<i>Drosophila</i> estrogen-related receptor directs a transcriptional switch that supports adult glycolysis and lipogenesis

Beebe, Katherine; Robins, M. Moreno; Hernández, Edgar Javier; Lam, Geanette; Horner, Michael A.; Thummel, Carl S.

doi:10.1101/gad.335281.119

Cited by 41 publications

(31 citation statements)

References 53 publications

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“…The hang gene encodes a neuronal nuclear RNA-binding protein that regulates transcript levels ( 12 ), and the ERR encodes a nuclear hormone receptor that induces a transcriptional switch ( 29 ). To investigate whether hang regulates the transcript of candidate genes, the transcript levels of the candidate genes were determined in the heads of the hang AE 10 mutants ( Figure 4B ).…”

Section: Resultsmentioning

confidence: 99%

ERR and dPECR Suggest a Link Between Neuroprotection and the Regulation of Ethanol Consumption Preference

Escarcena¹,

Neufeld²,

Rietschel³

et al. 2021

Front. Psychiatry

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Reconsumption of ethanol after withdrawal is a hallmark for relapse in recovering patients with alcohol use disorders. We show that the preference of Drosophila melanogaster to reconsume ethanol after abstinence shares mechanistic similarities to human behavior by feeding the antirelapse drug acamprosate to flies and reducing the ethanol consumption preference. The Drosophila cellular stress mutant hangover also reduced ethanol consumption preference. Together with the observation that an increasing number of candidate genes identified in a genome-wide association study on alcohol use disorders are involved in the regulation of cellular stress, the results suggest that cellular stress mechanisms might regulate the level of ethanol reconsumption after abstinence. To address this, we analyzed mutants of candidate genes involved in the regulation of cellular stress for their ethanol consumption level after abstinence and cellular stress response to free radicals. Since hangover encodes a nuclear RNA-binding protein that regulates transcript levels, we analyzed the interactions of candidate genes on transcript and protein level. The behavioral analysis of the mutants, the analysis of transcript levels, and protein interactions suggested that at least two mechanisms regulate ethanol consumption preference after abstinence—a nuclear estrogen-related receptor-hangover-dependent complex and peroxisomal trans-2-enoyl-CoA reductase (dPECR)-dependent component in peroxisomes. The loss of estrogen-like receptor and dPECR in neurons share a protective function against oxidative stress, suggesting that the neuroprotective function of genes might be a predictor for genes involved in the regulation of ethanol reconsumption after abstinence.

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Section: Resultsmentioning

confidence: 99%

ERR and dPECR Suggest a Link Between Neuroprotection and the Regulation of Ethanol Consumption Preference

Escarcena¹,

Neufeld²,

Rietschel³

et al. 2021

Front. Psychiatry

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“…In addition, genetic and pharmacological silencing of ERRα activity in mouse liver downregulates the expression of TCA cycle genes leading to the accumulation of various TCA intermediates and hepatic hyperlipidemia [ 34 ]. Interestingly, this function of the ERRs is profoundly conserved as a mutant of the drosophila ortholog of ERR (dERR) exhibits a similar reduction in TCA intermediates as well as a decrease in ETC components, resulting in a two-fold decrease in ATP levels in second-instar larvae [ 81 , 82 ].…”

Section: Transcriptional Control Of Ros Metabolism By the Errsmentioning

confidence: 99%

Transcriptional Regulation of ROS Homeostasis by the ERR Subfamily of Nuclear Receptors

Scholtes

Giguère

2021

Antioxidants

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Reactive oxygen species (ROS) such as superoxide anion (O2−) and hydrogen peroxide (H2O2) are generated endogenously by processes such as mitochondrial oxidative phosphorylation, or they may arise from exogenous sources like bacterial invasion. ROS can be beneficial (oxidative eustress) as signaling molecules but also harmful (oxidative distress) to cells when ROS levels become unregulated in response to physiological, pathological or pharmacological insults. Indeed, abnormal ROS levels have been shown to contribute to the etiology of a wide variety of diseases. Transcriptional control of metabolic genes is a crucial mechanism to coordinate ROS homeostasis. Therefore, a better understanding of how ROS metabolism is regulated by specific transcription factors can contribute to uncovering new therapeutic strategies. A large body of work has positioned the estrogen-related receptors (ERRs), transcription factors belonging to the nuclear receptor superfamily, as not only master regulators of cellular energy metabolism but, most recently, of ROS metabolism. Herein, we will review the role played by the ERRs as transcriptional regulators of ROS generation and antioxidant mechanisms and also as ROS sensors. We will assess how the control of ROS homeostasis by the ERRs can be linked to physiology and disease and the possible contribution of manipulating ERR activity in redox medicine.

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“…To more directly address potential metabolic functions for E78A, we compared our RNA-seq dataset to a list of genes that act in metabolism in Drosophila. 22 Interestingly, the third gene that is expressed at reduced levels on this list is a predicted lipase encoded by CG17192 (Figure 5B). This is the fifteenth most down-regulated gene in E78A mutant adults (Table S1).…”

Section: E78a Regulates Expression Of the Cg17192 Intestinal Lipase Genementioning

confidence: 99%

The Drosophila E78 nuclear receptor regulates dietary triglyceride uptake and systemic lipid levels

Praggastis¹,

Lam

Horner

et al. 2021

Developmental Dynamics

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Background: Lipid levels are maintained by balancing lipid uptake, synthesis, and mobilization. Although many studies have focused on the control of lipid synthesis and mobilization, less is known about the regulation of lipid digestion and uptake.Results: Here we show that the Drosophila E78A nuclear receptor plays a central role in intestinal lipid homeostasis through regulation of the CG17192 digestive lipase. E78A mutant adults fail to maintain proper systemic lipid levels following eclosion, with this effect largely restricted to the intestine. Transcriptional profiling by RNA-seq revealed a candidate gene for mediating this effect, encoding the predicted adult intestinal lipase CG17192. Intestinespecific disruption of CG17192 results in reduced lipid levels similar to that seen in E78A mutants. In addition, dietary supplementation with free fatty acids, or intestine-specific expression of either E78A or CG17192, is sufficient to restore lipid levels in E78A mutant adults. Conclusion:These studies support the model that E78A is a central regulator of adult lipid homeostasis through its effects on CG17192 expression and lipid digestion. This work also provides new insights into the control of intestinal lipid uptake and demonstrate that nuclear receptors can play an important role in these pathways.

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Drosophila estrogen-related receptor directs a transcriptional switch that supports adult glycolysis and lipogenesis

Cited by 41 publications

References 53 publications

ERR and dPECR Suggest a Link Between Neuroprotection and the Regulation of Ethanol Consumption Preference

ERR and dPECR Suggest a Link Between Neuroprotection and the Regulation of Ethanol Consumption Preference

Transcriptional Regulation of ROS Homeostasis by the ERR Subfamily of Nuclear Receptors

The Drosophila E78 nuclear receptor regulates dietary triglyceride uptake and systemic lipid levels

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