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PPARα mouse liver cistrome

ABSTRACT: Autophagy is an evolutionally conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis1-3. Its acute regulation by nutrient sensing signaling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors PPARα and FXR are activated in the fasted or fed liver, respectively4,5. Here we show that both regulate hepatic autophagy. Pharmacologic activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (PPARα-/-) mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (FXR-/-) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status.

ORGANISM(S): Mus musculus

PROVIDER: GSE61817 | GEO | 2014/09/27

SECONDARY ACCESSION(S): PRJNA262387

REPOSITORIES: GEO

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PPARα mouse liver cistrome

Project description:Autophagy is an evolutionally conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis1-3. Its acute regulation by nutrient sensing signaling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors PPARα and FXR are activated in the fasted or fed liver, respectively4,5. Here we show that both regulate hepatic autophagy. Pharmacologic activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (PPARα-/-) mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (FXR-/-) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status. Mouse liver PPARα cistromes in fed 8-week-old male WT or PPARα KO mice treated with or without its synthetic agonist ligand GW7647twice a day were generated by deep sequencing in quadruplicate using illumina

2014-09-27 | E-GEOD-61817 | biostudies-arrayexpress

The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα

Project description:The class 3 phosphoinositide 3-kinase (PI3K) is required for the lysosomal degradation by autophagy and vesicular trafficking, assuring adaptation to energy shortages. Mitochondrial lipid catabolism is another important energy source. Autophagy and mitochondrial metabolism are transcriptionally controlled by nutrient sensing nuclear receptors. However, it is not known whether the class 3 PI3K contributes to this regulation. Here we show that hepatocyte-specific inactivation of Vps15, the essential regulatory subunit of the class 3 PI3K, results in mitochondrial depletion and a failure to oxidize fatty acids. Mechanistically, the transcriptional activity of Peroxisome Proliferator Activated Receptor alpha (PPARα), a nuclear receptor that orchestrates fatty acid catabolism, is blunted in Vps15-deficient livers. We find PPARα transcriptional repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15-deficient livers due to defective autophagic flux. Pharmacologic activation of PPARα with a synthetic ligand, re-expression of its co-activator Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α) or inhibition of Hdac3 restored mitochondrial biogenesis and lipid oxidation in Vps15-deficient hepatocytes. These findings reveal a role for the class 3 PI3K and autophagy in transcriptional coordination of mitochondrial metabolism.

2020-02-06 | E-MTAB-7685 | biostudies-arrayexpress

Steroidogenic Control of Liver Metabolism Through a Nuclear Receptor-Network

Project description:Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic-tissues are largely unknown. Here, we show that in the liver, the classical steroidogenic enzyme, Cyp17a1, forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyses the production of a hormone-ligand (DHEA) for PPARα, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPARα activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signalling, involving the receptors FXR, SHP and LRH-1. Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis.

2020-01-16 | PXD012876 | Pride

The nuclear receptors ERRα and PPARα co-ordinately control starvation-induced gene expression in hepatocytes.

Project description:Peroxisome-proliferator activated receptor α (PPARα) activation reprograms liver gene expression to support fatty acid oxidation during fasting. How PPARα engages in transcriptional programs coping with catabolic fasting responses is insufficiently understood. By applying a protein-protein interaction methodology that also captures transient interactions, we revealed the orphan nuclear receptor estrogen-related receptor α (ERRα) as a novel interaction partner of liganded PPARα and found that this interaction is enhanced following cellular nutrient starvation. Among target genes affected by PPARα-ERRα transcriptional crosstalk in fasted murine livers, multiple components of the electron transport chain were identified. Using pharmacological tools to study hepatic gene subsets under dual PPARα and ERRα control and moving from short-term to prolonged nutrient deprivation, we found that ERRα can switch from being a PPARα target gene suppressor to a marked PPARα target gene activator. Mechanistically, ERRα may control PPARα transcriptional activity via binding onto PPARα’s coactivator interaction site and via facilitating cofactor relays. In sum, a variety of crosstalk mechanisms between PPARα and ERRα seems to co-ordinately drive essential gene regulatory changes in the starving hepatocyte.

2024-04-01 | GSE200658 | GEO

Lipolysis-derived Lipids Determine Autophagy Initiation during Fasting

Project description:For survival, autophagy is a crucial intracellular self-degradation process to provide energy sources, helping adapt to nutrient deprivation. Although nutrient availability is a key determinant of autophagy initiation, it remains elusive underlying mechanism(s) of perceiving nutritional scarcity by which cells timely turn on autophagy as the last self-destructive process for energy supply. Here, we showed that PKA-dependent lipolysis can block the initiation of futile autophagy during short-term nutritional deprivation by repressing AMPK. Using Raman microscopy imaging and metabolomics, we found that autophagy occurred by reduction in available free fatty acids (FFAs) for energy sources. By modulating genes involved in lipolysis and fatty acid oxidation, we found that the use of lipolysis-derived FFAs precedes autophagy initiation. The dysregulated autophagy suppression during short-term fasting decreased motility and lifespan extension of worms. Taken together, these data suggest that PKA is a pivotal factor to orchestrate sophisticated catabolic pathways, preferring the use of PKA-mediated lipolytic products to repress futile autophagic degradation during short-term fasting through AMPK inhibition.

2022-04-27 | ST002206 | MetabolomicsWorkbench

Epigenetic and transcriptional regulation of starvation-induced atrophy and autophagy programs by Foxk1 and Sin3A

Project description:Autophagy is the primary catabolic process triggered in response to starvation. Although autophagic regulation within the cytosolic compartment is well established, it is becoming clear that nuclear events also regulate the induction or repression of autophagy. Nevertheless, a thorough understanding of the mechanisms by which sequence-specific transcription factors modulate expression of genes required for autophagy is lacking. Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy in muscle cells and fibroblasts. Interestingly, Foxk1/2 serve to counter-balance another forkhead transcription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets in muscle. Foxk1/2 specifically recruits Sin3A-HDAC complexes to restrict acetylation of histone H4 and expression of critical autophagy genes. Remarkably, mTOR promotes the transcriptional activity of Foxk1 by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions. Our study highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR to restrict autophagy by repressing essential autophagy genes via Foxk-Sin3-mediated transcriptional control. Examination of (1) chromatin binding of Foxk1 and Sin3A in non-starved myoblasts and (2) gene expression profiling upon either starvation or siRNA-mediated depletion of Foxk1 relative to a non-starved control.

2014-11-17 | E-GEOD-56932 | biostudies-arrayexpress

Transcriptomic profiling of human HAP1 cells before and after nutrient deprivation

Project description:Autophagy is a lysosomal degradation pathway critical for maintaining cellular homeostasis and viability, and is predominantly regarded as a rapid and dynamic cytoplasmic process. To improve our understanding of the transcriptional and epigenetic events associated with autophagy, we performed genome-wide transcriptomic and epigenomic profiling after nutrient deprivation in human wildtype and autophagy-deficient cells. We observed that nutrient deprivation leads to the transcriptional induction of numerous autophagy-associated genes. These transcriptional changes are reflected at the epigenetic level (H3K4me3, H3K27ac, and H3K56ac) and are independent of autophagic flux.

2018-09-28 | GSE107600 | GEO

Epigenetic profiling of human HAP1 cells before and after nutrient deprivation

2018-09-28 | GSE107599 | GEO

Regulatory Role for PC-TP/StarD2 in the Metabolic Response to Peroxisome Proliferator Activated Receptor Alpha (PPARα)

Project description:Phosphatidylcholine transfer protein (PC-TP, a.k.a StarD2) is abundantly expressed in liver and is regulated by PPARα. When fed the synthetic PPARα ligand fenofibrate, Pctp-/- mice exhibited altered lipid and glucose homeostasis. Microarray profiling of liver from fenofibrate fed wild type and Pctp-/- mice revealed differential expression of a broad array of metabolic genes, as well as their regulatory transcription factors. Because its expression controlled the transcriptional activities of both PPARα and HNF4α in cell culture, the broader impact of PC-TP on nutrient metabolism is most likely secondary to its role in fatty acid metabolism. 6 livers collected from PC-TP knockout mice fed a fenobrate-supplemented diet were used as the experimental group. 6 livers collected from wild type mice fed a fenofibrate-supplemented diet were used as the control group. RNA prepared from one liver was used to hybridize one GeneChip, so that there were 6 experimental GeneChips and 6 control GeneChips.

2010-08-12 | E-GEOD-17666 | biostudies-arrayexpress

Single cell RNA sequencing of mouse embryonic fibroblasts in autophagy processes

Project description:Autophagy, a catabolic process to remove unnecessary or dysfunctional cells, is triggered by various signals including nutrient starvation. Depending on the type of the nutrient deficiency, diverse sensing mechanisms and pathways are used for autophagy, suggesting subsequent nutrient dependent transcriptional regulation. Still, however, our knowledge about nutrient specific transcriptional regulation during autophagy is limited. To understand nutrient type dependent transcriptional mechanisms during autophagy, we performed single cell RNA sequencing (scRNAseq) for the mouse embryonic fibroblasts (MEFs) before and after applying glucose- (GS) as well as amino acid starvation (AAS). Trajectory analysis using scRNAseq identified sequential induction of potential transcriptional regulators for each deficiency condition. Gene regulatory rules inferred using TENET newly identified CCAAT/enhancer binding protein γ (C/EBPγ) regulates autophagy processes specifically to AAS condition. Strikingly, knockdown of C/EBPγ attenuated the autophagic process only in the AAS condition. Cell biological and biochemical studies validated that C/EBPγ plays a switching role for ATF4 to activate autophagy genes under AAS, but not under GS. Together, our data identified C/EBPγ as a previously unidentified key regulator under amino acid starvation-induced autophagy.

2021-12-01 | GSE189710 | GEO

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