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Free keywords:
FXR isoforms; Splicing; NAFLD; Insulin resistance; Energy metabolism
Abstract:
Objective:
Farnesoid X receptor (FXR) plays a prominent role in hepatic lipid metabolism. The FXR gene encodes four proteins with structural
differences suggestive of discrete biological functions about which little is known.
Methods:
We expressed each FXR variant in primary hepatocytes and evaluated global gene expression, lipid pro
fi
le, and metabolic
fl
uxes. Gene
delivery of FXR variants to Fxr
/
mouse liver was performed to evaluate their role
in vivo
. The effects of fasting and physical exercise on hepatic
Fxr splicing were determined.
Results:
We show that FXR splice isoforms regulate largely different gene sets and have speci
fi
c effects on hepatic metabolism. FXR
a
2 (but not
a
1) activates a broad transcriptional program in hepatocytes conducive to lipolysis, fatty acid oxidation, and ketogenesis. Consequently, FXR
a
2
decreases cellular lipid accumulation and improves cellular insulin signaling to AKT. FXR
a
2 expression in Fxr
/
mouse liver activates a similar
gene program and robustly decreases hepatic triglyceride levels. On the other hand, FXR
a
1 reduces hepatic triglyceride content to a lesser extent
and does so through regulation of lipogenic gene expression. Bioenergetic cues, such as fasting and exercise, dynamically regulate Fxr splicing in
mouse liver to increase Fxr
a
2 expression.
Conclusions:
Our results show that the main FXR variants in human liver (
a
1 and
a
2) reduce hepatic lipid accumulation through distinct
mechanisms and to different degrees. Taking this novel mechanism into account could greatly improve the pharmacological targeting and
therapeutic ef
fi
cacy of FXR agonists.
