PPARα mouse liver cistrome

Autophagy is an evolutionally conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis1-3. Its acute regulation by nutrient sensing signaling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors PPARα and FXR are activated in the fasted or fed liver, respectively4,5. Here we show that both regulate hepatic autophagy. Pharmacologic activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (PPARα-/-) mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (FXR-/-) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status. Mouse liver PPARα cistromes in fed 8-week-old male WT or PPARα KO mice treated with or without its synthetic agonist ligand GW7647twice a day were generated by deep sequencing in quadruplicate using illumina

自噬（Autophagy）是一类进化保守的分解代谢过程，可在饥饿状态下回收营养物质并维持细胞能量稳态1-3。目前学界已充分阐明其通过营养感知信号通路实现的急性调控，但对其长期转录调控机制仍有待进一步解析。核受体PPARα与FXR分别在禁食与进食状态的肝脏中被激活4,5。本研究证实二者均可调控肝脏自噬：对PPARα进行药理学激活，可逆转进食状态下自噬的生理性抑制，诱导自噬性脂质降解，即脂噬（lipophagy）；该效应在PPARα基因敲除（PPARα-/-）小鼠中完全消失，此类小鼠在禁食诱导自噬的过程中存在部分功能缺陷。而对胆汁酸受体FXR进行药理学激活，则可强烈抑制禁食状态下自噬的诱导，该效应在FXR基因敲除（FXR-/-）小鼠中不复存在，此类小鼠在进食状态下的肝脏自噬抑制过程中存在部分功能缺陷。PPARα与FXR可竞争性结合自噬基因启动子区域的共有结合位点，并产生截然相反的转录调控效应。上述结果揭示了营养状态调控自噬的互补且相互关联的分子机制。本研究采用Illumina测序平台，对每日两次给予合成激动剂GW7647或安慰剂的8周龄雄性野生型（WT）与PPARα敲除（KO）小鼠的进食状态肝脏组织，通过四重重复深度测序获取了其PPARα结合位点组（cistromes）数据。