Fibroblast growth factor 21 (Fgf21) is a liver‐derived, fasting‐induced hormone with broad effects on growth, nutrient metabolism, and insulin sensitivity. Here, we report the discovery of a novel mechanism regulating Fgf21 expression under growth and fasting‐feeding. The Sel1L‐Hrd1 complex is the most conserved branch of mammalian endoplasmic reticulum (ER)‐associated degradation (ERAD) machinery. Mice with liver‐specific deletion of Sel1L exhibit growth retardation with markedly elevated circulating Fgf21, reaching levels close to those in Fgf21 transgenic mice or pharmacological models. Mechanistically, we show that the Sel1L‐Hrd1 ERAD complex controls Fgf21 transcription by regulating the ubiquitination and turnover (and thus nuclear abundance) of ER‐resident transcription factor Crebh, while having no effect on the other well‐known Fgf21 transcription factor Pparα. Our data reveal a physiologically regulated, inverse correlation between Sel1L‐Hrd1 ERAD and Crebh‐Fgf21 levels under fasting‐feeding and growth. This study not only establishes the importance of Sel1L‐Hrd1 ERAD in the liver in the regulation of systemic energy metabolism, but also reveals a novel hepatic “ERAD‐Crebh‐Fgf21” axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation.

See also: J Wei et al (November 2018) and L‐S Dreher & T Hoppe (November 2018)

成纤维细胞生长因子21（Fgf21）是一种来自肝脏的，空腹诱导的激素，对生长，营养代谢和胰岛素敏感性具有广泛的影响。在这里，我们报道了一种在生长和禁食下调节Fgf21表达的新型机制的发现。Sel1L-Hrd1复合体是哺乳动物内质网（ER）相关降解（ERAD）机器中最保守的分支。肝特异性缺失Sel1L的小鼠表现出生长迟缓，循环Fgf21明显升高，达到接近Fgf21转基因小鼠或药理模型的水平。从机理上讲，我们显示了Sel1L‐Hrd1 ERAD复合体控制Fgf21通过调节ER驻留转录因子Crebh的遍在蛋白化和更新（以及因此的核丰度）进行转录，而对其他知名的Fgf21转录因子Pparα没有影响。我们的数据揭示了在禁食和生长条件下，Sel1L-Hrd1 ERAD与Crebh-Fgf21水平之间存在生理调节的负相关。这项研究不仅确定了Sel1L-Hrd1 ERAD在肝脏中调节全身能量代谢的重要性，而且还揭示了一种新颖的肝脏“ ERAD-Crebh-Fgf21”轴，其直接将ER蛋白更新与基因转录和全身性代谢调节联系起来。

另请参阅：J Wei等人（2018年11月）和L‐S Dreher＆T Hoppe（2018年11月）