Gastroenterology

Gastroenterology

Volume 158, Issue 7, May 2020, Pages 1948-1966.e1
Gastroenterology

Circadian Rhythms in the Pathogenesis and Treatment of Fatty Liver Disease

https://doi.org/10.1053/j.gastro.2020.01.050Get rights and content

Circadian clock proteins are endogenous timing mechanisms that control the transcription of hundreds of genes. Their integral role in coordinating metabolism has led to their scrutiny in a number of diseases, including nonalcoholic fatty liver disease (NAFLD). Discoordination between central and peripheral circadian rhythms is a core feature of nearly every genetic, dietary, or environmental model of metabolic syndrome and NAFLD. Restricting feeding to a defined daily interval (time-restricted feeding) can synchronize the central and peripheral circadian rhythms, which in turn can prevent or even treat the metabolic syndrome and hepatic steatosis. Importantly, a number of proteins currently under study as drug targets in NAFLD (sterol regulatory element–binding protein [SREBP], acetyl-CoA carboxylase [ACC], peroxisome proliferator–activator receptors [PPARs], and incretins) are modulated by circadian proteins. Thus, the clock can be used to maximize the benefits and minimize the adverse effects of pharmaceutical agents for NAFLD. The circadian clock itself has the potential for use as a target for the treatment of NAFLD.

Section snippets

Molecular Organization of the Clock

The circadian clock in mammals, expressed in nearly every cell, is comprised of a series of transcription-translation feedback loops (Figure 2). These include circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1) as transcriptional activators. These are opposed by period (PER) and cryptochrome (CRY) as transcriptional repressors (Figure 3A). CLOCK and BMAL1 are two central components that make up the positive (or activation) limb of the molecular clock. The

The Circadian Clock Regulates Metabolic Processes

Hepatic metabolic processes, including glucose, lipid, and cholesterol/bile acid metabolism, are highly dynamic, influenced by feeding/fasting and circadian rhythms. Data supporting these relationships come from several lines of research, including metabolic phenotyping data from circadian clock genetically modified mouse lines, molecular biology studies showing direct interactions between regulators of nutrient homeostasis and circadian clock proteins, and the relationship of feeding/fasting

Luminal Content Entrains Hepatic Clock

The SCN functions as the master pacemaker and is sensitive to light signals but largely unresponsive to feeding patterns. On the other hand, the peripheral clock in the liver is dependent on feeding pattern for the amplitude and phase of the oscillation of its transcripts.4,121 Restricting feeding in mice to only the daytime (when they normally sleep) results in a phase shift between the central and peripheral clocks.81 Recent studies show that feeding is a stronger driver of rhythmic gene

Dyssynchrony and Metabolic Syndrome

Synchrony between the SCN and hepatic circadian clock temporally organizes the expression of a large number of metabolic regulatory genes to the daily pattern of food availability. In the absence of a robust hepatic circadian clock, the organism becomes susceptible to various metabolic disorders, including increased adiposity, ectopic steatosis, and insulin resistance.12 Genetically modified mouse lines affecting various clock genes show the interconnectedness between circadian rhythms and

Correction of Dyssynchrony With Time-Restricted Feeding

It was not clear until recently whether correcting circadian dyssynchrony is sufficient to reverse the dysmetabolic effects of these various insults. TRF, a behavioral paradigm where feeding is consolidated to the active period, aligns peripheral and central circadian rhythms.151 Correction of circadian dyssynchrony with TRF prevents and treats the metabolic consequences of a large variety of insults.12,152, 153, 154, 155 It should be noted that TRF is not synonymous with intermittent fasting;

Conclusion

NAFLD is a complex disease that is associated with a multitude of metabolic perturbations.7,165 Because many circadian clock–controlled genes are vital participants in metabolic processes of the body, it is not surprising that some of these rhythmic genes can be potential targets for therapy. Behavioral interventions, such as TRF, may have benefits in NAFLD that are independent of its weight loss effects. TRF may be easier for patients to adopt because it does not restrict calories or require a

References (200)

  • D. Yamajuku et al.

    Cellular DBP and E4BP4 proteins are critical for determining the period length of the circadian oscillator

    FEBS Lett

    (2011)
  • X. Sun et al.

    Glucagon-CREB/CRTC2 signaling cascade regulates hepatic BMAL1 protein

    J Biol Chem

    (2015)
  • A. Kalsbeek et al.

    Circadian control of glucose metabolism

    Mol Metab

    (2014)
  • A.K. Luciano et al.

    CLOCK phosphorylation by AKT regulates its nuclear accumulation and circadian gene expression in peripheral tissues

    J Biol Chem

    (2018)
  • G. Asher et al.

    Crosstalk between components of circadian and metabolic cycles in mammals

    Cell Metab

    (2011)
  • Y. Nakahata et al.

    The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control

    Cell

    (2008)
  • C.W. Lin et al.

    Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice

    J Hepatol

    (2013)
  • R. Fucho et al.

    ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis

    J Hepatol

    (2014)
  • U. Albrecht

    Timing to perfection: the biology of central and peripheral circadian clocks

    Neuron

    (2012)
  • R. Doi et al.

    CLOCK regulates circadian rhythms of hepatic glycogen synthesis through transcriptional activation of Gys2

    J Biol Chem

    (2010)
  • C. Liu et al.

    Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism

    Nature

    (2007)
  • Y. Li et al.

    AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice

    Cell Metab

    (2011)
  • J.M. Ferrell et al.

    Short-term circadian disruption impairs bile acid and lipid homeostasis in mice

    Cell Mol Gastroenterol Hepatol

    (2015)
  • X. Yang et al.

    Nuclear receptor expression links the circadian clock to metabolism

    Cell

    (2006)
  • J.H. Stroeve et al.

    Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice

    Lab Invest

    (2010)
  • B.A. Neuschwander-Tetri et al.

    Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

    Lancet

    (2015)
  • C. Galman et al.

    Bile acid synthesis in humans has a rapid diurnal variation that is asynchronous with cholesterol synthesis

    Gastroenterology

    (2005)
  • L. Abu-Elheiga et al.

    Acetyl-CoA carboxylase 2–/– mutant mice are protected against fatty liver under high-fat, high-carbohydrate dietary and de novo lipogenic conditions

    J Biol Chem

    (2012)
  • M. Pawlak et al.

    Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease

    J Hepatol

    (2015)
  • G.P. Aithal et al.

    Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis

    Gastroenterology

    (2008)
  • F. Gachon et al.

    The mammalian circadian timing system: from gene expression to physiology

    Chromosoma

    (2004)
  • S. Yamazaki et al.

    Resetting central and peripheral circadian oscillators in transgenic rats

    Science

    (2000)
  • L.S. Mure et al.

    Diurnal transcriptome atlas of a primate across major neural and peripheral tissues

    Science

    (2018)
  • F. Damiola et al.

    Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus

    Genes Dev

    (2000)
  • A. Shetty et al.

    Role of the circadian clock in the metabolic syndrome and nonalcoholic fatty liver disease

    Dig Dis Sci

    (2018)
  • D. Shi et al.

    Circadian clock genes in the metabolism of non-alcoholic fatty liver disease

    Front Physiol

    (2019)
  • D. Gnocchi et al.

    Circadian rhythms: a possible new player in non-alcoholic fatty liver disease pathophysiology

    J Mol Med (Berl)

    (2019)
  • Y. Tahara et al.

    Circadian rhythms of liver physiology and disease: experimental and clinical evidence

    Nat Rev Gastroenterol Hepatol

    (2016)
  • E. Challet

    The circadian regulation of food intake

    Nat Rev Endocrinol

    (2019)
  • S. Panda

    Circadian physiology of metabolism

    Science

    (2016)
  • D.J. Stenvers et al.

    Circadian clocks and insulin resistance

    Nat Rev Endocrinol

    (2019)
  • Z. Wang et al.

    Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

    Cell Res

    (2013)
  • J. Yan et al.

    Analysis of gene regulatory networks in the mammalian circadian rhythm

    PLoS Comput Biol

    (2008)
  • L. Busino et al.

    SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins

    Science

    (2007)
  • E. Vielhaber et al.

    Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon

    Mol Cell Biol

    (2000)
  • Y. Zhang et al.

    Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock

    Science

    (2015)
  • M. Akashi et al.

    The orphan nuclear receptor RORα regulates circadian transcription of the mammalian core-clock Bmal1

    Nat Struct Mol Biol

    (2005)
  • F. Guillaumond et al.

    Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors

    J Biol Rhythms

    (2005)
  • S. Honma et al.

    Dec1 and Dec2 are regulators of the mammalian molecular clock

    Nature

    (2002)
  • H. Yoshitane et al.

    Functional D-box sequences reset the circadian clock and drive mRNA rhythms

    Commun Biol

    (2019)
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    Conflicts of interest Dr Zarrinpar is a co-founder and equity holder of Tortuga Biosciences. The remaining authors disclose no conflicts.

    Funding Amir Zarrinpar is supported by K08 DK102902, R03 DK114536, R21 MH117780, and R01 HL148801. All authors receive institutional support from P30 DK120515, P30 DK063491, and UL1 TR001442.

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