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Circadian Rhythms in Liver Physiology and Liver Diseases

Xin Tong, Lei Yin

10.1002/cphy.c120017

Source: Volume 3, Issue 2, April 2013

Published online: April 2013

Full Article on Wiley Online Library



Abstract

In mammals, circadian rhythms function to coordinate a diverse panel of physiological processes with environmental conditions such as food and light. As the driving force for circadian rhythmicity, the molecular clock is a self‐sustained transcription‐translational feedback loop system consisting of transcription factors, epigenetic modulators, kinases/phosphatases, and ubiquitin E3 ligases. The molecular clock exists not only in the suprachiasmatic nuclei of the hypothalamus but also in the peripheral tissues to regulate cellular and physiological function in a tissue‐specific manner. The circadian clock system in the liver plays important roles in regulating metabolism and energy homeostasis. Clock gene mutant animals display impaired glucose and lipid metabolism and are susceptible to diet‐induced obesity and metabolic dysfunction, providing strong evidence for the connection between the circadian clock and metabolic homeostasis. Circadian‐controlled hepatic metabolism is partially achieved by controlling the expression and/or activity of key metabolic enzymes, transcription factors, signaling molecules, and transporters. Reciprocally, intracellular metabolites modulate the molecular clock activity in response to the energy status. Although still at the early stage, circadian clock dysfunction has been implicated in common chronic liver diseases. Circadian dysregulation of lipid metabolism, detoxification, reactive oxygen species (ROS) production, and cell‐cycle control might contribute to the onset and progression of liver steatosis, fibrosis, and even carcinogenesis. In summary, these findings call for a comprehensive study of the function and mechanisms of hepatic circadian clock to gain better understanding of liver physiology and diseases. © 2013 American Physiological Society. Compr Physiol 3:917‐940, 2013.

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Figure 1. Figure 1.

Daily entrainment signals of the central and peripheral circadian clocks. Light is the dominant signal to reset the central circadian clock located in the suprachiasmatic nucleaus (SCN) via the retino‐hypothalamus tract. Following resetting, the SCN dictates rhythms of locomotor activity, sleep‐wake cycle, blood pressure, and body temperature. In parallel, the SCN entrains the peripheral clock tissues via direct humoral factors or autonomic innervations. The major peripheral clock tissues associated with metabolism include the liver, adipose tissues, skeletal muscle, pancreas, and adrenal glands. The synchronized activities of peripheral clock tissues are required for maintaining metabolic homeostasis and balancing energy utilization. Food and feeding regimen reset the peripheral clock tissues without affecting the SCN.
Figure 2. Figure 2.

The molecular clock network is driven by a transcription‐translational feedback mechanism. The primary molecular oscillator is composed of the primary positive loop (CLOCK/NAPS2 and BMAL1) and the primary negative loop (PERs and CRYs). BMAL1:CLOCK transcription complex binds to E‐box sequences located in the promoter of Per and Cry genes to activate their transcription. PER and CRY proteins are necessary components of the feedback inhibition of BMAL1:CLOCK transcription complex. Once accumulated in the cytosol, PER and CRY proteins undergo dimerization, nuclear translocation to inhibit their own gene transcription by BMAL1: CLOCK complex. Both PER and CRY are targets of phosphorylation and ubiquitination‐mediated proteasome degradation. BMAL1:CLOCK is also required for activation of nuclear receptors NR1D1/2 and ROR, which constitutes the secondary circadian feedback loop. NR1D1/2 represses Bmal1 transcription and competes with ROR for binding to RRE (ROR response element) within the Bmal1 promoter. The maximal repression of NR1D1 is achieved via recruitment of corepressor complex NCoR‐HDAC3 in a heme‐dependent manner. BMAL1:CLOCK also participates E‐box dependent rhythmic expression of circadian controlled genes (CCGs). NR1D1 and NR1D2 also contribute to rhythmic expression of CCGs via a RRE‐dependent manner.
Figure 3. Figure 3.

Regulation of the molecular clock by the intracellular energy state. (A) The role of nicotinamide adenosine dinucleotide (NAD)/NAD(P)H levels in regulation of the molecular clock. High levels of NAD(P)H enhances BMAL1:CLOCK binding to targeted DNA. CLOCK with intrinsic HAT activity catalyzes BMAL1 acetylation and in turn activates transcription of Cry (s) and Per(s) and circadian‐controlled gene Nampt, a key enzyme for NAD biosynthesis. When NAD level rises during each circadian cycle, NAD stimulates SIRT1 enzymatic activity, which in turn deacetylates PER protein for proteasome degradation. SIRT1 also deacetylates BMAL1 and releases the repression of CRY:PER on BMAL1:CLOCK transcription activity. (B) The role adenosine monophosphate/adenosine triphosphate (AMP/ATP) levels in regulation of the molecular clock. High level of AMP activates AMPK, a cellular sensor for lower energy state. AMPK inhibits negative feedback loop via its activation of SIRT1 and phosphorylation CRY protein. AMPK‐dependent phosphorylation of CRY promotes its ubiquitianation and proteasome‐mediated degradation. In addition, AMPK enhances PER2 degradation by promoting the kinase activity of CKI ɛ/δ.
Figure 4. Figure 4.

The physiology and potential disease relevance of hepatic liver clock. The circadian network within the hepatocyte shares the same molecular structure with that found in the SCN. BMAL1:CLOCK activates the expression of Per and Cry while PER:CRY repress their own transcription via inhibiting BMAL1:CLOCK. The hepatic circadian clock can be entrained or phase shifted by a variety of hormones (insulin, glucagons, and glucocorticoid), nutrients (glucose, fatty acid, and bile acid) and environmental chemicals (Dioxin). Specific input signaling resets or shifts the molecular clock, subsequently affecting its output pathways, including nutrient metabolic pathways, xenobiotic metabolism, and cell‐cycle regulation. Impaired circadian clock might be an underlying mechanism for chronic liver diseases.


Figure 1.

Daily entrainment signals of the central and peripheral circadian clocks. Light is the dominant signal to reset the central circadian clock located in the suprachiasmatic nucleaus (SCN) via the retino‐hypothalamus tract. Following resetting, the SCN dictates rhythms of locomotor activity, sleep‐wake cycle, blood pressure, and body temperature. In parallel, the SCN entrains the peripheral clock tissues via direct humoral factors or autonomic innervations. The major peripheral clock tissues associated with metabolism include the liver, adipose tissues, skeletal muscle, pancreas, and adrenal glands. The synchronized activities of peripheral clock tissues are required for maintaining metabolic homeostasis and balancing energy utilization. Food and feeding regimen reset the peripheral clock tissues without affecting the SCN.



Figure 2.

The molecular clock network is driven by a transcription‐translational feedback mechanism. The primary molecular oscillator is composed of the primary positive loop (CLOCK/NAPS2 and BMAL1) and the primary negative loop (PERs and CRYs). BMAL1:CLOCK transcription complex binds to E‐box sequences located in the promoter of Per and Cry genes to activate their transcription. PER and CRY proteins are necessary components of the feedback inhibition of BMAL1:CLOCK transcription complex. Once accumulated in the cytosol, PER and CRY proteins undergo dimerization, nuclear translocation to inhibit their own gene transcription by BMAL1: CLOCK complex. Both PER and CRY are targets of phosphorylation and ubiquitination‐mediated proteasome degradation. BMAL1:CLOCK is also required for activation of nuclear receptors NR1D1/2 and ROR, which constitutes the secondary circadian feedback loop. NR1D1/2 represses Bmal1 transcription and competes with ROR for binding to RRE (ROR response element) within the Bmal1 promoter. The maximal repression of NR1D1 is achieved via recruitment of corepressor complex NCoR‐HDAC3 in a heme‐dependent manner. BMAL1:CLOCK also participates E‐box dependent rhythmic expression of circadian controlled genes (CCGs). NR1D1 and NR1D2 also contribute to rhythmic expression of CCGs via a RRE‐dependent manner.



Figure 3.

Regulation of the molecular clock by the intracellular energy state. (A) The role of nicotinamide adenosine dinucleotide (NAD)/NAD(P)H levels in regulation of the molecular clock. High levels of NAD(P)H enhances BMAL1:CLOCK binding to targeted DNA. CLOCK with intrinsic HAT activity catalyzes BMAL1 acetylation and in turn activates transcription of Cry (s) and Per(s) and circadian‐controlled gene Nampt, a key enzyme for NAD biosynthesis. When NAD level rises during each circadian cycle, NAD stimulates SIRT1 enzymatic activity, which in turn deacetylates PER protein for proteasome degradation. SIRT1 also deacetylates BMAL1 and releases the repression of CRY:PER on BMAL1:CLOCK transcription activity. (B) The role adenosine monophosphate/adenosine triphosphate (AMP/ATP) levels in regulation of the molecular clock. High level of AMP activates AMPK, a cellular sensor for lower energy state. AMPK inhibits negative feedback loop via its activation of SIRT1 and phosphorylation CRY protein. AMPK‐dependent phosphorylation of CRY promotes its ubiquitianation and proteasome‐mediated degradation. In addition, AMPK enhances PER2 degradation by promoting the kinase activity of CKI ɛ/δ.



Figure 4.

The physiology and potential disease relevance of hepatic liver clock. The circadian network within the hepatocyte shares the same molecular structure with that found in the SCN. BMAL1:CLOCK activates the expression of Per and Cry while PER:CRY repress their own transcription via inhibiting BMAL1:CLOCK. The hepatic circadian clock can be entrained or phase shifted by a variety of hormones (insulin, glucagons, and glucocorticoid), nutrients (glucose, fatty acid, and bile acid) and environmental chemicals (Dioxin). Specific input signaling resets or shifts the molecular clock, subsequently affecting its output pathways, including nutrient metabolic pathways, xenobiotic metabolism, and cell‐cycle regulation. Impaired circadian clock might be an underlying mechanism for chronic liver diseases.

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Article Title: Circadian Rhythms in Liver Physiology and Liver Diseases
 

How to Cite

Xin Tong, Lei Yin. Circadian Rhythms in Liver Physiology and Liver Diseases. Compr Physiol 2013, 3: 917-940. doi: 10.1002/cphy.c120017