Evolving roles of circadian rhythms in liver homeostasis and pathology

Abstract

Circadian clock in mammals is determined by a core oscillator in the suprachiasmatic nucleus (SCN) of the hypothalamus and synchronized peripheral clocks in other tissues. The coherent timing systems could sustain robust output of circadian rhythms in response to the entrainment controlled environmentally. Disparate approaches have discovered that clock genes and clock-controlled genes (CCGs) exist in nearly all mammalian cell types and are essential for establishing the mechanisms and complexity of internal time-keeping systems. Accumulating evidence demonstrates that the control of homeostasis and pathology in the liver involves intricate loops of transcriptional and post-translational regulation of clock genes expression. This review will focus on the recent advances with great importance concerning clock rhythms linking liver homeostasis and diseases. We particularly highlight what is currently known of the evolving insights into the mechanisms underlying circadian clock . Eventually , findings during recent years in the field might prompt new circadian-related chronotherapeutic strategies for the diagnosis and treatment of liver diseases by coupling these processes.

Keywords: circadian rhythms; epigenetic modifications; hepatocellular carcinoma; liver fibrosis; liver metabolism.

Figure 1. Schematic representation of molecular interactions in mammalian circadian transcriptional negative feedback loops

For simplicity, many cells and tissues have the capacity to oscillate with a wide variety of periodicities, and the circadian oscillators can be entrained to local time in response to environmental stimuli including daylight, temperature and feeding availability. Firstly, the interactions between positive elements (BMAL1 and CLOCK) and negative elements (CRY and PER) which form the interconnect negative feedback loop in mammals through inhibiting CLOCK-BMAL1-dependent transcription. Then, RORα and Rev-ERBα, which form the secondary loop that regulates rhythms, resulting from the activation and inhibition the expression of BMAL1, respectively. Finally, phosphorylation and ubiquitination of the negative components results in their eventual degradation, allowing the positive components to restart the cycle.

Figure 2. The disruption of circadian rhythms exists in the liver injury and fibrosis

The livers undergo the variously chronic damages, such as alcohol, LPS, BDL, drug, CCl₄ and high fat, leading to the liver injury and fibrosis characterized by the activation of HSCs and the hepatocytes injury, apoptosis or death. Particularly, it could disrupt the circadian rhythm in livers through causing misalignment of the amplitude and phase of a normal rhythm in key cell types, such as HSCs and hepatocytes.

Figure 3. The molecular mechanisms involved in the manipulation of the circadian rhythms in hepatic stellate cell

Several of the key signaling pathways, for example TGF-β/Smad, TRAIL/DRs and LPS/TLRs, might either directly or indirectly interact with the circadian rhythms in HSCs via regulating the transcription of core clock genes and other CCGs. In addition, the epigenetic modifications, such as miR-155, might be also involved in the rhythmic genes expression. Some other conditions have not yet been described need further study to investigate.