Liver as a nexus of daily metabolic cross talk

Abstract

Over the course of a day, the circadian clock promotes a homeostatic balance between energy intake and energy expenditure by aligning metabolism with nutrient availability. In mammals, this process is driven by central clocks in the brain that control feeding behavior, the peripheral nervous system, and humoral outputs, as well as by peripheral clocks in non-brain tissues that regulate gene expression locally. Circadian organization of metabolism is critical, as circadian disruption is associated with increased risk of metabolic disease. Emerging evidence shows that circadian metabolism hinges upon inter-organ cross talk involving the liver, a metabolic hub that integrates many facets of systemic energy homeostasis. Here, we review spatiotemporal interactions, mainly metabolite exchange, signaling factors, and hormonal control, between the liver and skeletal muscle, pancreas, gut, microbiome, and adipose tissue. Modern society presents the challenge of circadian disturbances from rotating shift work to social jet lag and 24/7 food availability. Thus, it is important to better understand the mechanisms by which the clock system controls metabolic homeostasis and work toward targeted therapies.

Keywords: Circadian clock; Circadian rhythm; Hepatic metabolism; Inter-organ cross talk; Liver; Molecular clock; Systems biology.

Figure 1.. The Core Circadian Clock Machinery.

A. The molecular clock is a transcription-translation negative feedback loop. Transcriptional activators are shown above motifs in gray. Transcriptional repressors are shown below motifs in red. Heterodimerization of brain and muscle arnt-like protein 1 (BMAL1) with clock locomotor ouput cycle kaput (CLOCK) results in transcriptional activation at E-box elements of the repressors period (Per) and cryptochrome (Cry). PER and CRY inhibit CLOCK:BMAL1 through formation of a larger repressor complex. Another activator-repressor pair, the nuclear receptors retinoic acid-related orphan receptor-α (RORα/β) and nuclear receptor subfamily 1 group D member 1 (REV-ERBα/β), act through ROR response elements (RORE) to regulate Bmal1, Cry and nuclear factor interleukin-3 related (Nfil3). Additionally, D-box elements are regulated by D-box binding PAR bZIP transcription factor (DBP) and control expression of Ror and Rev-Erb. These interlocking loops constitute the molecular clockwork B. The rhythmic expression of a gene is defined by the distribution of E-box, D-box, and RORE motifs. So called clock-controlled output genes are also defined by the activities of ubiquitous or cell type-specific transcription factors as well as mechanisms of the three-dimensional chromatin landscape. TF – transcription factor. C. Simplified scheme of liver co-regulatory transcription factors that integrate another layer of metabolic information to the interlocking circadian loop by controlling output of various transcriptional programs. C/EBPB – CCAAT enhancer binding protein beta; GR – Glucocorticoid Receptor; CREBH – cAMP response element – binding protein – 3 – like 3; DBP - D-box binding PAR bZIP transcription factor; TEF - Thyrotroph embryonic factor; HLF - Hepatic leukemia factor; NFIL3 - Nuclear factor interleukin 3; SREBP – Sterol responsive – element binding protein; PPAR – peroxisome proliferator-activated receptor; HNF6 – Hepatic nuclear factor 6.

Figure 2.. Synchrony and Coupling are Fundamental Elements of the Circadian Clock System.

A. In isolation, devoid of exogenous signals, non-neuronal cells function as autonomous oscillators with cell-to-cell variability in the period and phase of rhythmicity. In situ, systemic cues synchronize cells such that phases are aligned (i.e., in time with each other) and periods are set precisely to ~24 h. Synchronizing cues may also provide a driving force to cells and enhance oscillatory amplitude. Secreted factors and physical contacts can serve as a means of coupling. When cell clocks are coupled, they take on properties of a unit rather than solely as individual oscillators. Coupling can result in a population of cell clocks that remains synchronized for a longer time in the absence of a synchronizing cue, is more resilient to perturbations, or exhibits large amplitudes. Synchrony and coupling are likely interacting/overlapping processes. B. Top – examples of known synchronizing cues for the liver. Bottom – potential mediators of clock coupling in peripheral cells. AMPK – AMP-activated protein kinase; ANGPTL8 – angiopoietin like 8; HSF1 – heat shock factor 1; HSP70 – heat shock protein 70; SIRT7 – sirtuin 7; Rs – receptor; TGFβ - transforming growth factor beta; CSF1 – colony stimulating factor 1; PDGFD – platelet derived growth factor D; NS – nervous system.

Figure 3.. Temporal Cross Talk Between the Liver and Skeletal Muscle.

Daily periods of feeding and fasting, as well as rest and activity or exercise, modulate cross talk between the liver and muscle, which are intimately linked through the systemic circulation via shared metabolic pathways. The Cori and Cahil cycles are under circadian control. Liver BMAL1 promotes gluconeogenesis during the fasting phase, and muscle BMAL1 promotes insulin-stimulated glucose uptake into muscle. Systemically, feeding rhythms and liver and muscle clocks interact to maintain glucose tolerance. Branch chain amino acids (BCAA) fluctuate over the course of a day, with a peak during the active, feeding phase, and a trough during the inactive, fasting phase. In addition to dietary intake, the circadian abundance of BCAAs is regulated through release from liver, uptake by the muscle, and the return of alanine and glutamine to the liver for nitrogen disposal. Secreted proteins also mediate temporal liver-muscle cross talk. Interleukin-6 (IL-6) is a clock-controlled myokine associated with obesity that regulates hepatic glucose production and fatty acid oxidation.

Figure 4.. Temporal Cross Talk Between Liver and Peripheral Metabolic Organs.

The liver is positioned to respond to top-down signals from the light entrained suprachiasmatic nucleus (SCN) in the hypothalamus as well as to feeding cues which require the activities of peripheral organs including the gut (and microbiome), pancreas, white adipose tissue, and skeletal muscle (depicted in Figure 3), among others. The release of metabolites and secreted proteins from the liver, which tunes metabolism in distal organs, is also regulated in a circadian fashion. See also Table 1. Colored stars related to the key shown on the right indicate the disease contexts wherein the mediators of cross talk are impaired (from animal studies). PUFA – polyunsaturated fatty acid; SCFA – short chain fatty acid; Adipoq – adiponectin; FGF21 – fibroblast growth factor 21; RBP4 – retinol binding protein 4. MASLD – metabolic dysfunction-associated steatotic liver disease.