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    Effects of Overexpression of Fibroblast Growth Factor 15/19 on Hepatic Drug Metabolizing Enzymes.

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    Author
    Rizzolo, Daniel
    Kong, Bo
    Piekos, Stephanie
    Chen, Liming
    Zhong, Xiaobo
    Lu, Jie
    Shi, Jian
    Zhu, Hao-Jie
    Yang, Qian
    Li, Albert
    Li, Linhao
    Wang, Hongbing
    Siemiątkowska, Anna
    Park, Celine
    Kagan, Leonid
    Guo, Grace L
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    Date
    2021-12-29
    Journal
    Drug Metabolism and Disposition: the Biological Fate of Chemicals
    Publisher
    American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1124/dmd.121.000416
    Abstract
    Fibroblast growth factors 15 (FGF15) and 19 (FGF19) are endocrine growth factors that play an important role in maintaining bile acid homeostasis. FGF15/19-based therapies are currently being tested in clinical trials for the treatment of nonalcoholic steatohepatitis and cholestatic liver diseases. To determine the physiologic impact of long-term elevations of FGF15/19, a transgenic mouse model with overexpression of Fgf15 (Fgf15 Tg) was used in the current study. The RNA sequencing (RNA-seq) analysis revealed elevations of the expression of several genes encoding phase I drug metabolizing enzymes (DMEs), including Cyp2b10 and Cyp3a11, in Fgf15 Tg mice. We found that the induction of several Cyp2b isoforms resulted in increased function of CYP2B in microsomal metabolism and pharmacokinetics studies. Because the CYP2B family is known to be induced by constitutive androstane receptor (CAR), to determine the role of CAR in the observed inductions, we crossed Fgf15 Tg mice with CAR knockout mice and found that CAR played a minor role in the observed alterations in DME expression. Interestingly, we found that the overexpression of Fgf15 in male mice resulted in a phenotypical switch from the male hepatic expression pattern of DMEs to that of female mice. Differences in secretion of growth hormone (GH) between male and female mice are known to drive sexually dimorphic, STAT5b-dependent expression patterns of hepatic genes. We found that male Fgf15 Tg mice presented with many features similar to GH deficiency, including lowered body length and weight, Igf-1 and Igfals expression, and STAT5 signaling. SIGNIFICANCE STATEMENT: The overexpression of Fgf15 in mice causes an alteration in DMEs at the mRNA, protein, and functional levels, which is not entirely due to CAR activation but associated with lower GH signaling.
    Rights/Terms
    U.S. Government work not protected by U.S. copyright.
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/18677
    ae974a485f413a2113503eed53cd6c53
    10.1124/dmd.121.000416
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