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

Highlights

• Deletion of hepatic Xbp1 in mice allows for normal induction of FGF21 upon fasting.

• ER stress induces FGF21 independently of hepatic Xbp1.

• Mice lacking hepatic Xbp1 show enhanced FGF21 induction when fed a ketogenic diet.

• Hepatic Xbp1 is not required for induction of FGF21 in vivo.

Abstract

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 (Xbp1^LKO) 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, Xbp1^LKO mice exhibited normal induction of FGF21 target genes and normal ketogenesis in response to fasting or a ketogenic diet.

Conclusion

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