TRIB3 limits FGF21 induction during in vitro and in vivo nutrient deficiencies by inhibiting C/EBP–ATF response elements in the Fgf21 promoter

Abstract

Mammals must be able to endure periods of limited food availability, and the liver plays a central role in the adaptation to nutritional stresses. TRIB3 (Tribbles homolog 3) is a cellular stress-inducible gene with a liver-centric expression pattern and it has been implicated in stress response regulation and metabolic control. In the current article, we study the involvement of TRIB3 in responses to nutrient deficiencies, including fasting for up to 48 h in mice. We show that hepatic expression of Trib3 is increased after 48 h of fasting and mice with a targeted deletion of the Trib3 gene present elevated hepatic triglyceride content and liver weight at 48 h, along with an upregulation of lipid utilization genes in the liver. Further, hepatic and serum levels of the metabolic stress hormone FGF21 are considerably increased in 48-h-fasted Trib3 knockout mice compared to wild type. Trib3 deficiency also leads to elevated FGF21 levels in the mouse liver during essential amino acid deficiency and in cultured mouse embryonic fibroblasts during glucose starvation. Reporter assays reveal that TRIB3 regulates FGF21 by inhibiting ATF4-mediated, C/EBP–ATF site-dependent activation of Fgf21 transcription. Based on chromatin immunoprecipitation from mouse liver, the binding of TRIB3 and ATF4, a transcription factor known to physically interact with TRIB3, is significantly increased at the Fgf21 promoter following 48 h of fasting. Thus, under nutrient-limiting conditions that stimulate ATF4 activity, TRIB3 is implicated in the regulation of metabolic adaptation by restraining the transcription of Fgf21.