Editors' ChoiceMetabolism

ERAD suppresses the starvation response

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Sci. Signal.  04 Dec 2018:
Vol. 11, Issue 559, eaaw2150
DOI: 10.1126/scisignal.aaw2150

Endoplasmic reticulum–associated protein degradation suppresses the production of the fasting-associated hepatokine Fgf21.

Endoplasmic reticulum–associated protein degradation (ERAD) protects cells by shunting misfolded proteins into proteasomal-mediated degradation pathways that depend on cytosolic E3 ubiquitin ligases, such as Hrd1. Wei et al. found that Hrd1 expression in the livers of fasted mice increased upon refeeding; similarly, Bhattacharya et al. found that the abundance of both Hrd1 and its essential partner Sel1L increased in the liver upon refeeding. Both groups removed Hrd1-Sel1L function in the liver by generating tissue-specific knockouts of Hrd1 (Wei et al.) or Sel1L (Bhattacharya et al.). Knockout of either gene resulted in an overall reduction in growth (smaller body size), as well as metabolic and circadian behavioral phenotypes similar to those of mice overexpressing the hepatokine fibroblast growth factor 21 (Fgf21), which stimulates adipocytes to take up glucose. Both knockout mice also showed increases in hepatic Fgf21 expression, the abundance of circulating Fgf21, and the abundance of Crebh (cAMP-responsive element–binding protein 3–like protein 3, hepatocyte-specific), a transcription factor that stimulates the expression of Fgf21 during fasting. Both research groups demonstrated that Hrd1 and Sel1L stimulated the ubiquitylation and proteasomal degradation of Crebh under fed conditions. Knocking down Crebh systemically or knocking out Fgf21 liver specifically in Hrd1 knockout mice (Wei et al.) or knocking down Fgf21 in Sel1L knockout mice (Bhattacharya et al.) rescued the growth and metabolic phenotypes of the mutants. Given that the unfolded protein response (UPR) is induced upon refeeding after fasting and stimulates ERAD (see commentary by Dreher and Hoppe), it seems likely that the UPR may also be important for restricting Fgf21 production to the fasting state. In addition to shedding light on how Fgf21 production is suppressed under fed conditions, these findings also contribute to the growing body of evidence linking ER proteostasis to critical systemic processes and to pathologies such as diabetes, neurodegeneration, and cancer.

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