The circadian clock and liver function in health and disease

Abstract

Each day, all organisms are subjected to changes in light intensity because of the Earth's rotation around its own axis. To anticipate this geo-physical variability, and to appropriately respond biochemically, most species, including mammals, have evolved an approximate 24-hour endogenous timing mechanism known as the circadian clock (CC). The 'clock' is self-sustained, cell autonomous and present in every cell type. At the core of the clock resides the CC-oscillator, an exquisitely crafted transcriptional-translational feedback system. Remarkably, components of the CC-oscillator not only maintain daily rhythmicity of their own synthesis, but also generate temporal variability in the expression levels of numerous target genes through transcriptional, post-transcriptional and post-translational mechanisms, thus, ensuring proper chronological coordination in the functioning of cells, tissues and organs, including the liver. Indeed, a variety of physiologically critical hepatic functions and cellular processes are CC-controlled. Thus, it is not surprising that modern lifestyle factors (e.g. travel and jet lag, night and rotating shift work), which force 'circadian misalignment', have emerged as major contributors to global health problems including obesity, non-alcoholic fatty liver disease and steatohepatitis. Herein, we provide an overview of the CC-dependent pathways which play critical roles in mediating several hepatic functions under physiological conditions, and whose deregulation is implicated in chronic liver diseases including non-alcoholic steatohepatitis and alcohol-related liver disease.

Keywords: ALD; Circadian clock; Hepatic metabolism; NAFLD; Transcriptional regulation.

Figure 1. The molecular architecture of the Circadian Clock (CC)-oscillator

The recruitment of BMAL1/ CLOCK-heterodimer to the E-Box DBS present in the promoter-enhancer elements of numerous CCGs, including Periods (Per1/2) and Cryptochromes (Cry1/2) augment their expression during the rest phase. Following accumulation, PERs and CRYs proteins dimerize and translocate to inhibit BMAL1/CLOCK-dependent transcription during the active phase. Next, post-translational modifications including ubiquitination induce proteasomal degradation of PERs and CRYs, thus, initiating the next circadian cycle. In the second loop, BMAL1/CLOCK-dependent expression of Rev-Erbα/β during the rest phase, leads to the trans-repression of several RORE-DBS-containing CCGs including, Bmal1, Clock and E4BP4. In the active phase, the reduction in REV-ERBs levels permit the RORα/γ-dependent RORE-mediated activation of CCGs including Bmal1 and Clock, which enables the turning of the circadian clock. Furthermore, DBP expression during the rest phase activates D-Box DBS containing CCGs, which are transcriptionally repressed by E4BP4 during the active phase. These coupled transcriptional-translational regulatory circuits are ubiquitously present in almost all cell types and directly control the expression of a vast number of mammalian genes. CCG-Clock Controlled Genes. E-CCGs: E-Box DBS-containing CCGs, R-CCGs: RORE-containing CCGs, D-CCGs: D-Box-containing CCGs.

Figure 2. The clock controls the physiology of liver

Light-entrained central SCN-clock synchronizes peripheral tissue clocks including that of liver. The ‘clock’ machinery in turn drives the expression of several key transcription factors, rate limiting enzymes and transport proteins to spatiotemporally regulate several biochemical processes, which, together maintain physiological homeostasis. The ‘clock’-connections to some of these processes and their connections to NAFLD and NASH have been discussed in detail.

Figure 3. Multidimensional connections of the ‘clock’ to the pathogenesis of fatty liver

Model representing a global view of how alterations in circadian clock-controlled ‘rhythmic’ functions/pathways and processes could predispose to non-alcoholic fatty liver disease. Knowledge of the mechanisms through which the ‘clock’-system influences all these systems and essential pharmacological parameters, in turn, could be utilized to develop novel chronotherapeutics. Green arrowheads represent activation and red bar-heads represent inhibition. See text for details.