CREBH Regulates Mitochondrial Unfolded Protein Response to Maintain Energy Homeostasis
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ABSTRACT:
PROVIDER: PRJNA1184793 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31307887.fastq.gz | Fastqsanger.gz | |||
| SRR31307888.fastq.gz | Fastqsanger.gz | |||
| SRR31307889_1.fastq.gz | Fastqsanger.gz | |||
| SRR31307889_2.fastq.gz | Fastqsanger.gz | |||
| SRR31307890_1.fastq.gz | Fastqsanger.gz |
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Project description:The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.
2024-11-15 | GSE281608 | GEO
Project description:ER-tethered Stress Sensor CREBH Regulates Mitochondrial Unfolded Protein Response to Maintain Energy Homeostasis
| PRJNA1183368 | ENA
Project description:Cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is a transcription factor that regulates the expression of genes that control lipid and glucose metabolism, as well as inflammation. CREBH is upregulated in the liver under conditions of overnutrition, and mice globally lacking the gene (CREBH-/-) are highly susceptible to diet-induced obesity, insulin resistance (IR) and hepatic steatosis. The net protective effects of CREBH have been attributed in large part to the activities of Fibroblast growth factor (Fgf)-21 (Fgf21), a target gene that promotes weight loss, improves glucose homeostasis and reduces hepatic lipid accumulation. To explore the possibility that activation of the CREBH-Fgf21 axis could ameliorate established effects of high fat feeding, we generated an inducible transgenic hepatocyte-specific CREBH overexpression mouse model (Tg-rtTA). Acute overexpression of CREBH in livers of Tg-rtTA mice effectively reversed diet-induced obesity, IR and hepatic steatosis. These changes were associated with increased activities of thermogenic brown and beige adipose tissues in Tg-rtTA mice, leading to reductions in fat mass, along with enhanced insulin sensitivity and glucose tolerance. Genetically silencing of Fgf21 in Tg-rtTA mice abrogated the CREBH-mediated reductions in body weight loss, but only partially reversed the observed improvements in glucose metabolism. These findings reveal that the protective effects of CREBH activation may be leveraged to mitigate diet-induced obesity and associated metabolic abnormalities in both Fgf21-dependent and -independent pathways.
2021-04-30 | GSE173548 | GEO
Project description:To determine CREBH-mediated hepatic gene expression changes in hifh-fat high-sucrose (HFHS) dit feeding, we employed the microarray analysis. We collected the livers from male WT and CREBH-Tg mice fed with HFHS diet for 12 weeks from 6 weeks old.
2020-01-11 | GSE143421 | GEO
Project description:Fibroblast growth factor 21 (Fgf21) is a liver-derived, fasting-induced hormone with broad effects on growth, nutrient metabolism and insulin sensitivity. Here, we report the discovery of a novel mechanism regulating Fgf21 expression under growth and fasting-feeding. The Sel1LHrd1 complex is the most conserved branch of mammalian endoplasmic reticulum (ER)- associated degradation (ERAD) machinery. Mice with liver-specific deletion of Sel1L exhibit growth retardation with markedly elevated circulating Fgf21, reaching levels close to those in Fgf21 transgenic mice or pharmacological models. Mechanistically, we show that the Sel1LHrd1 ERAD complex controls Fgf21 transcription by regulating the ubiquitination and turnover (and thus nuclear abundance) of ER-resident transcription factor Crebh, while having no effect on the other well-known Fgf21 transcription factor Pparα. Our data reveal a physiologically regulated, inverse correlation between Sel1L-Hrd1 ERAD and Crebh-Fgf21 levels under fasting-feeding and growth. This study not only establishes the importance of Sel1L-Hrd1 ERAD in the liver in the regulation of systemic energy metabolism, but also reveals a novel hepatic “ERADCrebh- Fgf21” axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation.
2018-08-17 | GSE118658 | GEO
Project description:Homeostatic control mechanisms are essentil to life. One such mechanism, the unfolded protein response (UPR) operates in all eukarytic cells to adjust protein folding capacity of the endoplasmic reticulum (ER) according to need. UPR induction in all eurkarytic cells to date involves Ire1 (kinase/endonuclease transmembrane protein) mediated a non-convential splicing of Hac1/XBP1 mRNA, encoding for a potent transcription factor. UPR induction causes a comprehensive transcriptional upregulation of the folding capacity in the ER. Here we studied the global transcriptional profile of the UPR in fission yeast. Fission yeast lacks a clear homolog of Hac1/XBP1. Instead Ire1 maintains ER homeostasis through two post-transciptional programs: selective mRNA decay and processing of Bip1 mRNA (encoding for a major HS70-familiy member in the ER) thereby stabilizing it. S. pombe cells were grown in liquid medium (YE5S) to OD600=0.25. Cells were treated with or without 2 mM DTT (Dithiothreitol, impairs disulfid bond formation) for 60 min at 30℃. Total RNA was extracted from cells using hot phenol method. PolyA+ mRNA were enriched by two sequential rounds of oligo-dT (Invitrogen) selection. rRNA depletion was performed by depletion of ll RNA smaller than 200nt (mirVana miRNA Purification Kit (Ambion) followed by two rounds of subtractive hybridization using Ribominus EukaryoteKit for RNA-seq (Invitrogen). To sequence 2',3'-cyclic phosphate cleavage products tRNA ligase was used to selectively ligate an RNA linker to all 2',3'-cyclic phosphatesin total RNA. (described in Schutz et al., 2010). Two biological repeats were performed for the following samples with different conditions and yeast strains: poly A+ mRNA sample and mRNA enriched (ribosome depletion). On replicate was performed for RNA 3' end mapping carrying a 2',3'-cyclic phosphate: 1 replicate
2012-11-21 | E-GEOD-40298 | biostudies-arrayexpress
Project description:We show that mitochondrial aconitase, ACO-2, a Krebs cycle enzyme that catalyzes the conversion of citrate to isocitrate, inhibits immunity against pathogenic bacteria in C. elegans. We found that genetic inhibition of aco-2 enhanced mitochondrial unfolded protein response, subsequently upregulating ATFS-1 transcription factor, which contributed to enhanced immunity against pathogenic bacteria.
2023-06-01 | GSE181546 | GEO
Project description:To determine hepatic gene expression changes in fasted state, we employed the microarray analysis. We collected the livers from 8-weeks-old male WT and CREBH KO mice in both fasted and fed ad lib states.
2020-01-11 | GSE143420 | GEO
Project description:Homeostatic control mechanisms are essentil to life. One such mechanism, the unfolded protein response (UPR) operates in all eukarytic cells to adjust protein folding capacity of the endoplasmic reticulum (ER) according to need. UPR induction in all eurkarytic cells to date involves Ire1 (kinase/endonuclease transmembrane protein) mediated a non-convential splicing of Hac1/XBP1 mRNA, encoding for a potent transcription factor. UPR induction causes a comprehensive transcriptional upregulation of the folding capacity in the ER. Here we studied the global transcriptional profile of the UPR in fission yeast. Fission yeast lacks a clear homolog of Hac1/XBP1. Instead Ire1 maintains ER homeostasis through two post-transciptional programs: selective mRNA decay and processing of Bip1 mRNA (encoding for a major HS70-familiy member in the ER) thereby stabilizing it.
2012-11-21 | GSE40298 | GEO
Project description:Mitochondrial aconitase inhibits immunity via reducing mitochondrial unfolded protein response
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