Hepatic transcriptional responses to fasting and feeding

Abstract

Mammals undergo regular cycles of fasting and feeding that engage dynamic transcriptional responses in metabolic tissues. Here we review advances in our understanding of the gene regulatory networks that contribute to hepatic responses to fasting and feeding. The advent of sequencing and -omics techniques have begun to facilitate a holistic understanding of the transcriptional landscape and its plasticity. We highlight transcription factors, their cofactors, and the pathways that they impact. We also discuss physiological factors that impinge on these responses, including circadian rhythms and sex differences. Finally, we review how dietary modifications modulate hepatic gene expression programs.

Keywords: liver; metabolism; transcription.

Figure 1.

Transcription factors that regulate lipid metabolism in fasted and fed states. (A) Transcription factors such as ChREBP, LXR, SREBP1c, XBP, USF-1, and SREBP2 are activated by various factors in response to feeding signals such as glucose and insulin. These transcription factors induce the expression of genes that promote lipogenesis and cholesterol biosynthesis. Some of these transcription factors are also known to be actively inhibited during fasting. (B) Transcription factors such as PPARα and PGC-1α are activated by glucagon, SIRT1, and glucocorticoid receptor during fasting. These transcription factors induce the expression of genes that promote fatty acid oxidation and ketogenesis during fasting. Ketone bodies can be used as energy source for many other tissues.

Figure 2.

Transcription factors that regulate glucose metabolism in fasted and fed states. (A) Transcription factors such as ChREBP, HIF2α-ARNT, IRE1, STAT3, LRH-1, and FXR are activated by various factors in response to feeding such as glucose and insulin. These factors induce the transcription of genes that promote glycolysis and glycogen synthesis. In response to an increase in available glucose and insulin, energy metabolism switches to using glucose as fuel and replenishes glycogen stores. (B) Transcription factors such as FOXO1, GR, PGC-1α, CREB, PPARα, and FXR are activated by glucagon, AMPK, SIRT1, and glucocorticoids during fasting. These transcription factors induce the expression of genes that promote gluconeogenesis and glycogenolysis. This switch is crucial in maintaining blood glucose levels during fasting. There is evidence for cross talk between these transcription factors, one inducing the expression of another. Some of these transcription factors are also known to be actively inhibited by insulin signaling in response to feeding.

Figure 3.

Interplay of circadian rhythm and hepatic gene regulation in mice. (Left) PER/CRY is the major effector of the circadian clock in the liver during the day, while mice are asleep. Effects of PER/CRY include inhibition of gluconeogenesis and suppression of BMAL1/CLOCK. BMAL/CLOCK activity is also repressed by REV-ERB transcription factors and glucagon via CREB/CRTC2. (Right) At night, when mice are active and feeding, the BMAL1/CLOCK complex is the main circadian regulator of the liver transcriptome. Its effects include increasing LDL uptake and glycogenesis while also increasing levels of the PER/CRY complex. Among the factors that increase BMAL1/CLOCK expression is the daytime accumulation of ROR. As feeding occurs throughout the night, rising insulin levels cause AKT to suppress BMAL1/CLOCK activity.