Hepatic perilipin 5 is required for fasting-induced autophagy to prevent fatty acid-induced inflammation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE140024 | GEO | 2019/11/07
REPOSITORIES: GEO
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Project description:Hepatic perilipin 5 is required for fasting-induced autophagy to prevent fatty acid-induced inflammation
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Project description:Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health 1. The natural polyamine spermidine has been linked to autophagy regulation, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders 2. Here, we report that spermidine levels increase upon acute fasting in yeast, flies, mice and healthy humans. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, worms and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan-extending, cardioprotective and antiarthritic effects of intermittent fasting. Mechanistically, spermidine mediated these effects via hypusination of the autophagy regulator eIF5A. In sum, the polyamine-hypusination axis thus emerges as a bona fide and phylogenetically conserved metabolic control hub for longevity and autophagy induction.
2024-04-30 | PXD035909 | Pride
Project description:Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we identify Jumonji-D3 (JMJD3/KDM6B) histone demethylase as a key epigenetic activator of hepatic autophagy. Upon fasting-induced fibroblast growth factor-21 (FGF21) signaling, JMJD3 epigenetically upregulated global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increased its nuclear localization and interaction with the nuclear receptor PPARa to transcriptionally activate autophagy. Chronic administration of FGF21 in obese mice improved defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and bKL were substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.
2019-10-01 | GSE138157 | GEO
Project description:Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase
| PRJNA574943 | ENA
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
Project description:Animal models have been utilized to understand the pathogenesis of Zellweger spectrum disorders (ZSD), but the link between the clinical manifestations and molecular pathways has not yet been clearly established. We generated a peroxin 5 homozygous mutant zebrafish (pex5-/-) to gain insight into the molecular pathogenesis of peroxisome dysfunction. pex5-/- displays hallmarks of ZSD in humans and die within one month after birth. Fasting rapidly depletes the liver lipids and glycogen in pex5-/- and expedites their mortality. Mechanistically, abnormal mitochondrial activity and mechanistic target of rapamycin (mTOR) signaling act together to induce metabolic alterations to deplete the hepatic nutrients and accumulate the damaged mitochondria. Accordingly, the use of chemical interventions blocking either the mitochondrial activities or the mechanistic target of rapamycin complex 1 or a combination of both improves the metabolic imbalance shown in the fasted pex5-/- livers and extends the survival of the animals. Furthermore, the use of an autophagy activator also effectively ameliorated the early mortality of the fasted pex5-/-. These results suggest that fasting may be detrimental to patients with peroxisome dysfunction and that modulating the mitochondria, mTOR, or autophagy activities may provide a therapeutic option to alleviate the symptoms of peroxisomal diseases associated with metabolic dysfunction.
2022-06-05 | GSE205349 | GEO
Project description:Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we identify Jumonji-D3 (JMJD3/KDM6B) histone demethylase as a key epigenetic activator of hepatic autophagy. Upon fasting-induced fibroblast growth factor-21 (FGF21) signaling, JMJD3 epigenetically upregulated global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increased its nuclear localization and interaction with the nuclear receptor PPARa to transcriptionally activate autophagy. Chronic administration of FGF21 in obese mice improved defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and bKL were substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.
2019-09-18 | GSE137555 | GEO
Project description:ApoL6 is a new LD-associated protein containing an apoprotein-like domain, expressed mainly in adipose tissue, specifically in adipocytes. ApoL6 expression is low in fasting but induced upon feeding. ApoL6 knockdown results in smaller LD with lower triglyceride (TAG) content in adipocytes, while ApoL6 overexpression causes larger LD with higher TAG content. We show that ApoL6 effect in adipocytes is by inhibition of lipolysis. While ApoL6, Perilipin 1 (Plin1) and HSL can form a complex on LD, C-terminal domain of ApoL6 directly interacts with Plin1, to compete with Plin1 binding to HSL through Plin1 N-terminal domain, thereby keeping HSL in a stand by status. Thus, ApoL6 ablation decreases WAT mass, protecting mice from diet-induced obesity, while adipose overexpression increases WAT mass to bring obesity and insulin resistance with hepatosteatosis, making ApoL6 a potential future target against obesity and diabetes.
2024-05-24 | PXD038334 | Pride
Project description:Dietary restriction extends lifespan and delays the age-related physiological decline in many species. Intermittent fasting (IF) is one of the most effective dietary restriction regimens that extends lifespan in C. elegans and mammals1,2. In C. elegans, the FOXO transcription factor DAF-16 is implicated in fasting-induced gene expression changes and the longevity response to IF3; however, the mechanisms that sense and transduce fasting-stress stimuli have remained largely unknown. Here we show that a KGB-1/AP1 (activator protein 1) module is a key signalling pathway that mediates fasting-induced transcriptional changes and IF-induced longevity. Our promoter analysis coupled to genome-wide microarray results has shown that the AP-1-binding site, together with the FOXO-binding site, is highly over-represented in the promoter regions of fasting-induced genes. We find that JUN-1 (C. elegans c-Jun) and FOS-1 (C. elegans c-Fos), which constitute the AP-1 transcription factor complex, are required for IF-induced longevity. We also find that KGB-1 acts as a direct activator of JUN-1 and FOS-1, is activated in response to fasting, and, among the three C. elegans JNKs, is specifically required for IF-induced longevity. Our results demonstrate that most fasting-induced upregulated genes, including almost all of the DAF-16-dependent genes, require KGB-1 and JUN-1 function for their induction, and that the loss of kgb-1 suppresses the fasting-induced upregulation of DAF-16 target genes without affecting fasting-induced DAF-16 nuclear translocation. These findings identify the evolutionarily conserved JNK/AP-1 module as a key mediator of fasting-stress responses, and suggest a model in which two fasting-induced signalling pathways leading to DAF-16 nuclear translocation and KGB-1/AP-1 activation, respectively, integrate in the nucleus to coordinately mediate fasting-induced transcriptional changes and IF-induced longevity. To delineate the whole picture of transcriptional changes in response to fasting, we performed genome-wide gene expression analyses during 2 days (48 h) fasting. Two and three independent experiments were performed in the time course and mutants, respectively.
2013-03-15 | E-GEOD-27677 | biostudies-arrayexpress
Project description:Perilipin A (PeriA) exclusively locates on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Adipocyte specific overexpression of PeriA caused resistance to diet-induced obesity and resulted in improved insulin sensitivity. In order to better understand the biological basis for this observed phenotype we performed DNA microarray analysis on white adipose tissue (WAT) from PeriA transgenic (Tg) and control wildtype (WT) mice.
2010-05-13 | GSE21754 | GEO