NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in Mus musculus

Wible, R; Ramanathan, Chidambaram; Sutter, Carrie Hayes; Olesen, Kristin M.; Kensler, Thomas W.; Liu, Andrew C.; Sutter, Thomas R.

doi:10.7554/elife.31656

Cited by 97 publications

(90 citation statements)

References 72 publications

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“…In accordance with our study, the expression level of the Nrf2 shows circadian rhythm, and is higher at the start of inactive phase than that of the active phase in lung of mice [41]. On the other hand, both Nrf2 knockout mice and Keap1 knockout mice which is regarded as Nrf2 constitutive active mice, demonstrate disruption of circadian rhythm [42]. A Nrf2 activator, tertiary butylhydroquinone, also affects clock gene expression [42].…”

Section: Plos Onesupporting

confidence: 86%

“…On the other hand, both Nrf2 knockout mice and Keap1 knockout mice which is regarded as Nrf2 constitutive active mice, demonstrate disruption of circadian rhythm [42]. A Nrf2 activator, tertiary butylhydroquinone, also affects clock gene expression [42]. These reports suggest that luteolin can regulate the circadian rhythm though the Nrf2 activation.…”

Section: Plos Onementioning

confidence: 99%

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Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase

et al. 2020

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A flavone luteolin has various health-promoting activities. Several studies reported that high dose of luteolin activates the Nrf2/ARE pathway in the liver. However, the effect of the low dose of luteolin that can be taken from a dietary meal on the Nrf2 activation remain unclear. It is expected that the flavonoid metabolism possesses a circadian rhythm, since nutritional metabolism processes daily cycle. In this study we investigated whether an administration affects the Nrf2 activation. ICR mice were orally administered 0.01-10 mg/kg body weight of luteolin once a day for 7 days at two time-points: at the start of active phase (ZT12) or at that of inactive phase (ZT0). Luteolin increased the nuclear translocation of Nrf2, resulting in the increases in its target gene products HO-1 and NQO1 at ZT12 but not at ZT0. The expression level of Nrf2 was lower at ZT12 than at ZT0 in the liver. We also found that the level of luteolin aglycon in the plasma is higher at ZT12 than at ZT0. These results suggest that the low dose of luteolin can activate Nrf2 pathway and the aglycon form of luteolin may mainly contribute to activate the Nrf2 pathway at ZT12 in the liver. OPEN ACCESSCitation: Kitakaze T, Makiyama A, Yamashita Y, Ashida H (2020) Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase. PLoS ONE 15(4): e0231403. https://doi.org/10.beneficial functions for human health. However, most of study have not considered feeding time of flavonoids. Thus, the involvement of feeding time on the function of flavonoids remain unclear.Flavonoids possess various health-promoting activities as antioxidants. Evidences from the cultured cells and animal studies revealed that individual flavonoids have many health benefits, such as prevention of oxidative stress, inflammation and lipid accumulation [5,6]. Epidemiological studies suggest that high dietary intake of flavonoids is associated with lower risk of diseases including cardiovascular disease and several types of cancer [7,8]. The mean daily intake of flavonoids has been estimated in many countries; e.g., US (207.0 mg/day), Korea (318.0 mg/ day) and Spain (376.69 mg/day) [9][10][11]. A number of animal studies are intended to evaluate the effects of high dose of flavonoids (more than 10 mg/kg), but little is known about the function of low dose of flavonoids that can be taken from a dietary meal.Many flavonoids have antioxidant activity not only by its free radical scavenging ability but also by inducing the expression of antioxidant enzymes. Nuclear factor-erythroid-2-related factor 2 (Nrf2) belongs to the cap'n'collar basic leucine zipper family, and is a key regulator of oxidative stress in numerous types of cells, as well as hepatocytes. Nrf2 is primarily regulated by Kelch-like ECH-associated protein 1 (Keap1), a substrate adaptor for a cul3-containing E3 ubiquitin ligase [12]. Under the normal condition, Nrf2 interacts with Keap1 in the cytoplasm and is rapidly degraded by the ubiquitin-proteasome pathway ...

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Section: Plos Onesupporting

confidence: 86%

Section: Plos Onementioning

confidence: 99%

Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase

et al. 2020

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“…These studies used genetic or feeding regime manipulations, including restricted feeding, calorie restriction, high fat diet, and genetic models of type 2 diabetes, and showed that changes in animal metabolic homeostasis alter the clock function in the SCN and peripheral tissues such as the liver and heart[ 57 – 61 ]. Recent studies have revealed several input mechanisms: AMP-activated protein kinase (AMPK) phosphorylates CRY1 for accelerated degradation[ 62 ], NAD + -dependent deacetylase sirtuin-1 (SIRT1) promotes BMAL1 and PER2 deacetylation[ 63 – 65 ], poly(ADP-ribose) polymerase (PARP1) ribosylates CLOCK[ 66 ], NADP + /NADPH ratio and oxidative stress regulates BMAL1/CLOCK activity that involves the redox-sensitive antioxidative transcription factor NRF2[ 67 , 68 ], hypoxia-inducible factor 1-alpha (HIF1α) regulates Per2 transcription[ 69 – 71 ], and the tumor suppressor p53 modulates Per2 both at the transcriptional and post-transcriptional levels[ 72 , 73 ]. Our work provides additional mechanistic details about how the mTOR pathway links metabolic signals to the circadian clock function.…”

Section: Discussionmentioning

confidence: 99%

mTOR signaling regulates central and peripheral circadian clock function

et al. 2018

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The circadian clock coordinates physiology and metabolism. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of tissues and cells including the SCN, here we continued to investigate the role of mTOR in orchestrating autonomous clock functions in central and peripheral circadian oscillators. Using a combination of genetic and pharmacological approaches we show that mTOR regulates intrinsic clock properties including period and amplitude. In peripheral clock models of hepatocytes and adipocytes, mTOR inhibition lengthens period and dampens amplitude, whereas mTOR activation shortens period and augments amplitude. Constitutive activation of mTOR in Tsc2–/–fibroblasts elevates levels of core clock proteins, including CRY1, BMAL1 and CLOCK. Serum stimulation induces CRY1 upregulation in fibroblasts in an mTOR-dependent but Bmal1- and Period-independent manner. Consistent with results from cellular clock models, mTOR perturbation also regulates period and amplitude in the ex vivo SCN and liver clocks. Further, mTOR heterozygous mice show lengthened circadian period of locomotor activity in both constant darkness and constant light. Together, these results support a significant role for mTOR in circadian timekeeping and in linking metabolic states to circadian clock functions.

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“…Hydrogen sulphide (H 2 S), which acts as an entraining agent and population synchroniser, is also likely to act via transient inhibition of electron transport (Sohn, Murray, & Kuriyama, ). Timekeeping, redox state and cellular function are also closely intertwined in higher eukaryotes; in the SCN, daily redox rhythms modulate the activity of potassium channels and neuronal excitability (Wang et al., ; Wible et al., ).…”

Section: Characteristics Of Metabolic Rhythmsmentioning

confidence: 99%

Metabolic rhythms: A framework for coordinating cellular function

Causton

2018

Eur J of Neuroscience

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Circadian clocks are widespread among eukaryotes and generally involve feedback loops coupled with metabolic processes and redox balance. The organising power of these oscillations has not only allowed organisms to anticipate day–night cycles, but also acts to temporally compartmentalise otherwise incompatible processes, enhance metabolic efficiency, make the system more robust to noise and propagate signals among cells. While daily rhythms and the function of the circadian transcription‐translation loop have been the subject of extensive research over the past four decades, cycles of shorter period and respiratory oscillations, with which they are intertwined, have received less attention. Here, we describe features of yeast respiratory oscillations, which share many features with daily and 12 hr cellular oscillations in animal cells. This relatively simple system enables the analysis of dynamic rhythmic changes in metabolism, independent of cellular oscillations that are a product of the circadian transcription‐translation feedback loop. Knowledge gained from studying ultradian oscillations in yeast will lead to a better understanding of the basic mechanistic principles and evolutionary origins of oscillatory behaviour among eukaryotes.

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NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in Mus musculus

Cited by 97 publications

References 72 publications

Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase

Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase

mTOR signaling regulates central and peripheral circadian clock function

Metabolic rhythms: A framework for coordinating cellular function

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