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Biomedicines Oct 2023Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-binding transcription factors with pivotal action in regulating pleiotropic signaling pathways... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-binding transcription factors with pivotal action in regulating pleiotropic signaling pathways of energetic metabolism, immune responses and cell proliferation and differentiation. A significant body of evidence indicates that the PPARα receptor is an important modulator of plasma lipid and lipoprotein metabolism, with pluripotent effects influencing the lipid and apolipoprotein cargo of both atherogenic and antiatherogenic lipoproteins and their functionality. Clinical evidence supports an important role of PPARα agonists (fibric acid derivatives) in the treatment of hypertriglyceridemia and/or low high-density lipoprotein (HDL) cholesterol levels, although the effects of clinical trials are contradictory and point to a reduction in the risk of nonfatal and fatal myocardial infarction events. In this manuscript, we provide an up-to-date critical review of the existing relevant literature.
PubMed: 37893070
DOI: 10.3390/biomedicines11102696 -
JHEP Reports : Innovation in Hepatology Nov 2023The gut-liver axis modulates the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), a spectrum of conditions characterised by hepatic...
BACKGROUND & AIMS
The gut-liver axis modulates the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), a spectrum of conditions characterised by hepatic steatosis and a progressive increase of inflammation and fibrosis, culminating in metabolic dysfunction-associated steatohepatitis. Peroxisome proliferator-activated receptor-gamma coactivator 1α (Pgc1α) is a transcriptional co-regulator of mitochondrial activity and lipid metabolism. Here, the intestinal-specific role of Pgc1α was analysed in liver steatosis and fibrosis.
METHODS
We used a mouse model in which Pgc1α was selectively deleted from the intestinal epithelium. We fed these mice and their wild-type littermates a Western diet to recapitulate the major features of liver steatosis (after 2 months of diet) and metabolic dysfunction-associated steatohepatitis (after 4 months of diet). The chow diet was administered as a control diet.
RESULTS
In humans and mice, low expression of intestinal Pgc1α is inversely associated with liver steatosis, inflammation, and fibrosis. Intestinal disruption of Pgc1α impairs the transcription of a wide number of genes, including the cholesterol transporter Niemann-Pick C1-like 1 (), thus limiting the uptake of cholesterol from the gut. This results in a lower cholesterol accretion in the liver and a decreased production of new fatty acids, which protect the liver from lipotoxic lipid species accumulation, inflammation, and related fibrotic processes.
CONCLUSIONS
In humans and mice, intestinal Pgc1α induction during Western diet may be another culprit driving hepatic steatosis and fibrosis. Here, we show that enterocyte-specific Pgc1α ablation protects the liver from steatosis and fibrosis by reducing intestinal cholesterol absorption, with subsequent decrease of cholesterol and fatty acid accumulation in the liver.
IMPACT AND IMPLICATIONS
Liver diseases result from several insults, including signals from the gut. Although the incidence of liver diseases is continuously increasing worldwide, effective drug therapy is still lacking. Here, we showed that the modulation of an intestinal coactivator regulates the liver response to a Western diet, by limiting the uptake of dietary cholesterol. This results in a lower accumulation of hepatic lipids together with decreased inflammation and fibrosis, thus limiting the progression of liver steatosis and fibrosis towards severe end-stage diseases.
PubMed: 37886435
DOI: 10.1016/j.jhepr.2023.100853 -
MBio Aug 2023Peroxisomes are versatile eukaryotic organelles essential for many functions in fungi, including fatty acid metabolism, reactive oxygen species detoxification, and...
Peroxisomes are versatile eukaryotic organelles essential for many functions in fungi, including fatty acid metabolism, reactive oxygen species detoxification, and secondary metabolite biosynthesis. A suite of Pex proteins (peroxins) maintains peroxisomes, while peroxisomal matrix enzymes execute peroxisome functions. Insertional mutagenesis identified peroxin genes as essential components supporting the intraphagosomal growth of the fungal pathogen . Disruption of the peroxins Pex5, Pex10, or Pex33 in prevented peroxisome import of proteins targeted to the organelle via the PTS1 pathway. This loss of peroxisome protein import limited intracellular growth in macrophages and attenuated virulence in an acute histoplasmosis infection model. Interruption of the alternate PTS2 import pathway also attenuated virulence, although only at later time points of infection. The Sid1 and Sid3 siderophore biosynthesis proteins contain a PTS1 peroxisome import signal and localize to the peroxisome. Loss of either the PTS1 or PTS2 peroxisome import pathway impaired siderophore production and iron acquisition in , demonstrating compartmentalization of at least some biosynthetic steps for hydroxamate siderophore biosynthesis. However, the loss of PTS1-based peroxisome import caused earlier virulence attenuation than either the loss of PTS2-based protein import or the loss of siderophore biosynthesis, indicating additional PTS1-dependent peroxisomal functions are important for virulence. Furthermore, disruption of the Pex11 peroxin also attenuated virulence independently of peroxisomal protein import and siderophore biosynthesis. These findings demonstrate peroxisomes contribute to pathogenesis by facilitating siderophore biosynthesis and another unidentified role(s) for the organelle during fungal virulence. IMPORTANCE The fungal pathogen infects host phagocytes and establishes a replication-permissive niche within the cells. To do so, overcomes and subverts antifungal defense mechanisms which include the limitation of essential micronutrients. replication within host cells requires multiple distinct functions of the fungal peroxisome organelle. These peroxisomal functions contribute to pathogenesis at different times during infection and include peroxisome-dependent biosynthesis of iron-scavenging siderophores to enable fungal proliferation, particularly after activation of cell-mediated immunity. The multiple essential roles of fungal peroxisomes reveal this organelle as a potential but untapped target for the development of therapeutics.
Topics: Histoplasma; Virulence; Siderophores; Peroxins; Peroxisomes; Adaptation, Physiological
PubMed: 37432032
DOI: 10.1128/mbio.03284-22 -
BioRxiv : the Preprint Server For... Sep 2023Peroxisome biogenesis requires yet unidentified mitochondrial proteins. We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital...
UNLABELLED
Peroxisome biogenesis requires yet unidentified mitochondrial proteins. We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. MARCH5 knockout results in accumulation of immature peroxisomes and lower expression of various peroxisomal proteins. Upon fatty acid-induced peroxisomal biogenesis, MARCH5 redistributes to newly formed peroxisomes; the peroxisomal biogenesis under these conditions is inhibited in MARCH5 knockout cells. MARCH5 activity-deficient mutants are stalled on peroxisomes and induce accumulation of peroxisomes containing high levels of the OMM protein Tom20 (mitochondria-derived pre-peroxisomes). Furthermore, depletion of peroxisome biogenesis factor Pex14 leads to the formation of MARCH5- and Tom20-positive peroxisomes, while no peroxisomes are detected in Pex14/MARCH5 dko cells. Reexpression of WT, but not MARCH5 mutants, restores Tom20-positive pre-peroxisomes in Pex14/MARCH5 dko cells. Thus, MARCH5 acts upstream of Pex14 in mitochondrial steps of peroxisome biogenesis. Our data validate the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.
SUMMARY
The authors found that mitochondrial E3 Ub ligase MARCH5 controls the formation of mitochondria-derived pre-peroxisomes. The data support the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.
PubMed: 37693581
DOI: 10.1101/2023.08.31.555756 -
Frontiers in Medicine 2024Endometriosis constitutes the most common cause of chronic pelvic pain in female patients and is associated with infertility. Although there is no known cause for the... (Review)
Review
Endometriosis constitutes the most common cause of chronic pelvic pain in female patients and is associated with infertility. Although there is no known cause for the disease, it is a heritable condition that is determined by numerous genetic, epigenetic, and environmental aspects. Peroxisome proliferator-activated receptors (PPARs) represent nuclear receptor proteins that control gene expression. By using the MEDLINE and LIVIVO databases we conducted a literature review in order to look into the role of PPARs in the endometriosis pathophysiology and succeeded in revealing 36 pertinent publications between 2001 and 2022. In regards to PPAR expression in endometriosis, PPARγ seems to represent the most studied PPAR isoform in endometriosis and to influence various pathways involved in the disease onset and progression. It's interesting to note that diverse treatment agents targeting the PPAR system have been identified as innovative, effective therapeutic alternatives in the context of endometriosis treatment. In conclusion, PPARs appear to contribute an important role in both endometriosis pathophysiology and therapy.
PubMed: 38690174
DOI: 10.3389/fmed.2024.1329406 -
Cell Calcium Nov 2023Parkinson's disease (PD) is a neurodegenerative disease caused by multifactorial pathogenic mechanisms. Familial PD is linked with genetic mutations in genes whose...
Parkinson's disease (PD) is a neurodegenerative disease caused by multifactorial pathogenic mechanisms. Familial PD is linked with genetic mutations in genes whose products are either associated with mitochondrial function or endo-lysosomal pathways. Of note, mitochondria are essential to sustain high energy demanding synaptic activity of neurons and alterations in mitochondrial Ca signaling have been proposed as causal events for neurodegenerative process, although the mechanisms responsible for the selective loss of specific neuronal populations in the different neurodegenerative diseases is still not clear. Here, we specifically discuss the importance of a correct mitochondrial communication with the other organelles occurring at regions where their membranes become in close contact. We discuss the nature and the role of contact sites that mitochondria establish with ER, lysosomes, and peroxisomes, and how PD related proteins participate in the regulation/dysregulation of the tethering complexes. Unravelling molecular details of mitochondria tethering could contribute to identify specific therapeutic targets and develop new strategies to counteract the progression of the disease.
Topics: Humans; Parkinson Disease; Neurodegenerative Diseases; Signal Transduction; Mitochondria; Neurons
PubMed: 37597300
DOI: 10.1016/j.ceca.2023.102783 -
Revista Da Associacao Medica Brasileira... 2024Obesity is an increasingly prevalent global health problem, which is generally caused by the increase in body fat mass above normal and observed in all societies. If the...
OBJECTIVE
Obesity is an increasingly prevalent global health problem, which is generally caused by the increase in body fat mass above normal and observed in all societies. If the blood glucose level is higher than normal but not high enough to diagnose diabetes, this condition is defined as prediabetes. Adiponectin increases fatty acid oxidation and insulin sensitivity and is closely associated with obesity. One of the nuclear receptor superfamily member peroxisome proliferator-activated receptors is shown to have an important role in various metabolic reactions. This study aimed to investigate the serum levels of adiponectin and peroxisome proliferator-activated receptors-gamma parameters, which are closely related to adipose tissue, energy metabolism, and insulin sensitivity, in obese patients with and without prediabetes.
METHODS
For this purpose, 52 obese patients with prediabetes, 48 obese patients with non-prediabetes, and 76 healthy individuals were included in this study. Serum adiponectin and peroxisome proliferator-activated receptors-γ levels were analyzed by ELISA.
RESULTS
Serum adiponectin levels were significantly higher in obese patients with prediabetes (18.15±15.99) compared with the control group (15.17±15.67; p=0.42). No significant difference was observed in both adiponectin and peroxisome proliferator-activated receptors-γ levels in the obese patients with the non-prediabetes group compared with the control group. However, no significant difference was observed in the obese patients with prediabetes group and obese patients with non-prediabetes group.
CONCLUSION
Our results suggest that adiponectin may serve as an indicator of prediabetes. This implies that examining adiponectin levels in individuals diagnosed with prediabetes may enhance our understanding of the metabolic processes closely linked to prediabetes and related conditions.
Topics: Humans; Prediabetic State; PPAR gamma; Obesity; Adiponectin; Female; Male; Adult; Middle Aged; Case-Control Studies; Body Mass Index; Enzyme-Linked Immunosorbent Assay; Blood Glucose; Insulin Resistance
PubMed: 38655997
DOI: 10.1590/1806-9282.20231000 -
Frontiers in Microbiology 2023Despite the introduction of effective treatments for hepatitis C in clinics, issues remain regarding the liver disease induced by chronic hepatitis C virus (HCV)...
Despite the introduction of effective treatments for hepatitis C in clinics, issues remain regarding the liver disease induced by chronic hepatitis C virus (HCV) infection. HCV is known to disturb the metabolism of infected cells, especially lipid metabolism and redox balance, but the mechanisms leading to HCV-induced pathogenesis are still poorly understood. In an APEX2-based proximity biotinylation screen, we identified ACBD5, a peroxisome membrane protein, as located in the vicinity of HCV replication complexes. Confocal microscopy confirmed the relocation of peroxisomes near HCV replication complexes and indicated that their morphology and number are altered in approximately 30% of infected Huh-7 cells. Peroxisomes are small versatile organelles involved among other functions in lipid metabolism and ROS regulation. To determine their importance in the HCV life cycle, we generated Huh-7 cells devoid of peroxisomes by inactivating the PEX5 and PEX3 genes using CRISPR/Cas9 and found that the absence of peroxisomes had no impact on replication kinetics or infectious titers of HCV strains JFH1 and DBN3a. The impact of HCV on peroxisomal functions was assessed using sub-genomic replicons. An increase of ROS was measured in peroxisomes of replicon-containing cells, correlated with a significant decrease of catalase activity with the DBN3a strain. In contrast, HCV replication had little to no impact on cytoplasmic and mitochondrial ROS, suggesting that the redox balance of peroxisomes is specifically impaired in cells replicating HCV. Our study provides evidence that peroxisome function and morphology are altered in HCV-infected cells.
PubMed: 37808318
DOI: 10.3389/fmicb.2023.1254728 -
Frontiers in Physiology 2023
PubMed: 38143916
DOI: 10.3389/fphys.2023.1338852 -
Cell Reports Oct 2023The receptor protein PEX5, an important component of peroxisomes, regulates growth, development, and immunity in yeast and mammals. PEX5 also influences growth and...
The receptor protein PEX5, an important component of peroxisomes, regulates growth, development, and immunity in yeast and mammals. PEX5 also influences growth and development in plants, but whether it participates in plant immunity has remained unclear. Here, we report that knockdown of OsPEX5 enhances resistance to the rice blast fungus Magnaporthe oryzae. We demonstrate that OsPEX5 interacts with the E3 ubiquitin ligase APIP6, a positive regulator of plant immunity. APIP6 ubiquitinates OsPEX5 in vitro and promotes its degradation in vivo via the 26S proteasome pathway. In addition, OsPEX5 interacts with the aldehyde dehydrogenase OsALDH2B1, which functions in growth-defense trade-offs in rice. OsPEX5 stabilizes OsALDH2B1 to enhance its repression of the defense-related gene OsAOS2. Our study thus uncovers a previously unrecognized hierarchical regulatory mechanism in which an E3 ubiquitin ligase targets a peroxisome receptor protein that negatively regulates immunity in rice by stabilizing an aldehyde dehydrogenase that suppresses defense gene expression.
Topics: Magnaporthe; Ascomycota; Ubiquitin-Protein Ligases; Aldehyde Dehydrogenase; Plant Diseases; Disease Resistance; Plant Proteins; Gene Expression Regulation, Plant
PubMed: 37862164
DOI: 10.1016/j.celrep.2023.113315