Circadian Rhythms in the Pathogenesis and Treatment of Fatty Liver Disease
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)
- et al.
Peripheral circadian oscillators: time and food
Prog Mol Biol Transl Sci
(2013) - et al.
Circadian clock control of liver metabolic functions
Gastroenterology
(2016) - et al.
The circadian clock and liver function in health and disease
J Hepatol
(2019) - et al.
Daily eating patterns and their impact on health and disease
Trends Endocrinol Metab
(2016) - et al.
Medicine in the fourth dimension
Cell Metab
(2019) - et al.
The casein kinase 1 family: participation in multiple cellular processes in eukaryotes
Cell Signal
(2005) - et al.
A functional genomics strategy reveals Rora as a component of the mammalian circadian clock
Neuron
(2004) - et al.
The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator
Cell
(2002) - et al.
Nuclear receptor Rev-erbα: up, down, and all around
Trends Endocrinol Metab
(2014) - et al.
DEC1/STRA13/SHARP2 and DEC2/SHARP1 coordinate physiological processes, including circadian rhythms in response to environmental stimuli
Curr Top Dev Biol
(2014)
Cellular DBP and E4BP4 proteins are critical for determining the period length of the circadian oscillator
FEBS Lett
Glucagon-CREB/CRTC2 signaling cascade regulates hepatic BMAL1 protein
J Biol Chem
Circadian control of glucose metabolism
Mol Metab
CLOCK phosphorylation by AKT regulates its nuclear accumulation and circadian gene expression in peripheral tissues
J Biol Chem
Crosstalk between components of circadian and metabolic cycles in mammals
Cell Metab
The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control
Cell
Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice
J Hepatol
ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis
J Hepatol
Timing to perfection: the biology of central and peripheral circadian clocks
Neuron
CLOCK regulates circadian rhythms of hepatic glycogen synthesis through transcriptional activation of Gys2
J Biol Chem
Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism
Nature
AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice
Cell Metab
Short-term circadian disruption impairs bile acid and lipid homeostasis in mice
Cell Mol Gastroenterol Hepatol
Nuclear receptor expression links the circadian clock to metabolism
Cell
Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice
Lab Invest
Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial
Lancet
Bile acid synthesis in humans has a rapid diurnal variation that is asynchronous with cholesterol synthesis
Gastroenterology
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
Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease
J Hepatol
Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis
Gastroenterology
The mammalian circadian timing system: from gene expression to physiology
Chromosoma
Resetting central and peripheral circadian oscillators in transgenic rats
Science
Diurnal transcriptome atlas of a primate across major neural and peripheral tissues
Science
Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus
Genes Dev
Role of the circadian clock in the metabolic syndrome and nonalcoholic fatty liver disease
Dig Dis Sci
Circadian clock genes in the metabolism of non-alcoholic fatty liver disease
Front Physiol
Circadian rhythms: a possible new player in non-alcoholic fatty liver disease pathophysiology
J Mol Med (Berl)
Circadian rhythms of liver physiology and disease: experimental and clinical evidence
Nat Rev Gastroenterol Hepatol
The circadian regulation of food intake
Nat Rev Endocrinol
Circadian physiology of metabolism
Science
Circadian clocks and insulin resistance
Nat Rev Endocrinol
Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA
Cell Res
Analysis of gene regulatory networks in the mammalian circadian rhythm
PLoS Comput Biol
SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins
Science
Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon
Mol Cell Biol
Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock
Science
The orphan nuclear receptor RORα regulates circadian transcription of the mammalian core-clock Bmal1
Nat Struct Mol Biol
Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors
J Biol Rhythms
Dec1 and Dec2 are regulators of the mammalian molecular clock
Nature
Functional D-box sequences reset the circadian clock and drive mRNA rhythms
Commun Biol
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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.