Rando Gianpaolo, Tan Chek Kun, Khaled Nourhène, Montagner Alexandra, Leuenberger Nicolas, Bertrand-Michel Justine, Paramalingam Eeswari, Guillou Hervé, Wahli Walter
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Lee Kong Chian School of Medicine, Nanyang Technological University, , Singapore.
Elife. 2016 Jul 1;5:e11853. doi: 10.7554/eLife.11853.
In mammals, hepatic lipid catabolism is essential for the newborns to efficiently use milk fat as an energy source. However, it is unclear how this critical trait is acquired and regulated. We demonstrate that under the control of PPARα, the genes required for lipid catabolism are transcribed before birth so that the neonatal liver has a prompt capacity to extract energy from milk upon suckling. The mechanism involves a fetal glucocorticoid receptor (GR)-PPARα axis in which GR directly regulates the transcriptional activation of PPARα by binding to its promoter. Certain PPARα target genes such as Fgf21 remain repressed in the fetal liver and become PPARα responsive after birth following an epigenetic switch triggered by β-hydroxybutyrate-mediated inhibition of HDAC3. This study identifies an endocrine developmental axis in which fetal GR primes the activity of PPARα in anticipation of the sudden shifts in postnatal nutrient source and metabolic demands.
在哺乳动物中，肝脏脂质分解代谢对于新生儿有效利用乳脂作为能量来源至关重要。然而，目前尚不清楚这种关键特性是如何获得和调节的。我们证明，在过氧化物酶体增殖物激活受体α（PPARα）的控制下，脂质分解代谢所需的基因在出生前就被转录，从而使新生儿肝脏在哺乳时能够迅速从乳汁中提取能量。该机制涉及胎儿糖皮质激素受体（GR）-PPARα轴，其中GR通过结合其启动子直接调节PPARα的转录激活。某些PPARα靶基因，如Fgf21，在胎儿肝脏中保持抑制状态，并在出生后由于β-羟基丁酸介导的组蛋白去乙酰化酶3（HDAC3）抑制引发的表观遗传开关而变得对PPARα有反应。本研究确定了一种内分泌发育轴，其中胎儿GR在出生后营养来源和代谢需求突然转变之前启动PPARα的活性。
