;Ishida et al, 2018;X. Li et al, 2019;Lütgehetmann et al, 2012;Mesalam et al, 2016;Morosan et al, 2006;Soulard et al, 2015;Tsuge et al, 2005).…”

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confidence: 99%

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Liver‐humanized mice: A translational strategy to study metabolic disorders

Luo

Peng

et al. 2021

Journal Cellular Physiology

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The liver is the metabolic core of the whole body. Tools commonly used to study the human liver metabolism include hepatocyte cell lines, primary human hepatocytes, and pluripotent stem cells-derived hepatocytes in vitro, and liver genetically humanized mouse model in vivo. However, none of these systems can mimic the human liver in physiological and pathological states satisfactorily. Liver-humanized mice, which are established by reconstituting mouse liver with human hepatocytes, have emerged as an attractive animal model to study drug metabolism and evaluate the therapeutic effect in "human liver" in vivo because the humanized livers greatly replicate enzymatic features of human hepatocytes. The application of liverhumanized mice in studying metabolic disorders is relatively less common due to the largely uncertain replication of metabolic profiles compared to humans. Here, we summarize the metabolic characteristics and current application of liver-humanized mouse models in metabolic disorders that have been reported in the literature, trying to evaluate the pros and cons of using liver-humanized mice as novel mouse models to study metabolic disorders.

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Section: Basis For the Application Of Lhm In Metabolic Disordersmentioning

confidence: 92%

Section: Bile Duct Systemmentioning

confidence: 97%

Section: Basis For the Application Of Lhm In Metabolic Disordersmentioning

confidence: 99%

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confidence: 99%

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Liver‐humanized mice: A translational strategy to study metabolic disorders

Luo

Peng

et al. 2021

Journal Cellular Physiology

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Changes in Bile Acid Concentrations after Administration of Ketoconazole or Rifampicin to Chimeric Mice with Humanized Liver

Sanoh

Tamura

Fujino

et al. 2019

Biological & Pharmaceutical Bulletin

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Drug-induced liver injury (DILI) is a common side effect of several medications and is considered a major factor responsible for the discontinuation of drugs during their development. Cholestasis is a DILI that results from impairment of bile acid transporters, such as the bile salt export pump (BSEP), leading to accumulation of bile acids. Both in vitro and in vivo studies are required to predict the risk of drug-induced cholestasis. In the present study, we used chimeric mice with humanized liver as a model to study druginduced cholestasis. Administration of a single dose of ketoconazole or rifampicin, known to potentially cause cholestasis by inhibiting BSEP, did not result in elevated levels of alkaline phosphatase (ALP), which are known hepatic biomarkers. The concentration of taurodeoxycholic acid increased in the liver after ketoconazole administration, whereas rifampicin resulted in increased tauromuricholic acid and taurocholic acid (TCA) levels in the liver and plasma. Furthermore, rifampicin resulted in an increase in the uniform distribution of a compound with m/z 514.3, presumed as TCA through imaging mass spectrometry. The mRNA levels of bile acid-related genes were also altered after treatment with ketoconazole or rifampicin. We believe these observations to be a part of a feedback mechanism to decrease bile acid concentrations. The changes in bile acid concentrations results may reflect the initial responses of the human body to cholestasis. Furthermore, these findings may contribute to the screening of drug candidates, thereby avoiding drug-induced cholestasis during clinical trials and drug development.

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Changes in Bile Acid Concentrations in Chimeric Mice Transplanted with Different Replacement Indexes of Human Hepatocytes

Cited by 2 publications

References 24 publications

Liver‐humanized mice: A translational strategy to study metabolic disorders

Liver‐humanized mice: A translational strategy to study metabolic disorders

Changes in Bile Acid Concentrations after Administration of Ketoconazole or Rifampicin to Chimeric Mice with Humanized Liver

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