Induction of fibroblast growth factor 21 does not require activation of the hepatic X-box binding protein 1 in mice

Shantel Olivares, Anne S. Henkel

Fibroblast growth factor 21 (FGF21) has emerged as a key regulator of the metabolic response to fasting. Endoplasmic reticulum (ER) stress is a well-established inducer of hepatic FGF21 expression. X-box binding protein 1 (XBP1) has been strongly implicated in regulating hepatic lipid and glucose metabolism, making it an intriguing candidate for mediating the effect of ER stress on FGF21 expression. To directly determine whether hepatic Xbp1 is required for induction of hepatic Fgf21 in vivo, Olivares and Henkel subjected mice bearing a hepatocyte-specific deletion of Xbp1 to fasting, a ketogenic diet, or pharmacologic ER stress, all potent stimuli of Fgf21 expression. By this, they provide definitive evidence that hepatic Xbp1 is not required for induction of hepatic Fgf21.

Objective: Fibroblast growth factor 21 (FGF21), a key regulator of the metabolic response to fasting, is highly induced by endoplasmic reticulum (ER) stress. The X-box binding protein 1 (Xbp1) is one of several ER stress proteins that has been shown to directly activate the FGF21 promoter. We aimed to determine whether hepatic Xbp1 is required for induction of hepatic FGF21 in vivo.

Methods: Mice bearing a hepatocyte-specific deletion of Xbp1 (Xbp1LKO) were subjected to fasting, pharmacologic ER stress, or a ketogenic diet, all potent stimuli of Fgf21 expression.

Results: Hepatocyte-specific Xbp1 knockout mice demonstrated normal induction of FGF21 in response to fasting or pharmacologic ER stress and enhanced induction of FGF21 in response to a ketogenic diet. Consistent with preserved induction of FGF21, Xbp1LKO mice exhibited normal induction of FGF21 target genes and normal ketogenesis in response to fasting or a ketogenic diet.

Conclusions: Hepatic Xbp1 is not required for induction of FGF21 under physiologic or pathophysiologic conditions in vivo.