Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Hepatic Lipid Catabolism via PPAR?-Lysosomal Crosstalk.

ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which belong to the nuclear hormone receptor superfamily. They regulate key aspects of energy metabolism within cells. Recently, PPAR? has been implicated in the regulation of autophagy-lysosomal function, which plays a key role in cellular energy metabolism. PPAR? transcriptionally upregulates several genes involved in the autophagy-lysosomal degradative pathway that participates in lipolysis of triglycerides within the hepatocytes. Interestingly, a reciprocal regulation of PPAR? nuclear action by autophagy-lysosomal activity also exists with implications in lipid metabolism. This review succinctly discusses the unique relationship between PPAR? nuclear action and lysosomal activity and explores its impact on hepatic lipid homeostasis under pathological conditions such as non-alcoholic fatty liver disease (NAFLD).

SUBMITTER: Sinha RA

PROVIDER: S-EPMC7170715 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk.

Sinha Rohit A RA Rajak Sangam S Singh Brijesh K BK Yen Paul M PM

International journal of molecular sciences 20200331 7

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which belong to the nuclear hormone receptor superfamily. They regulate key aspects of energy metabolism within cells. Recently, PPARα has been implicated in the regulation of autophagy-lysosomal function, which plays a key role in cellular energy metabolism. PPARα transcriptionally upregulates several genes involved in the autophagy-lysosomal degradative pathway that participates in lipolysis of trigl ...[more]

PMID: 32244266

Similar Datasets

FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk.

Project description:The liver regulates energy partitioning and use in a sex-dependent manner, coupling hepatic substrate availability to female reproductive status. Fibroblast growth factor 21 (FGF21) is a hepatokine produced in response to metabolic stress that adaptively directs systemic metabolism and substrate use to reduce hepatic lipid storage. Here we report that FGF21 altered hepatic transcriptional and metabolic responses, and reduced liver triglycerides, in a sex-dependent manner. FGF21 decreased hepatic triglycerides in obese male mice in a weight loss-independent manner; this was abrogated among female littermates. The effect of FGF21 on hepatosteatosis is thought to derive, in part, from increased adiponectin secretion. Accordingly, plasma adiponectin and its upstream adrenergic receptor → cAMP → exchange protein directly activated by cAMP signaling pathway was stimulated by FGF21 in males and inhibited in females. Both ovariectomized and reproductively senescent old females responded to FGF21 treatment by decreasing body weight, but liver triglycerides and adiponectin remained unchanged. Thus, the benefit of FGF21 treatment for improving hepatosteatosis depends on sex but not on a functional female reproductive system. Because FGF21 provides a downstream mechanism contributing to several metabolic interventions, and given its direct clinical importance, these findings may have broad implications for the targeted application of nutritional and pharmacological treatments for metabolic disease.

| S-EPMC9675565 | biostudies-literature

ROR? controls hepatic lipid homeostasis via negative regulation of PPAR? transcriptional network.

Project description:The retinoic acid receptor-related orphan receptor-? (ROR?) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic ROR? controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-? (PPAR?) that mediates hepatic lipid metabolism. Liver-specific Ror?-deficient mice develop hepatic steatosis, obesity and insulin resistance when challenged with a high-fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Ror? leads to the dysregulation of PPAR? signaling and increases hepatic glucose and lipid metabolism. ROR? specifically binds and recruits histone deacetylase 3 (HDAC3) to PPAR? target promoters for the transcriptional repression of PPAR?. PPAR? antagonism restores metabolic homeostasis in HFD-fed liver-specific Ror? deficient mice. Our data indicate that ROR? has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate ROR? activity may be beneficial for the treatment of metabolic disorders.Hepatic steatosis development may result from dysregulation of lipid metabolism, which is finely tuned by several transcription factors including the PPAR family. Here Kim et al. show that the nuclear receptor ROR? inhibits PPAR?-mediated transcriptional activity by interacting with HDAC3 and competing for the promoters of lipogenic genes.

| S-EPMC5534431 | biostudies-literature

Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy.

Project description:For more than a century, thyroid hormones (THs) have been known to exert powerful catabolic effects, leading to weight loss. Although much has been learned about the molecular mechanisms used by TH receptors (TRs) to regulate gene expression, little is known about the mechanisms by which THs increase oxidative metabolism. Here, we report that TH stimulation of fatty acid ?-oxidation is coupled with induction of hepatic autophagy to deliver fatty acids to mitochondria in cell culture and in vivo. Furthermore, blockade of autophagy by autophagy-related 5 (ATG5) siRNA markedly decreased TH-mediated fatty acid ?-oxidation in cell culture and in vivo. Consistent with this model, autophagy was altered in livers of mice expressing a mutant TR that causes resistance to the actions of TH as well as in mice with mutant nuclear receptor corepressor (NCoR). These results demonstrate that THs can regulate lipid homeostasis via autophagy and help to explain how THs increase oxidative metabolism.

| S-EPMC3386813 | biostudies-other

Glucocorticoid receptor-PPAR? axis in fetal mouse liver prepares neonates for milk lipid catabolism.

Project description:In mammals, hepatic lipid catabolism is essential for the newborns to efficiently use milk fat as an energy source. However, it is unclear how this critical trait is acquired and regulated. We demonstrate that under the control of PPAR?, the genes required for lipid catabolism are transcribed before birth so that the neonatal liver has a prompt capacity to extract energy from milk upon suckling. The mechanism involves a fetal glucocorticoid receptor (GR)-PPAR? axis in which GR directly regulates the transcriptional activation of PPAR? by binding to its promoter. Certain PPAR? target genes such as Fgf21 remain repressed in the fetal liver and become PPAR? responsive after birth following an epigenetic switch triggered by ?-hydroxybutyrate-mediated inhibition of HDAC3. This study identifies an endocrine developmental axis in which fetal GR primes the activity of PPAR? in anticipation of the sudden shifts in postnatal nutrient source and metabolic demands.

| S-EPMC4963200 | biostudies-literature

SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPAR?.

Project description:The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPAR? signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPAR? and its response element within promoter regions and activates gene transcription. Sirt6+/- results in significantly reduced PPAR?-induced ?-oxidation and its metabolites and reduced alanine and lactate levels, while inducing pyruvate oxidation. Reciprocally, starved SIRT6 transgenic mice show increased pyruvate, acetylcarnitine, and glycerol levels and significantly induce ?-oxidation genes in a PPAR?-dependent manner. Furthermore, SIRT6 mediates PPAR? inhibition of SREBP-dependent cholesterol and triglyceride synthesis. Mechanistically, SIRT6 binds PPAR? coactivator NCOA2 and decreases liver NCOA2 K780 acetylation, which stimulates its activation of PPAR? in a SIRT6-dependent manner. These coordinated SIRT6 activities lead to regulation of whole-body respiratory exchange ratio and liver fat content, revealing the interactions whereby SIRT6 synchronizes various metabolic pathways, and suggest a mechanism by which SIRT6 maintains healthy liver.

| S-EPMC7165364 | biostudies-literature

Hepatic PPAR? function and lipid metabolic pathways are dysregulated in polymicrobial sepsis.

Project description:Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease; however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPAR? is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPAR? in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPAR? levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPAR? agonist pemafibrate protects against bacterial sepsis by improving hepatic PPAR? function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point toward new therapeutic leads in sepsis.

| S-EPMC7005534 | biostudies-literature

ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1.

Project description:Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic X receptors, and coactivation by PPAR-γ coactivator-1α or PPAR-γ coactivator-1β (PGC-1α or PGC-1β, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1β expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-α agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.

| S-EPMC3244833 | biostudies-literature

Erythropoietin alleviates hepatic insulin resistance via PPAR?-dependent AKT activation.

Project description:Erythropoietin (EPO) has beneficial effects on glucose metabolism and insulin resistance. However, the mechanism underlying these effects has not yet been elucidated. This study aimed to investigate how EPO affects hepatic glucose metabolism. Here, we report that EPO administration promoted phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation in palmitic acid (PA)-treated HepG2 cells and in the liver of high-fat diet (HFD)-fed mice, whereas adenovirus-mediated silencing of the erythropoietin receptor (EPOR) blocked EPO-induced AKT signalling in HepG2 cells. Importantly, a peroxisome proliferator-activated receptor ? (PPAR?) antagonist and PPAR? small interfering RNA (siRNA) abrogated the EPO-induced increase in p-AKT in HepG2 cells. Lentiviral vector-mediated hepatic PPAR? silencing in HFD-fed C57BL/6 mice impaired EPO-mediated increases in glucose tolerance, insulin sensitivity and hepatic AKT activation. Furthermore, EPO activated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signalling pathway, and AMPK? and SIRT1 knockdown each attenuated the EPO-induced PPAR? expression and deacetylation and PPAR?-dependent AKT activation in HepG2 cells. In summary, these findings suggest that PPAR? is involved in EPO/EPOR-induced AKT activation, and targeting the PPAR?/AKT pathway via EPO may have therapeutic implications for hepatic insulin resistance and type 2 diabetes.

| S-EPMC4672330 | biostudies-literature

PPAR-alpha dependent regulation of vanin-1 mediates hepatic lipid metabolism.

Project description:Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of hepatic fat oxidation that serves as an energy source during starvation. Vanin-1 has been described as a putative PPARα target gene in liver, but its function in hepatic lipid metabolism is unknown. We investigated the regulation of vanin-1, and total vanin activity, by PPARα in mice and humans. Furthermore, the function of vanin-1 in the development of hepatic steatosis in response to starvation was examined in Vnn1 deficient mice, and in rats treated with an inhibitor of vanin activity. Liver microarray analyses reveals that Vnn1 is the most prominently regulated gene after modulation of PPARα activity. In addition, activation of mouse PPARα regulates hepatic- and plasma vanin activity. In humans, consistent with regulation by PPARα, plasma vanin activity increases in all subjects after prolonged fasting, as well as after treatment with the PPARα agonist fenofibrate. In mice, absence of vanin-1 exacerbates the fasting-induced increase in hepatic triglyceride levels. Similarly, inhibition of vanin activity in rats induces accumulation of hepatic triglycerides upon fasting. Microarray analysis reveal that the absence of vanin-1 associates with gene sets involved in liver steatosis, and reduces pathways involved in oxidative stress and inflammation. We show that hepatic vanin-1 is under extremely sensitive regulation by PPARα and that plasma vanin activity could serve as a readout of changes in PPARα activity in human subjects. In addition, our data propose a role for vanin-1 in regulation of hepatic TG levels during fasting.

2014-04-24 | GSE51712 | GEO

PPAR-alpha dependent regulation of vanin-1 mediates hepatic lipid metabolism.

Project description:Peroxisome proliferator-activated receptor alpha (PPARÎ±) is a key regulator of hepatic fat oxidation that serves as an energy source during starvation. Vanin-1 has been described as a putative PPARÎ± target gene in liver, but its function in hepatic lipid metabolism is unknown. We investigated the regulation of vanin-1, and total vanin activity, by PPARÎ± in mice and humans. Furthermore, the function of vanin-1 in the development of hepatic steatosis in response to starvation was examined in Vnn1 deficient mice, and in rats treated with an inhibitor of vanin activity. Liver microarray analyses reveals that Vnn1 is the most prominently regulated gene after modulation of PPARÎ± activity. In addition, activation of mouse PPARÎ± regulates hepatic- and plasma vanin activity. In humans, consistent with regulation by PPARÎ±, plasma vanin activity increases in all subjects after prolonged fasting, as well as after treatment with the PPARÎ± agonist fenofibrate. In mice, absence of vanin-1 exacerbates the fasting-induced increase in hepatic triglyceride levels. Similarly, inhibition of vanin activity in rats induces accumulation of hepatic triglycerides upon fasting. Microarray analysis reveal that the absence of vanin-1 associates with gene sets involved in liver steatosis, and reduces pathways involved in oxidative stress and inflammation. We show that hepatic vanin-1 is under extremely sensitive regulation by PPARÎ± and that plasma vanin activity could serve as a readout of changes in PPARÎ± activity in human subjects. In addition, our data propose a role for vanin-1 in regulation of hepatic TG levels during fasting. Livers of wild type and vanin-1 knockout mice that were fed or fasted for 24h were subjected to gene expression analysis

2014-04-24 | E-GEOD-51712 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data