Circadian rhythms in liver metabolism and disease

Abstract

Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease.

Keywords: ARC, arcuate nucleus; BMAL1, brain and muscle ARNT-like 1; CAR, constitutive androstane receptor; CLOCK, circadian locomotor output cycles kaput; CRY, cryptochrome; CYP7A1, cholesterol 7α-hydroxylase; CYPs, cytochrome P450 enzymes; Circadian rhythm; DBP, D-site binding protein; E-box, enhance box; EMT, emergency medical technician; FAA, food anticipatory activity; FASPS, familial advanced sleep-phase syndrome; FEO, food entrainable oscillator; FOXO3, forkhead box O3; FXR, farnesoid-X receptor; GLUT2, glucose transporter 2; HDAC3, histone deacetylase 3; HIP, hypoxia inducing protein; HLF, hepatic leukemia factor; LDL, low-density lipoprotein; LRH1, liver receptor homolog 1; Liver; Metabolic syndrome; NAD+, nicotinamide adenine dinucleotide; PER, period; RHT, retinohypothalamic tract; RORE, ROR-response element; RORα, retinoid-related orphan receptor α; SCN, suprachiasmatic nucleus; SHP, small heterodimer partner; SIRT1, sirtuin 1; TEF, thyrotroph embryonic factor; TGR5, G protein-coupled bile acid receptor; TTFL, transcriptional translational feedback loop; Type 2 diabetes.

Graphical abstract

Figure 1

(A) Environmental signals perceived via the retinohypothalamic tract (RHT) by the biological clock, the suprachiasmatic nucleus (SCN) are the most prominent clock resetting agents. The SCN integrates photic and nonphotic signals to produce rhythmic outputs resulting in circadian regulation of locomotor activity, food intake, body temperature, hormonal release, and peripheral and xenobiotic metabolism. (B) Diagram depicting the transcriptional translational feedback loop (TTFL) that composes the molecular biological clock in almost all mammalian tissue types. Clock proteins CLOCK and BMAL1 heterodimerize to induce transcription of PER and CRY genes. PER1/2 and CRY1/2 proteins bind to E-box elements in the BMAL1 promoter to inhibit PER/CRY transcription via negative feedback. Additional regulatory clock components REV-ERBα and RORα positively and negatively regulate CLOCK/BMAL transcription, respectively, through binding to ROR-response elements in the BMAL1 promoter. This feedback loop takes approximately 24 h to complete and is the molecular basis for the mammalian biological clock that produces rhythmic outputs of neural and hormonal signals and gene transcripts.

Figure 2

The suprachiasmatic nucleus (SCN) generates endogenous biological rhythms, ensuring that internal physiology is synchronized with the external environment. Under normal conditions, rhythms in glucose and insulin, bile acids, lipids and drug enzymes contribute to homeostatic control of liver physiology. Under conditions of circadian disruption, including shift work, perturbations in these physiological rhythms result in desynchronized timing between SCN and the periphery and are associated with diabetes, obesity, and other symptoms of metabolic syndrome.