Small Heterodimer Partner (NR0B2) Coordinates Nutrient Signaling and the Circadian Clock in Mice

Wu, Nan; Kim, Kang Ho; Zhou, Ying; Lee, Jae Man; Kettner, Nicole M.; Mamrosh, Jennifer L.; Choi, Sung-Woo; Fu, Loning; Moore, David D.

doi:10.1210/me.2015-1295

Cited by 13 publications

(10 citation statements)

References 38 publications

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“…Interestingly, Shp lost its rhythm in the 6M condition suggesting that Shp mRNA expression is more strongly driven by food intake than by the hepatic molecular clock. This fits with the suggestion that SHP could signal nutrient availability back to the clock, thereby linking metabolism upstream to the clock (Wu et al 2016). In further support of this concept, Shp expression did not only follow the daily rhythm in food intake when rats were on a chow diet, but also in both HF diet groups.…”

Section: Discussionsupporting

confidence: 86%

Complex interaction between circadian rhythm and diet on bile acid homeostasis in male rats

Eggink

Oosterman

Goede

et al. 2017

Chronobiology International

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Desynchronization between the master clock in the brain, which is entrained by (day) light, and peripheral organ clocks, which are mainly entrained by food intake, may have negative effects on energy metabolism. Bile acid metabolism follows a clear day/night rhythm. We investigated whether in rats on a normal chow diet the daily rhythm of plasma bile acids and hepatic expression of bile acid metabolic genes is controlled by the light/dark cycle or the feeding/fasting rhythm. In addition, we investigated the effects of high caloric diets and time-restricted feeding on daily rhythms of plasma bile acids and hepatic genes involved in bile acid synthesis. In experiment 1 male Wistar rats were fed according to three different feeding paradigms: food was available ad libitum for 24 h (ad lib) or time-restricted for 10 h during the dark period (dark fed) or 10 h during the light period (light fed). To allow further metabolic phenotyping, we manipulated dietary macronutrient intake by providing rats with a chow diet, a free choice high-fat-high-sugar diet or a free choice high-fat (HF) diet. In experiment 2 rats were fed a normal chow diet, but food was either available in a 6-meals-a-day (6M) scheme or ad lib. During both experiments, we measured plasma bile acid levels and hepatic mRNA expression of genes involved in bile acid metabolism at eight different time points during 24 h. Time-restricted feeding enhanced the daily rhythm in plasma bile acid concentrations. Plasma bile acid concentrations are highest during fasting and dropped during the period of food intake with all diets. An HF-containing diet changed bile acid pool composition, but not the daily rhythmicity of plasma bile acid levels. Daily rhythms of hepatic Cyp7a1 and Cyp8b1 mRNA expression followed the hepatic molecular clock, whereas for Shp expression food intake was leading. Combining an HF diet with feeding in the light/inactive period annulled CYp7a1 and Cyp8b1 gene expression rhythms, whilst keeping that of Shp intact. In conclusion, plasma bile acids and key genes in bile acid biosynthesis are entrained by food intake as well as the hepatic molecular clock. Eating during the inactivity period induced changes in the plasma bile acid pool composition similar to those induced by HF feeding. ARTICLE HISTORY

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Section: Discussionsupporting

confidence: 86%

Complex interaction between circadian rhythm and diet on bile acid homeostasis in male rats

Eggink

Oosterman

Goede

et al. 2017

Chronobiology International

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“…Among such ubiquitous sites the nuclear receptor Nr5a2/LRH-1 binding motif was highly enriched. Nr5a2 is a nuclear receptor that acts as a key metabolic sensor by regulating genes involved in bile acid synthesis and cholesterol homeostasis trough regulation of Cyp7a1 and Cyp8a1 circadian genes, triglyceride synthesis and lipid composition and metabolism (Chen et al, 2003;Chong, et al, 2012;Matsukuma, et al,, 2007;Wu et al, 2016). Interestingly, deficiencies in Nr5a2 are linked to non-alcoholic fatty liver disease where it seems to have an anti-inflammatory role (Schwaderer et al, 2020).…”

Section: Regulatory Elements Form Dynamic and Stable Chromatin Contacmentioning

confidence: 99%

The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle

Ando-Kuri

Arzate-Mejía

Morf

et al. 2020

Preprint

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SummaryCircadian gene expression is essential for organisms to adjust cellular responses and anticipate daily changes in the environment. In addition to its physiological importance, the clock circuit represents an ideal, temporally resolved, system to study transcription regulation. Here, we analysed changes in spatial mouse liver chromatin conformation using genome-wide and promoter-capture Hi-C alongside daily oscillations in gene transcription in mouse liver. We found circadian topologically associated domains switched assignments to the transcriptionally active, open chromatin compartment and the inactive compartment at different hours of the day while their boundaries stably maintain their structure over time. Individual circadian gene promoters displayed maximal chromatin contacts at times of peak transcriptional output and the expression of circadian genes and contacted transcribed regulatory elements, or other circadian genes, was phase-coherent. Anchor sites of promoter chromatin loops were enriched in binding sites for liver nuclear receptors and transcription factors, some exclusively present in either rhythmic or stable contacts. The circadian 3D chromatin maps provided here identify the scales of chromatin conformation that parallel oscillatory gene expression and protein factors specifically associated with circadian or stable chromatin configurations.

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“…SHP is a physiologically important nuclear receptor that acts as a transcriptional inhibitor of genes associated with various biological pathways ( 14 , 15 , 32 ). In the present study, alcohol-induced liver injury, as measured by AST and ALT levels in the plasma, was most severe in SHP-KO mice compared with WT mice.…”

Section: Discussionmentioning

confidence: 99%

Small heterodimer partner deficiency exacerbates binge drinking‑induced liver injury via modulation of natural killer T cell and neutrophil infiltration

Noh

Hwang

et al. 2018

Mol Med Report

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Binge drinking among alcohol consumers is a common occurrence, and may result in the development of numerous diseases, including liver disorders. It has previously been reported that natural killer T (NKT) cells induce alcohol-associated liver injury by promoting neutrophil infiltration. In the present study, the role of the orphan nuclear receptor small heterodimer partner (SHP), which is encoded by the NR0B2 gene, in acute binge drinking-induced liver injury was investigated. SHP-knockout (KO) and wild-type (WT) control mice were intragastrically administered single doses of alcohol. The plasma concentrations of alanine aminotransferase and aspartate aminotransferase in SHP-KO mice following alcohol treatment were significantly increased compared with WT mice. However, results of oil red O staining and 2′,7′-dichlorodihydrofluorescein diacetate staining indicated that levels of acute binge drinking-associated hepatic lipid accumulation and oxidative stress were not significantly different between WT and SHP-KO alcohol-treated mice. Notably, tumor necrosis factor-α mRNA expression in the liver of SHP-KO mice was significantly increased following alcohol administration, compared with WT mice. Furthermore, the mRNA expression levels of C-C motif chemokine ligand 2, C-X-C motif chemokine ligand 2 and interleukin-4, which are all potent chemoattractants of NKT cells, as well as neutrophil expression levels, were significantly increased in the livers of SHP-KO mice compared with WT mice following alcohol administration, as determined by reverse transcription-quantitative polymerase chain reaction and flow cytometry. Enhanced infiltration of NKT cells, determined by flow cytometry, was also demonstrated in the livers of SHP-KO mice following alcohol administration, compared with WT mice. The results of the present study indicate that SHP may be involved in liver-associated protective mechanisms, with regards to the attenuation of damage caused by acute binge drinking, via regulation of NKT cell and neutrophil migration to the liver. The modulation of SHP may be a novel therapeutic strategy for the treatment of acute binge drinking-induced liver injury.

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Small Heterodimer Partner (NR0B2) Coordinates Nutrient Signaling and the Circadian Clock in Mice

Cited by 13 publications

References 38 publications

Complex interaction between circadian rhythm and diet on bile acid homeostasis in male rats

Complex interaction between circadian rhythm and diet on bile acid homeostasis in male rats

The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle

Small heterodimer partner deficiency exacerbates binge drinking‑induced liver injury via modulation of natural killer T cell and neutrophil infiltration

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