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dc.contributor.authorRizzolo, Daniel
dc.contributor.authorKong, Bo
dc.contributor.authorPiekos, Stephanie
dc.contributor.authorChen, Liming
dc.contributor.authorZhong, Xiaobo
dc.contributor.authorLu, Jie
dc.contributor.authorShi, Jian
dc.contributor.authorZhu, Hao-Jie
dc.contributor.authorYang, Qian
dc.contributor.authorLi, Albert
dc.contributor.authorLi, Linhao
dc.contributor.authorWang, Hongbing
dc.contributor.authorSiemiątkowska, Anna
dc.contributor.authorPark, Celine
dc.contributor.authorKagan, Leonid
dc.contributor.authorGuo, Grace L
dc.date.accessioned2022-04-27T12:34:36Z
dc.date.available2022-04-27T12:34:36Z
dc.date.issued2021-12-29
dc.identifier.urihttp://hdl.handle.net/10713/18677
dc.description.abstractFibroblast 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.en_US
dc.description.urihttps://doi.org/10.1124/dmd.121.000416en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics (ASPET)en_US
dc.relation.ispartofDrug Metabolism and Disposition: the Biological Fate of Chemicalsen_US
dc.rightsU.S. Government work not protected by U.S. copyright.en_US
dc.titleEffects of Overexpression of Fibroblast Growth Factor 15/19 on Hepatic Drug Metabolizing Enzymes.en_US
dc.typeArticleen_US
dc.identifier.doi10.1124/dmd.121.000416
dc.identifier.pmid34965924
dc.source.journaltitleDrug metabolism and disposition: the biological fate of chemicals
dc.source.volume50
dc.source.issue4
dc.source.beginpage468
dc.source.endpage477
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States


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