Specific regulation of thermosensitive lipid droplet fusion by a nuclear hormone receptor pathway

Nuclear receptors play important roles in regulating fat metabolism and energy production in humans. The regulatory functions and endogenous ligands of many nuclear receptors are still unidentified, however. Here, we report that CYP-37A1 (ortholog of human cytochrome P450 CYP4V2), EMB-8 (ortholog of human P450 oxidoreductase POR), and DAF-12 (homolog of human nuclear receptors VDR/LXR) constitute a hormone synthesis and nuclear receptor pathway in Caenorhabditis elegans. This pathway specifically regulates the thermosensitive fusion of fat-storing lipid droplets. CYP-37A1, together with EMB-8, synthesizes a lipophilic hormone not identical to Δ7-dafachronic acid, which represses the fusion-promoting function of DAF-12. CYP-37A1 also negatively regulates thermotolerance and lifespan at high temperature in a DAF-12–dependent manner. Human CYP4V2 can substitute for CYP-37A1 in C. elegans. This finding suggests the existence of a conserved CYP4V2-POR–nuclear receptor pathway that functions in converting multilocular lipid droplets to unilocular ones in human cells; misregulation of this pathway may lead to pathogenic fat storage.

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Loss of autophagy impairs physiological steatosis by accumulation of NCoR1

Life Science Alliance ◽

10.26508/lsa.201900513 ◽

2019 ◽

Vol 3 (1) ◽

pp. e201900513 ◽

Cited By ~ 3

Author(s):

Shun-saku Takahashi ◽

Yu-Shin Sou ◽

Tetsuya Saito ◽

Akiko Kuma ◽

Takayuki Yabe ◽

...

Keyword(s):

Nuclear Receptors ◽

Nuclear Receptor ◽

Lipid Droplets ◽

Neutral Lipids ◽

Buffering Capacity ◽

Fine Tuning ◽

Dependent Manner ◽

Protein Levels ◽

Liver X Receptor Α ◽

Energy Excess

Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, such as after a meal. LDs serve as an energy reservoir during fasting and have a buffering capacity that prevents lipotoxicity. Autophagy and the autophagic machinery have been proposed to play a role in LD biogenesis, but the underlying molecular mechanism remains unclear. Here, we show that when nuclear receptor co-repressor 1 (NCoR1), which inhibits the transactivation of nuclear receptors, accumulates because of autophagy suppression, LDs decrease in size and number. Ablation of ATG7, a gene essential for autophagy, suppressed the expression of gene targets of liver X receptor α, a nuclear receptor responsible for fatty acid and triglyceride synthesis in an NCoR1-dependent manner. LD accumulation in response to fasting and after hepatectomy was hampered by the suppression of autophagy. These results suggest that autophagy controls physiological hepatosteatosis by fine-tuning NCoR1 protein levels.

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Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan in C. elegans

10.21203/rs.3.rs-452997/v1 ◽

2021 ◽

Author(s):

Anita Kumar ◽

Joslyn Mills ◽

Wesley Parker ◽

Joshua Leitão ◽

Celeste Ng ◽

...

Keyword(s):

Translational Regulation ◽

Lipid Droplets ◽

Dependent Manner ◽

Lipase Gene ◽

Triacylglycerol Lipase ◽

Selective Autophagy ◽

C Elegans ◽

Protein Ubiquitination ◽

Model Of Alzheimer’S Disease ◽

Age Related

Abstract The ability of organisms to live long depends largely on the maintenance of proteome stability via proteostatic mechanisms including translational regulation, protein chaperoning and degradation machineries. In several long-lived Caenorhabditis elegans strains, such as insulin/IGF-1 receptor daf-2 mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but the role of lipid droplets in longevity has remained obscure. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we unexpectedly uncovered a novel role for lipid droplets in proteostasis and longevity. Using an unbiased genomewide RNAi screening approach, we identified several SQST-1 modulators, including proteins found on lipid droplets and those prone to aggregate with age. SQST-1 accumulated on lipid droplets when autophagy was inhibited, suggesting that lipid droplets may serve a role in facilitating selective autophagy. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase gene atgl-1/ATGL enhanced autophagy, and extended lifespan in an HSF-1/HSF1-dependent and CDC-48/VCP-dependent manner. Silencing atgl-1 mitigated the age-related accumulation of SQST-1 and reduced overall ubiquitination of proteins. Reducing atgl-1 also improved proteostasis in a nematode model of Alzheimer’s disease. Subcellular analyses revealed that lipid droplets unexpectedly harbor more ubiquitinated proteins than the cytosol. Accordingly, low lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised. Altogether, our study uncovers a key role for lipid droplets in C. elegans as a proteostatic mediator that reduces protein ubiquitination, facilitates autophagy, and promotes longevity.

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Nuclear receptor coactivators: the key to unlock chromatin

Biochemistry and Cell Biology ◽

10.1139/o05-057 ◽

2005 ◽

Vol 83 (4) ◽

pp. 418-428 ◽

Cited By ~ 25

Author(s):

Wei Xu

Keyword(s):

Nuclear Receptors ◽

Nuclear Receptor ◽

Chromatin Remodeling ◽

Transcriptional Activation ◽

Transcriptional Control ◽

Biological Effects ◽

Gene Activation ◽

Nuclear Hormone Receptor ◽

Nuclear Receptor Coactivators ◽

Chromatin Remodeling Complex

The biological effects of hormones, ranging from organogenesis, metabolism, and proliferation, are transduced through nuclear receptors (NRs). Over the last decade, NRs have been used as a model to study transcriptional control. The conformation of activated NRs is favorable for the recruitment of coactivators, which promote transcriptional activation by directly communicating with chromatin. This review will focus on the function of different classes of coactivators and associated complexes, and on progress in our understanding of gene activation by NRs through chromatin remodeling.Key words: nuclear hormone receptor, p160 family of coactivators, histone modification, chromatin remodeling complex.

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Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators

Endocrine Reviews ◽

10.1210/er.2003-0023 ◽

2004 ◽

Vol 25 (1) ◽

pp. 45-71 ◽

Cited By ~ 626

Author(s):

Carolyn L. Smith ◽

Bert W. O’Malley

Keyword(s):

Estrogen Receptor ◽

Nuclear Receptors ◽

Nuclear Receptor ◽

Critical Role ◽

Dependent Manner ◽

Nuclear Receptor Superfamily ◽

Binding Domains ◽

Receptor Modulator ◽

Cellular Environment ◽

Receptor Modulators

Ligands for the nuclear receptor superfamily control many aspects of biology, including development, reproduction, and homeostasis, through regulation of the transcriptional activity of their cognate receptors. Selective receptor modulators (SRMs) are receptor ligands that exhibit agonistic or antagonistic biocharacter in a cell- and tissue context-dependent manner. The prototypical SRM is tamoxifen, which as a selective estrogen receptor modulator, can activate or inhibit estrogen receptor action. SRM-induced alterations in the conformation of the ligand-binding domains of nuclear receptors influence their abilities to interact with other proteins, such as coactivators and corepressors. It has been postulated, therefore, that the relative balance of coactivator and corepressor expression within a given target cell determines the relative agonist vs. antagonist activity of SRMs. However, recent evidence reveals that the cellular environment also plays a critical role in determining SRM biocharacter. Cellular signaling influences the activity and subcellular localization of coactivators and corepressors as well as nuclear receptors, and this contributes to gene-, cell-, and tissue-specific responses to SRM ligands. Increased understanding of the effect of cellular environment on nuclear receptors and their coregulators has the potential to open the field of SRM discovery and research to many members of the nuclear receptor superfamily.

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Nongenomic signaling of the retinoid X receptor through binding and inhibiting Gq in human platelets

Blood ◽

10.1182/blood-2006-05-022566 ◽

2007 ◽

Vol 109 (9) ◽

pp. 3741-3744 ◽

Cited By ~ 57

Author(s):

Leonardo A. Moraes ◽

Karen E. Swales ◽

Jessica A. Wray ◽

Amilcar Damazo ◽

Jonathan M. Gibbins ◽

...

Keyword(s):

G Protein ◽

Nuclear Receptors ◽

Nuclear Receptor ◽

Hormone Receptors ◽

Calcium Release ◽

Human Platelets ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

X Receptors

Abstract Retinoid X receptors (RXRs) are important transcriptional nuclear hormone receptors, acting as either homodimers or the binding partner for at least one fourth of all the known human nuclear receptors. Functional nongenomic effects of nuclear receptors are poorly understood; however, recently peroxisome proliferator-activated receptor (PPAR) \#947;, PPAR\#946;, and the glucocorticoid receptor have all been found active in human platelets. Human platelets express RXR\#945; and RXR\#946;. RXR ligands inhibit platelet aggregation and TXA2 release to ADP and the TXA2 receptors, but only weakly to collagen. ADP and TXA2 both signal via the G protein, Gq. RXR rapidly binds Gq but not Gi/z/o/t/gust in a ligand-dependent manner and inhibits Gq-induced Rac activation and intracellular calcium release. We propose that RXR ligands may have beneficial clinical actions through inhibition of platelet activation. Furthermore, our results demonstrate a novel nongenomic mode for nuclear receptor action and a functional cross-talk between G-protein and nuclear receptor signaling families.

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Glucocorticoid receptor interacts with PNRC2 in a ligand-dependent manner to recruit UPF1 for rapid mRNA degradation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1409612112 ◽

2015 ◽

Vol 112 (13) ◽

pp. E1540-E1549 ◽

Cited By ~ 30

Author(s):

Hana Cho ◽

Ok Hyun Park ◽

Joori Park ◽

Incheol Ryu ◽

Jeonghan Kim ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Nuclear Receptor ◽

Mrna Decay ◽

Rna Binding ◽

De Novo ◽

Mrna Degradation ◽

Nuclear Hormone Receptor ◽

Molecular Evidence ◽

Dependent Manner ◽

Coregulatory Protein

Glucocorticoid receptor (GR), which was originally known to function as a nuclear receptor, plays a role in rapid mRNA degradation by acting as an RNA-binding protein. The mechanism by which this process occurs remains unknown. Here, we demonstrate that GR, preloaded onto the 5′UTR of a target mRNA, recruits UPF1 through proline-rich nuclear receptor coregulatory protein 2 (PNRC2) in a ligand-dependent manner, so as to elicit rapid mRNA degradation. We call this process GR-mediated mRNA decay (GMD). Although GMD, nonsense-mediated mRNA decay (NMD), and staufen-mediated mRNA decay (SMD) share upstream frameshift 1 (UPF1) and PNRC2, we find that GMD is mechanistically distinct from NMD and SMD. We also identify de novo cellular GMD substrates using microarray analysis. Intriguingly, GMD functions in the chemotaxis of human monocytes by targeting chemokine (C-C motif) ligand 2 (CCL2) mRNA. Thus, our data provide molecular evidence of a posttranscriptional role of the well-studied nuclear hormone receptor, GR, which is traditionally considered a transcription factor.

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Nuclear hormone receptor NHR-49 shapes immuno-metabolic response of Caenorhabditis elegans to Enterococcus faecalis infection

10.1101/549907 ◽

2019 ◽

Cited By ~ 1

Author(s):

Madhumanti Dasgupta ◽

Meghana Shashikanth ◽

Nagagireesh Bojanala ◽

Anjali Gupta ◽

Salil Javed ◽

...

Keyword(s):

Enterococcus Faecalis ◽

Lipid Droplets ◽

Metabolic Response ◽

Lipid Synthesis ◽

Early Response ◽

Protective Role ◽

Nuclear Hormone Receptor ◽

Immune Effector ◽

C Elegans ◽

Nutritional Immunity

ABSTRACTImmune responses to pathogenic microbes include activation of resistance and tolerance mechanisms in the host both of which are energetically expensive. In this study, we show that C. elegans exposed to Gram positive bacteria Enterococcus faecalis and Staphylococcus aureus, rapidly utilizes lipid droplets, the major energy reserve in the nematode. Feeding on E. faecalis causes developmental arrest in C. elegans larvae and growth arrest in adults, pointing to starvation response. We find that nematode’s early response to infection entails upregulation of 25 genes involved in lipid hydrolysis and downregulation of 13 lipid synthesis genes as early as 8 hours following exposure. We also show that lipid droplets play a protective role in C. elegans during infection. NHR-49, a PPARα ortholog, is required for E. faecalis induced beta-oxidation of fatty acids and immune effector production. It regulates an immunometabolic axis required for survival of the nematode on E. faecalis. Our findings reveal a facet of nutritional immunity wherein lipid droplet homeostasis plays a central role in nematode microbe interactions.

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The Divergent Orphan Nuclear Receptor ODR-7 Regulates Olfactory Neuron Gene Expression via Multiple Mechanisms in Caenorhabditis elegans

Genetics ◽

10.1093/genetics/165.4.1779 ◽

2003 ◽

Vol 165 (4) ◽

pp. 1779-1791

Author(s):

Marc E Colosimo ◽

Susan Tran ◽

Piali Sengupta

Keyword(s):

Nuclear Receptors ◽

Nuclear Receptor ◽

Molecular Mechanisms ◽

Target Genes ◽

Receptor Gene ◽

Biological Processes ◽

Orphan Nuclear Receptor ◽

Olfactory Neurons ◽

C Elegans

Abstract Nuclear receptors regulate numerous critical biological processes. The C. elegans genome is predicted to encode ∼270 nuclear receptors of which >250 are unique to nematodes. ODR-7 is the only member of this large divergent family whose functions have been defined genetically. ODR-7 is expressed in the AWA olfactory neurons and specifies AWA sensory identity by promoting the expression of AWA-specific signaling genes and repressing the expression of an AWC-specific olfactory receptor gene. To elucidate the molecular mechanisms of action of a divergent nuclear receptor, we have identified residues and domains required for different aspects of ODR-7 function in vivo. ODR-7 utilizes an unexpected diversity of mechanisms to regulate the expression of different sets of target genes. Moreover, these mechanisms are distinct in normal and heterologous cellular contexts. The odr-7 ortholog in the closely related nematode C. briggsae can fully substitute for all ODR-7-mediated functions, indicating conservation of function across 25–120 million years of divergence.

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Hypoxia-inducible factor cell non-autonomously regulates C. elegans stress responses and behavior via a nuclear receptor

eLife ◽

10.7554/elife.36828 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 2

Author(s):

Corinne L Pender ◽

H Robert Horvitz

Keyword(s):

Cytochrome P450 ◽

Nuclear Receptor ◽

Stress Responses ◽

Neural Circuit ◽

Hypoxia Inducible Factor ◽

Nuclear Hormone Receptor ◽

Cytochrome P450 Enzyme ◽

C Elegans ◽

P450 Enzyme ◽

And Behavior

The HIF (hypoxia-inducible factor) transcription factor is the master regulator of the metazoan response to chronic hypoxia. In addition to promoting adaptations to low oxygen, HIF drives cytoprotective mechanisms in response to stresses and modulates neural circuit function. How most HIF targets act in the control of the diverse aspects of HIF-regulated biology remains unknown. We discovered that a HIF target, the C. elegans gene cyp-36A1, is required for numerous HIF-dependent processes, including modulation of gene expression, stress resistance, and behavior. cyp-36A1 encodes a cytochrome P450 enzyme that we show controls expression of more than a third of HIF-induced genes. CYP-36A1 acts cell non-autonomously by regulating the activity of the nuclear hormone receptor NHR-46, suggesting that CYP-36A1 functions as a biosynthetic enzyme for a hormone ligand of this receptor. We propose that regulation of HIF effectors through activation of cytochrome P450 enzyme/nuclear receptor signaling pathways could similarly occur in humans.

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Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan in C. elegans

10.1101/2021.04.22.440991 ◽

2021 ◽

Author(s):

Anita V. Kumar ◽

Joslyn Mills ◽

Wesley M. Parker ◽

Joshua A. Leitão ◽

Celeste Ng ◽

...

Keyword(s):

Translational Regulation ◽

Lipid Droplets ◽

Dependent Manner ◽

Lipase Gene ◽

Triacylglycerol Lipase ◽

Selective Autophagy ◽

C Elegans ◽

Protein Ubiquitination ◽

Model Of Alzheimer’S Disease ◽

Age Related

ABSTRACTThe ability of organisms to live long depends largely on the maintenance of proteome stability via proteostatic mechanisms including translational regulation, protein chaperoning and degradation machineries. In several long-lived Caenorhabditis elegans strains, such as insulin/IGF-1 receptor daf-2 mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but the role of lipid droplets in longevity has remained obscure. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we unexpectedly uncovered a novel role for lipid droplets in proteostasis and longevity. Using an unbiased genome-wide RNAi screening approach, we identified several SQST-1 modulators, including proteins found on lipid droplets and those prone to aggregate with age. SQST-1 accumulated on lipid droplets when autophagy was inhibited, suggesting that lipid droplets may serve a role in facilitating selective autophagy. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase gene atgl-1/ATGL enhanced autophagy, and extended lifespan in an HSF-1/HSF1-dependent and CDC-48/VCP-dependent manner. Silencing atgl-1 mitigated the age-related accumulation of SQST-1 and reduced overall ubiquitination of proteins. Reducing atgl-1 also improved proteostasis in a nematode model of Alzheimer’s disease. Subcellular analyses revealed that lipid droplets unexpectedly harbor more ubiquitinated proteins than the cytosol. Accordingly, low lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised. Altogether, our study uncovers a key role for lipid droplets in C. elegans as a proteostatic mediator that reduces protein ubiquitination, facilitates autophagy, and promotes longevity.

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