Circadian Rhythms in the Pathogenesis and Treatment of Fatty Liver Disease

Saran, Anand; Dave, Shravan; Zarrinpar, Amir

doi:10.1053/j.gastro.2020.01.050

Cited by 102 publications

(96 citation statements)

References 199 publications

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“…6c ). These biological pathways were previously reported to show circadian variation 25 , supporting the regulation of the liver clock by SR9009. In the human hepatocytes unique pathways were seen including insulin, Ras, and hypoxia signaling, that may reflect species differences or the consequence of HBV infection.…”

Section: Resultssupporting

confidence: 76%

“…Lipid and bile acid metabolism are circadian regulated including the expression of transcription factors, peroxisome proliferator-activated receptor and sterol regulatory element-binding protein (reviewed in ref. 25 ) that have been reported to activate HBV transcription [26][27][28] . The liver-specific transcription factor HNF4α has been linked to HBV tropism 29 and interacts with circadian components BMAL1/CLOCK 30 and REV-ERB 31 .…”

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confidence: 99%

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Circadian control of hepatitis B virus replication

et al. 2021

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Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses.

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Section: Resultssupporting

confidence: 76%

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confidence: 99%

Circadian control of hepatitis B virus replication

et al. 2021

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“…These effects, combined with those known of PPARα/γ activation, deserve further investigation. Given the importance of circadian clock proteins in coordinating energy metabolism, the clock regulation of drug targets should also be taken into account in the development of pharmaceuticals for the treatment of NAFLD [420]. Despite recent remarkable and fast progress in the field, there are still many challenges imposed by the complex physiopathology underlying the development and progression of NAFLD, not least of all its heterogeneity, which is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Fougerat

Montagner

Loiseau

et al. 2020

Cells

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Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.

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“…For therapeutic treatment of metabolic diseases like NAFLD a strategy could be to give to patients more scheduled eating habits, the so-called chrononutrition. In this regard, time-restricted feeding (TRF), a behavioral approach where feeding is solely restricted to the circadian active phase not only prevents circadian misalignment but also has been shown to correct several metabolic pathologies in animal models [130][131][132]. TRF is distinct from intermittent fasting and when applied to humans, the amount of calory ingested is not relevant [130][131][132].…”

Section: Circadian Clock-related Therapeutic Interventionsmentioning

confidence: 99%

“…In this regard, time-restricted feeding (TRF), a behavioral approach where feeding is solely restricted to the circadian active phase not only prevents circadian misalignment but also has been shown to correct several metabolic pathologies in animal models [130][131][132]. TRF is distinct from intermittent fasting and when applied to humans, the amount of calory ingested is not relevant [130][131][132]. Importantly, several small-scale human TRF investigations have indicated its usefulness in improving outcomes in patients with metabolic syndromes [133][134][135], however, the usefulness of TRF on NAFLD endpoints are yet to be ascertained.…”

Section: Circadian Clock-related Therapeutic Interventionsmentioning

confidence: 99%

Perturbation of the circadian clock and pathogenesis of NAFLD

2020

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All living organisms including humans, experience changes in the light exposure generated by the Earth's rotation. In anticipation of this unavoidable geo-physical variability, and to generate an appropriate biochemical response, species of many phyla, including mammals have evolved a nearly 24-hour endogenous timing device known as the circadian clock (CC), which is self-sustained, cell autonomous and is present in every cell type. At the heart of the 'clock' functioning resides the CC-oscillator, an elegantly designed transcriptionaltranslational feedback system. Notably, the core components of the CC-oscillator not only drive daily rhythmicity of their own synthesis, but also generate circadian phase-specific variability in the expression levels of thousands of target genes through transcriptional, post-transcriptional and post-translational mechanisms. Thereby, this 'clock'-system provides proper chronological coordination in the functioning of cells, tissues and organs. The CC governs many physiologically critical functions. Among these functions, the key role of the CC in maintaining metabolic homeostasis deserves special emphasis. Indeed, the several features of the modern lifestyle (e.g. travelinduced jet lag, rotating shift work, energy-dense food) which, force disruption of circadian rhythms have recently emerged as a major driver to global health problems like obesity, cardiovascular disease and metabolic liver disease such as non-alcoholic fatty liver disease (NAFLD). Here we review, the CC-dependent pathways in different tissues which play critical roles in mediating several critical metabolic functions under physiological conditions and discuss their impact for the development of metabolic disease with a focus on the liver.

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Circadian Rhythms in the Pathogenesis and Treatment of Fatty Liver Disease

Cited by 102 publications

References 199 publications

Circadian control of hepatitis B virus replication

Circadian control of hepatitis B virus replication

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Perturbation of the circadian clock and pathogenesis of NAFLD

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