Aryl Hydrocarbon Receptor Deficiency Enhances Insulin Sensitivity and Reduces PPAR-α Pathway Activity in Mice

Wang, Chun; Xu, Chenghai; Krager, Stacey L.; Bottum, Kathleen M.; Liao, Duan‐Fang; Tischkau, Shelley A.

doi:10.1289/ehp.1103593

Cited by 116 publications

(110 citation statements)

References 42 publications

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“…For example, feeding-fasting cycles regulate the core clock, as well as output regulators such as the REVERBs and RORs that subsequently coordinate the oscillatory expression patterns of downstream genes. Accumulating evidence suggests that AhR activation regulates peripheral circadian clocks (Wang et al , 2011). TCDD-elicited differential gene expression and AhR enrichment suggest that interactions with circadian regulators may modulate the phase, period and/or amplitude of oscillating gene expression associated with fatty acid biosynthesis/metabolism, contributing to the progression of TCDD-elicited hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity

Fader

Nault

Kirby

et al. 2017

Toxicology and Applied Pharmacology

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Persistent aryl hydrocarbon receptor (AhR) agonists elicit dose-dependent hepatic lipid accumulation, oxidative stress, inflammation, and fibrosis in mice. Iron (Fe) promotes AhR-mediated oxidative stress by catalyzing reactive oxygen species (ROS) production. To further characterize the role of Fe in AhR-mediated hepatotoxicity, male C57BL/6 mice were orally gavaged with sesame oil vehicle or 0.01–30 μg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4 days for 28 days. Duodenal epithelial and hepatic RNA-Seq data were integrated with hepatic AhR ChIP-Seq, capillary electrophoresis protein measurements, and clinical chemistry analyses. TCDD dose-dependently repressed hepatic expression of hepcidin (Hamp and Hamp2), the master regulator of systemic Fe homeostasis, resulting in a 2.6-fold increase in serum Fe with accumulating Fe spilling into urine. Total hepatic Fe levels were negligibly increased while transferrin saturation remained unchanged. Furthermore, TCDD elicited dose-dependent gene expression changes in heme biosynthesis including the induction of aminolevulinic acid synthase 1 (Alas1) and repression of uroporphyrinogen decarboxylase (Urod), leading to a 50% increase in hepatic hemin and a 13.2-fold increase in total urinary porphyrins. Consistent with this heme accumulation, differential gene expression suggests that heme activated BACH1 and REV-ERBα/β, causing induction of heme oxygenase 1 (Hmox1) and repression of fatty acid biosynthesis, respectively. Collectively, these results suggest that Hamp repression, Fe accumulation, and increased heme levels converge to promote oxidative stress and the progression of TCDD-elicited hepatotoxicity.

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Section: Discussionmentioning

confidence: 99%

Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity

Fader

Nault

Kirby

et al. 2017

Toxicology and Applied Pharmacology

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“…Once activated, PPAR␣ induces expression of downstream genes that metabolize fatty acids. It has been recently shown to be a circadian target gene (35,(55)(56)(57). Differentiated embryo chondrocyte 1 (DEC1), also known as basic helix-loop-helix protein 2, Sharp-2, or STRA13, is a basic helix-loop-helix transcriptional factor that binds to E-box response elements.…”

Section: Identification Of Ppar␣ and Dec1 As Per1 Target Genes In Amlmentioning

confidence: 99%

Opposing actions of Per1 and Cry2 in the regulation of Per1 target gene expression in the liver and kidney

Richards

All

Skopis

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Mounting evidence suggests that the circadian clock plays an integral role in the regulation of many physiological processes including blood pressure, renal function, and metabolism. The canonical molecular clock functions via activation of circadian target genes by Clock/Bmal1 and repression of Clock/Bmal1 activity by Per1–3 and Cry1/2. However, we have previously shown that Per1 activates genes important for renal sodium reabsorption, which contradicts the canonical role of Per1 as a repressor. Moreover, Per1 knockout (KO) mice exhibit a lowered blood pressure and heavier body weight phenotype similar to Clock KO mice, and opposite that of Cry1/2 KO mice. Recent work has highlighted the potential role of Per1 in repression of Cry2. Therefore, we postulated that Per1 potentially activates target genes through a Cry2-Clock/Bmal1-dependent mechanism, in which Per1 antagonizes Cry2, preventing its repression of Clock/Bmal1. This hypothesis was tested in vitro and in vivo. The Per1 target genes αENaC and Fxyd5 were identified as Clock targets in mpkCCDc14 cells, a model of the renal cortical collecting duct. We identified PPARα and DEC1 as novel Per1 targets in the mouse hepatocyte cell line, AML12, and in the liver in vivo. Per1 knockdown resulted in upregulation of Cry2 in vitro, and this result was confirmed in vivo in mice with reduced expression of Per1. Importantly, siRNA-mediated knockdown of Cry2 and Per1 demonstrated opposing actions for Cry2 and Per1 on Per1 target genes, supporting the potential Cry2-Clock/Bmal1-dependent mechanism underlying Per1 action in the liver and kidney.

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“…1). The timing of the OGTT was chosen to correspond to a point near the peak of the daily glucose rhythm in C57BL/6 mice19. The 12 animals were handled twice prior to each test to acclimate them to the procedure, usually before the lights were switched off.…”

Section: Methodsmentioning

confidence: 99%

Glucose tolerance in mice exposed to light–dark stimulus patterns mirroring dayshift and rotating shift schedules

Figueiro

Radetsky

Plitnick

et al. 2017

Sci Rep

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Glucose tolerance was measured in (nocturnal) mice exposed to light–dark stimulus patterns simulating those that (diurnal) humans would experience while working dayshift (DSS) and 2 rotating night shift patterns (1 rotating night shift per week [RSS1] and 3 rotating night shifts per week [RSS3]). Oral glucose tolerance tests were administered at the same time and light phase during the third week of each experimental session. In contrast to the RSS1 and RSS3 conditions, glucose levels reduced more quickly for the DSS condition. Glucose area-under-the-curve measured for the DSS condition was also significantly less than that for the RSS1 and RSS3 conditions. Circadian disruption for the 3 light–dark patterns was quantified using phasor magnitude based on the 24-h light–dark patterns and their associated activity–rest patterns. Circadian disruption for mice in the DSS condition was significantly less than that for the RSS1 and RSS3 conditions. This study extends previous studies showing that even 1 night of shift work decreases glucose tolerance and that circadian disruption is linked to glucose tolerance in mice.

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Aryl Hydrocarbon Receptor Deficiency Enhances Insulin Sensitivity and Reduces PPAR-α Pathway Activity in Mice

Cited by 116 publications

References 42 publications

Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity

Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity

Opposing actions of Per1 and Cry2 in the regulation of Per1 target gene expression in the liver and kidney

Glucose tolerance in mice exposed to light–dark stimulus patterns mirroring dayshift and rotating shift schedules

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