Abstract
Fibroblast growth factor 15/19 (FGF15/19) are endocrine growth factors that play an important role in bile acid homeostasis. FGF15/19 based therapies are currently being tested in clinical trials for the treatment of non-alcoholic steatohepatitis and cholestatic liver diseases. To determine the physiological impact of long-term elevations of FGF15/19, we developed a transgenic mouse model to overexpress Fgf15 (Fgf15 Tg). In the current study, RNA-seq analysis revealed elevations of the expression of several genes encoding phase I drug metabolizing enzymes, 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 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 drug metabolizing enzyme expression. Interestingly, we found that the overexpression of Fgf15 resulted in a phenotypical switch from a male hepatic expression pattern of drug metabolizing enzymes in wild type mice to a female expression pattern in Fgf15 Tg mice. Growth hormone differences between males and females is known to drive sexually dimorphic expression patterns in the livers of rodents in a STAT5b dependent manner. We found that male Fgf15 Tg mice presented with many features similar to wild type female mice, 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.
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