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Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies, ranging from steatosis to nonalcoholic steatohepatitis (NASH). The factors promoting the progression of steatosis to NASH are still unclear. Recent studies suggest that mitochondrial lipid composition is critical in NASH development. Here, we showed that CDP-DAG synthase 2 (Cds2) was downregulated in genetic or diet-induced NAFLD mouse models. Liver-specific deficiency of Cds2 provoked hepatic steatosis, inflammation and fibrosis in five-week-old mice. CDS2 is enriched in mitochondria-associated membranes (MAMs), and hepatic Cds2 deficiency impaired mitochondrial function and decreased mitochondrial PE levels. Overexpression of phosphatidylserine decarboxylase (PISD) alleviated the NASH-like phenotype in Cds2f/f;AlbCre mice and abnormal mitochondrial morphology and function caused by CDS2 deficiency in hepatocytes. Additionally, dietary supplementation with an agonist of peroxisome proliferator-activated receptor alpha (PPARα) attenuated mitochondrial defects and ameliorated the NASH-like phenotype in Cds2f/f;AlbCre mice. Finally, Cds2 overexpression protected against high-fat diet-induced hepatic steatosis and obesity. Thus, Cds2 modulates mitochondrial function and NASH development.

Many studies have demonstrated the protective effect of ergothioneine (EGT), the unique sulfur-containing antioxidant in mushrooms, on several aging-related diseases. Nevertheless, to date, no single study has explored the potential role of EGT in the lifespan of animal models. We show here that EGT consistently extended fly life span in diverse genetic backgrounds and both sexes, as well as in a dose and gender-dependent manner. Additionally, EGT is shown to increases the climbing activity of flies, enhances AchE activity, and maintains GSH/GSSG ratios of aged flies. An increase in life span by EGT was gut microorganisms dependent. Altogether, we proposed potential mechanisms of lifespan extension in Drosophila by EGT through RNA-seq analysis: preservation of the normal status of the central nervous system via the coordination of cholinergic neurotransmission, tyrosine metabolism, and peroxisomal proteins, regulated autophagic activity by altering the lysosomal protein CTSD, and the preservation of normal mitochondrial function through the controlled substrate feeding into the TCA cycle

Organelle-specific autophagy directs degradation of eukaryotic organelles under certain conditions. Like other organelles, peroxisomes are subject to autophagic turnover at lysosomes. However, peroxisome autophagy (pexophagy) has yet to be analyzed in a live-animal system, limiting knowledge on its regulation during an animal's life. Here, we generated a tandem-fluorophore reporter that enabled real-time tracking of pexophagy in live Caenorhabditis elegans. We observed that pexophagy occurred at a population of non-canonical, tubular lysosomes specifically during starvation and aging. Remarkably, in these contexts, tubular lysosomes were the predominant type of lysosome in the intestine, transforming from vesicles. Though we found that peroxisomes were largely eliminated in early adulthood, they appeared restored in new generations. We identified peroxisomal genes that regulated age-dependent peroxisome loss and demonstrated that modifying this process altered animal lifespan. These findings reveal new facets of peroxisome homeostasis relevant to aging and challenge the prevailing perception of lysosome homogeneity in autophagy.

Vascular mitochondria constantly integrate signals from environment and respond accordingly to match vascular function to metabolic requirements of the organ tissues, while mitochondrial dysfunction contributes to vascular aging and pathologies such as atherosclerosis, stenosis, and hypertension. As an effective lifestyle intervention, exercise induces extensive mitochondrial adaptations through vascular mechanical stress and the increased production and release of reactive oxygen species and nitric oxide that activate multiple intracellular signaling pathways, among which peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) plays a critical role. PGC-1α coordinates mitochondrial quality control mechanisms to maintain a healthy mitochondrial pool and promote endothelial nitric oxide synthase activity in vasculature. The mitochondrial adaptations to exercise improve bioenergetics, balance redox status, protect endothelial cells against detrimental insults, increase vascular plasticity, and ameliorate aging-related vascular dysfunction, thus benefiting vascular health. This review highlights recent findings of mitochondria as a central hub integrating exercise-afforded vascular benefits and its underlying mechanisms. A better understanding of the mitochondrial adaptations to exercise will not only shed light on the mechanisms of exercise-induced cardiovascular protection, but may also provide new clues to mitochondria-oriented precise exercise prescriptions for cardiovascular health.

BACKGROUND AND AIMS Globally, NAFLD is one of the most common liver disorders, with an estimated prevalence rate of more than 30% in men and 15% in women and an even higher prevalence in people with type 2 diabetes mellitus. Optimal pharmacologic therapeutic approaches for NAFLD are an urgent necessity. APPROACH AND RESULTS In this study, we showed that compared with healthy controls, hepatic ACSL4 levels in patients with NAFLD were found to be elevated. Suppression of ACSL4 expression promoted mitochondrial respiration, thereby enhancing the capacity of hepatocytes to mediate β-oxidation of fatty acids and to minimize lipid accumulation by up-regulating peroxisome proliferator-activated receptor coactivator-1 alpha. Moreover, we found that abemaciclib is a potent and selective ACSL4 inhibitor, and low dose of abemaciclib significantly ameliorated most of the NAFLD symptoms in multiple NAFLD mice models. CONCLUSIONS Therefore, inhibition of ACSL4 is a potential alternative therapeutic approach for NAFLD.

The sesquiterpene α-humulene has been shown to have anti-inflammatory and anticancer activities, which has led to its vast application potential in medicine. However, α-humulene production methods including phytoextraction and chemical synthesis currently were limited to low yield, high costs, and expensive catalysts, which cannot meet the increasing market demand. In this study, Yarrowia lipolytica was developed as a robust cell factory for α-humulene production. The peroxisome in Y. lipolytica was first engineered to boost the synthesis of the sesquiterpene α-humulene. By compartmentalization of the α-humulene biosynthesis pathway, improving ATP and acetyl-CoA supply, and optimizing the gene copy numbers of rate-limiting enzymes, the engineered strain GQ2012 could produce 3.2 g/L α-humulene in a 5 L bioreactor, the highest α-humulene titer reported so far. Our study provides a valuable reference for highly sustainable production of terpenoids by peroxisome engineering in Y. lipolytica.

The Hedgehog (Hh) signalling pathway plays a critical role in regulating liver lipid metabolism and related diseases. However, the underlying mechanisms are poorly understood. Here, we show that the Hh signalling pathway induces a previously undefined long non-coding RNA (Hilnc, Hedgehog signalling-induced long non-coding RNA), which controls hepatic lipid metabolism. Mutation of the Gli-binding sites in the Hilnc promoter region (HilncBM/BM) decreases the expression of Hilnc in vitro and in vivo. HilncBM/BM and Hilnc-knockout mice are resistant to diet-induced obesity and hepatic steatosis through attenuation of the peroxisome proliferator-activated receptor signalling pathway, as Hilnc directly interacts with IGF2BP2 to enhance Pparγ mRNA stability. Furthermore, we identify a potential functional human homologue of Hilnc, h-Hilnc, which has a similar function in regulating cellular lipid metabolism. These findings uncover a critical role of the Hh-Hilnc-IGF2BP2 signalling axis in lipid metabolism and suggest a potential therapeutic target for the treatment of diet-induced hepatic steatosis.

Developmental diapause is a widespread strategy for animals to survive seasonal starvation and environmental harshness. Diapaused animals often ration body fat to generate a basal level of energy for enduring survival. How diapause and fat rationing are coupled, however, is poorly understood. The nematode Caenorhabditis elegans excretes pheromones to the environment to induce a diapause form called dauer larva. Through saturated forward genetic screens and CRISPR knockout, we found that dauer pheromones feed back to repress the transcription of ACOX-3, MAOC-1, DHS-28, DAF-22 (peroxisomal β-oxidation enzymes dually involved in pheromone synthesis and fat burning), ALH-4 (aldehyde dehydrogenase for pheromone synthesis), PRX-10 and PRX-11 (peroxisome assembly and proliferation factors). Dysfunction of these pheromone enzymes and factors relieves the repression. Surprisingly, transcription is repressed not by pheromones excreted but by pheromones endogenous to each animal. The endogenous pheromones regulate the nuclear translocation of HNF4α family nuclear receptor NHR-79 and its co-receptor NHR-49, and, repress transcription through the two receptors. The feedback repression maintains pheromone homeostasis, increases fat storage, decreases fat burning, and prolongs dauer lifespan. Thus, the exocrine dauer pheromones possess an unexpected endocrine function to mediate a peroxisome-nucleus crosstalk, coupling dauer diapause to fat rationing.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor-type transcription factors that consist of three subtypes (α, γ, and β/δ) with distinct physiological functions and ligand recognition. PPARs regulate energy metabolism and therefore become therapeutic targets for various metabolic diseases. While PPARα agonists are used as anti-dyslipidemia drugs and PPARγ agonists as anti-type 2 diabetes drugs, PPAR dual/pan agonists (that acts on two or three subtypes) are expected to treat non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, etc. Structural analyses of PPAR-ligand-binding domain (LBD)-ligand co-crystals using X-ray crystallography have been done mainly on PPARγ, in which ligand-free apocrystals were prepared; however, the information on PPARα-LBD and PPARδ-LBD is limited. Recently, we succeeded to obtain 34 novel co-crystal structures of PPARα-LBD and various PPARα ligands (including fibrates) using various co-crystallization techniques. This procedure is applicable to preparation of PPARδ-LBD co-crystals, and contributes to molecular design of new PPAR targeted drugs based on all three PPAR-LBD structures.

Nonalcoholic fatty liver disease (NAFLD) has become one of the most prominent causes of chronic liver diseases and malignancies. However, few therapy has been approved. Radix Bupleuri (RB) is the most frequently used herbal medicine for the treatment of liver diseases. In the current study, we aim to systemically evaluate the therapeutic effects of saikosaponin A (SSa) and saikosaponin D (SSd), the major bioactive monomers in RB, against NAFLD and to investigate the underlying mechanisms. Our results demonstrated that both SSa and SSd improved diet-induced NAFLD. Integrative lipidomic and transcriptomic analysis revealed that SSa and SSd modulated glycerolipid metabolism by regulating related genes, like Lipe and Lipg. SSd profoundly suppressed the fatty acid biosynthesis by downregulating Fasn and Acaca expression and promoted fatty acid degradation by inducing Acox1 and Cpt1a expression. Bioinformatic analysis further predicted the implication of master transcription factors, including peroxisome proliferator-activated receptor alpha (PPARα), in the protective effects of SSa and SSd. These results were further confirmed in vitro in mouse primary hepatocytes. In summary, our study uncoded the complicated mechanisms underlying the promising anti-steatosis activities of saikosaponins (SSs), and provided critical evidence inspiring the discovery of innovative therapies based on SSa and SSd for the treatment of NAFLD and related complications., Graphical abstract Saikosaponins A and D (SSa and SSd) significantly alleviated diet-induced nonalcoholic fatty liver diseases by promoting promoted glycerolipid and fatty acid metabolism, as unraveled by integrative transcriptomic and lipidomic analysis.Image 1

Peroxisomes are the essential organelles in lipid metabolism. They contain enzymes for β-oxidation of very-long-chain fatty acids, which cannot break down in mitochondria. A reduced expression in hepatic Acyl-CoA oxidase1 (ACOX1), a peroxisome β-oxidation enzyme, followed by modification of the brain fatty acid profile has been seen in aged rodents. These studies have suggested a potential role for peroxisome β-oxidation in brain aging. This study was designed to examine the effect of hepatic ACOX1 inhibition on brain fatty acid composition and neuronal cell activities of young rats (200-250 g). A specific ACOX1 inhibitor, 10, 12- tricosadiynoic acid (TDYA), 100 μg/kg (in olive oil) was given by daily gavage administration for 25 days in male Wistar rats. The brain fatty acid composition and electrophysiological properties of dentate gyrus granule cells were determined by gas chromatography and whole-cell patch-clamp, respectively. A significant increase in C20, C22, C18:1, C20:1, and a decrease of C18, C24, C20:3n6 and C22:6n3 were found in TDYA treated rats compared to the control group. The results show that ACOX1 inhibition changes fatty acid composition similar to old rats. ACOX1 inhibition caused hyperpolarization of resting membrane potential, and also reduction of input resistance, action potential duration, and spike firing. Moreover, ACOX1 inhibition increased rheobase current and afterhyperpolarization amplitude in granule cells. The results indicate, systemic inhibition of ACOX1 causes hypo-excitability of neuronal cells. These findings provide a new evidence on the involvement of peroxisome function and hepatic ACOX1 activity in brain fatty acid profile and the electrophysiological properties of dentate gyrus cells.

The objective of the study was to investigate the effect of nobiletin on adipogenesis in 3T3-L1 cells. Here, we found that nobiletin could promote adipogenesis in 3T3-L1 cells in the absence of adipogenic inducers such as insulin, 3-Isobutyl-1-methylxanthine and dexamethasone. In addition, Real time quantitative PCR showed that the expression of adipogenic genes such as CCAAT/enhancer binding proteins, peroxisome proliferator-activated receptors-γ and fatty acid-binding protein aP2 were up-regulated in 3T3-L1 cells in the presence of nobiletin. Next, we investigated the role of Akt in the effect of nobiletin on the adipogenesis in 3T3-L1 cells by LY294002 blocking PI3K/Akt pathway. The experimental results showed that the promotive effect of nobiletin on adipogenesis was attenuated, accompanied by the down-regulation of adipogenic genes expression, after the activity of Akt was inhibited, suggesting that Akt plays an important role in the effect of nobiletin on promoting adipogenesis in 3T3-L1 cells. Still, the inhibition of Akt pathway by LY294002 was attenuated in the presence of nobiletin. These findings provide a possibility that nobiletin may be a potential candidate agent for stimulating Akt pathway in 3T3-L1 cells.

Peroxisomal disorders are a heterogeneous group of diseases caused by mutations in a large number of genes. One of the genetic disorders known to cause this situation is ACBD5 (Acyl-CoA binding-domain-containing-5) gene mutations that have been described in recent years. Here, we report two siblings with a novel homozygous nonsense variation (c.1297C>T, p.Arg433*) in ACBD5 (NM_145698.4) gene using Clinical Exome Sequencing (Sophia Genetics).

Subclinical necrotic enteritis (SNE) is a severe intestinal disease in broilers which brings huge economic losses to poultry industry. Herein, the effects of Bacillus amyloliquefaciens BLCC1-0238 (B. amyloliquefaciens BLCC1-0238) alone or in combination with mannan-oligosaccharides (MOS) on the SNE challenge model in broilers were comprehensively explored. A total of 360 broilers were randomly divided into 4 groups, including an SNE infection control (IC), an antibiotic pretreatment control (AC), a B. amyloliquefaciens BLCC1-0238 pretreatment (BP), and a B. amyloliquefaciens BLCC1-0238 + MOS pretreatment (BMP). The results showed that compared with the IC, three pretreatment groups significantly improved the growth performance, lowered the overall mortality, and reduced intestinal mucosal lesions in broilers. Additionally, the expression levels of claudin-3 and peroxisome proliferator-activated receptor-gamma coactivator-1α in the BP and BMP groups and the levels of mucin-2 and mechanistic target of rapamycin in the BMP group were significantly upregulated compared with the IC. By contrast, the expression levels of interferon-γ, interleukin-10, and secretory immunoglobulin A in the BP and BMP groups were significantly downregulated. In conclusion, these findings show that B. amyloliquefaciens BLCC1-0238 in combination with MOS can exert synergetic effects by the interplay between them on improving growth performance and combating the SNE infection in broilers.

Purpose: Quercetin has been reported as a more potent inhibitor of fat accumulation than other flavonoids. However, little information is available regarding the strength and mechanism of the repressive action of luteolin on fat accumulation. Therefore, the aim of the present study was to evaluate the comparative effects of luteolin and quercetin on the differentiation of 3T3-L1 preadipocytes into mature adipocytes. Methods: 3T3-L1 preadipocytes were differentiated by treatment with insulin, dexamethasone, and 3-isobutyl-1-methylxanthine in the presence of luteolin or quercetin. Alterations in triacylglycerol (TG) levels, lipid-filled adipocyte quantity, and the mRNA and protein expression levels of CCAAT-enhancer-binding protein α (C/EBPα) and peroxisome proliferator–activated receptor γ (PPARγ) were measured. Results: Both luteolin and quercetin reduced TG levels, the number of lipid-filled adipocytes, and the mRNA expression levels of C/EBPα and PPARγ; however, these effects occurred with lower concentrations of luteolin than quercetin. Conclusions: These results suggest that luteolin may be more potent than quercetin in inhibiting adipocyte differentiation. These effects may be explained by differences in the inhibitory effects of the two compounds on C/EBPα and PPARγ expression. This study suggests that luteolin might be a beneficial dietary supplement for obesity and lifestyle-related diseases.

Recently, nanozymes have attracted sustained attention for facilitating next generation of artificial enzymatic cascade systems (ECSs). However, the fabrication of integrated multi-ECSs based on a single nanozyme remains a great challenge. Here, inspired by the biological function and self-assembling ability of arginine (R), we synthesized arginine-rich peptide-Pt nanoparticle cluster (ARP-PtNC) nanozymes that mimic two typical enzymatic cascade systems of uricase/catalase and superoxide dismutase/catalase in natural peroxisome. ARPs containing at least 10 arginine residues contribute to the cluster formation based on hydrogen bonding and coordination. The well-designed peptide-Pt hybrid nanozyme not only possesses excellent uricase-mimicking activity to degrade uric acid effectively, but also serves as a desired scavenger for reactive oxygen species (ROS) harnessing two efficient enzyme cascade catalysis of uricase/catalase and superoxide dismutase/catalase. The surface microenvironment of the hybrid nanozymes provided by arginine-rich peptides and the cluster structure contribute to the efficient multiply enzyme-like activities. Fascinatingly, the hybrid nanozyme can inhibit the formation of monosodium urate monohydrate effectively based on the architecture of ARP-PtNCs. Thus, ARP-PtNC nanozyme has the potential in gout and hyperuricemia therapy. Rational design of ingenious peptide-metal hybrid nanozyme with unique physicochemical surface properties provides a versatile and designed strategy to fabricate multi-enzymatic cascade systems, which opens new avenues to broaden the application of nanozymes in practice.

Non-alcoholic fatty liver disease (NAFLD) represents a growing cause of liver morbidity and mortality globally with no proven effective therapy yet. The aim of this research is to investigate the effect of vitamin D treatment on choline deficient (CD) diet-induced nonalcoholic fatty liver disease (NAFLD) like lesions in rats, with the possible involvement of irisin in this effect. Thirty-two rats were divided into 4 equal groups; control group, vitamin D group, CD diet group, CD diet+ vitamin D group. It was found that CD diet led to significant elevations in liver weight and index, serum liver enzymes, hepatic triglycerides (TG), malondialdehyde (MDA), inflammatory markers with significant decreases in serum 25-(OH) D3, irisin, hepatic antioxidants and peroxisome proliferator–activated receptor alpha (PPAR–α). Administration of vitamin D caused a significant improvement in all previous parameters, these results were supported by histopathological examination. It seems that vitamin D supplementation significantly reduced NAFLD induced by CD diet even in part due to irisin.

Background: Multiple studies of tissue and cell samples from patients and pre-clinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. Peroxisomes interact with mitochondria physically and functionally, and congenital peroxisome biogenesis disorders can cause various phenotypes, including mitochondrial defects, metabolic abnormalities and renal cysts. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease. Methods: Using control and Pkd1-/-kidney epithelial cells, we investigated peroxisome abundance, biogenesis and morphology by immunoblotting, immunofluorescent and live cell imaging of peroxisome-related proteins and assayed peroxisomal specific β-oxidation. We further analyzed fatty acid composition by mass spectrometry in kidneys of Pkd1fl/fl; Ksp-Cre mice. We also evaluated peroxisome lipid metabolism in published metabolomics datasets of Pkd1 mutant cells and kidneys. Lastly, we investigated if the C-terminus or full-length polycystin-1 co-localize with peroxisome markers by imaging studies. Results: Peroxisome abundance, morphology and peroxisome-related protein expression in Pkd1 -/- cells were normal, suggesting preserved peroxisome biogenesis. Peroxisomal β-oxidation was not impaired in Pkd1-/-cells, and there was no obvious accumulation of very long chain fatty acids in kidneys of mutant mice. Re-analysis of published datasets provide little evidence of peroxisomal abnormalities in independent sets of Pkd1 mutant cells and cystic kidneys, while providing further evidence of mitochondrial fatty acid oxidation defects. Imaging studies with either full length polycystin-1 or its C-terminus, a fragment previously shown to go to the mitochondria, showed minimal co-localization with peroxisome markers restricted to putative mitochondrion-peroxisome contact sites. Conclusions: Our studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid (FA) metabolism.

The review presents data on the biological significance of plasmalogens, their synthesis in peroxisomes, subsequent transformation cascade, and the relevance of their role in the pathogenesis of a number of diseases. Plasmalogens, being a unique subclass of glycerophospholipids,play the role of structural proteins, signaling molecules, antioxidants. Deficiency of plasmalogens is known in genetically determined peroxisomal diseases – Refsum’s disease, rhizomelic point chondrodysplasia, Zellweger’s disease, etc. A number of age-related neurodegenerative diseases (Alzheimer’s, Parkinson’s) are also characterized by a decrease in the level of plasmalogens due to impaired synthesis and / or acceleration of their biodegradation. Along with the endogenous reasons for the decrease in the level of plasmalogens the authors consider the mechanism of their insufficient synthesis by anaerobes of the intestinal microbiota. These findings reinforce the clinicalrelevanceof the microbiota-gut-brain axis. Many companies allover the world develop drugs and biologically active additives (dietary supplements) with a high content of plasmalogens, being adsorbedin the small intestine and entering the targettissues and organs. The authors emphasizethe prospects of studying metabolites of intestinal microorganisms, directly or indirectly affecting developmental disorders in children, in particular, autism spectrum diseases.

Angiopoietin-like 4 (ANGPTL4) is a potent regulator of TAG metabolism, but knowledge of the mechanisms underlying ANGPTL4 transcription in response to fatty acids is still limited in teleost. In the current study, we explored the molecular characterisation of ANGPTL4 and regulatory mechanisms of ANGPTL4 in response to fatty acids in large yellow croaker (Larimichthys crocea). Here, croaker angptl4 contained a 1416 bp open reading frame encoding a protein of 471 amino acids with highly conserved 12-amino acid consensus motif. Angptl4 was widely expressed in croaker, with the highest expression in the liver. In vitro, oleic and palmitic acids (OA and PA) treatments strongly increased angptl4 mRNA expression in croaker hepatocytes. Moreover, angptl4 expression was positively regulated by PPAR family (PPAR-α, β and γ), and expression of PPARγ was also significantly increased in response to OA and PA. Moreover, inhibition of PPARγ abrogated OA- or PA-induced angptl4 mRNA expression. Beyond that, PA might increase angptl4 expression partly via the insulin signalling. Overall, the expression of ANGPTL4 is strongly upregulated by OA and PA via PPARγ in the liver of croaker, which contributes to improve the understanding of the regulatory mechanisms of ANGPTL4 in fish.

Aims Increasing preclinical and clinical reports have demonstrated the efficacy of gabapentin (GBP) in treating alcohol use disorder (AUD). However, the mechanism of the effects of GBP in AUD is largely unknown. Herein, we sought to investigate the effect of GBP in a rat model of AUD and explore the underlying mechanism. Methods The intermittent access to 20% ethanol in a 2-bottle choice (IA2BC) procedure was exploited to induce high voluntary ethanol consumption in rats. The rats were treated daily for 20 days with different doses of GBP, simultaneously recording ethanol/water intake. The locomotor activity and grooming behavior of rats were also tested to evaluate the potential effects of GBP on confounding motor in rats. The levels of IL-1β and TNF-α in serum and hippocampus homogenate from the rats were detected by using ELISA. The expressions of peroxisome proliferator-activated-receptor γ (PPAR-γ) and nuclear factor-κB (NF-κB) in the hippocampus were determined by immunofluorescence and western blot. Results GBP reduced alcohol consumption, whereas increased water consumption and locomotor activity of rats. GBP was also able to decrease the levels of IL-1β and TNF-α in both serum and hippocampus, in addition to the expression of NF-κB in the hippocampus. Furthermore, these effects attributed to GBP were observed to disappear in the presence of bisphenol A diglycidyl ether (BADGE), a specific inhibitor of PPAR-γ. Conclusions Our findings revealed that GBP could activate PPAR-γ to suppress the NF-κB signaling pathway, contributing to the decrease of ethanol consumption and ethanol-induced neuroimmune responses.

The article deals with the modern principles for the diagnosis and treatment of peroxisomal biogenesis disorders of Zellweger syndrome spectrum according to the recommendations of the Global Foundation for Peroxisomal Disorders 2016. The authors presented the clinical features of these diseases. The lesions of the nervous, bone, urinary, endocrine, sensory systems and tooth enamel are characteristic signs of the disease. Our own clinical observation on the disturbances of oxidation of very long chain fatty acids in an infant is considered separately. Section of Zellweger spectrum disorders diagnosis is based on world standards for disease diagnosis and includes markers of very long-chain fatty acid β-oxidation, as well as α-oxidation by pristanic and phytanic acids, metabolism of pipecolic acid and other peroxisomal dysfunctions. The final diagnosis of peroxisomal biogenesis disorders in Zellweger syndrome spectrum at the present stage is established by the genetic testing method, ­using the sequencing techniques of the new generation for the PEX genes. The severity of neurological disorders and the progressive course of the disease, as well as emergence of the possibility of treating X-linked adrenoleukodystrophy opened the prospects of screening for X-linked adrenoleukodystrophy based on a combination of liquid chromatography and tandem mass spectrometry to detect the elevated levels of very long-chain fatty acids in newborns in blood spots. Clinical monitoring since diagnosis was established includes correction of initial disturbances and revealing disease symptoms, which appear later.

Peroxisome proliferator-activated receptor (PPAR)β/δ activation is a potential target for modulation of inflammation in cardiovascular disease. PPARβ/δ activation depends on the presence of a ligan...

We report on the in vitro and ex vivo effects of chiral (R)-10-hydroxystearic acid (10-HSA) compared with other mono-hydroxystearic acid regioisomers and stearic acid (SA) together with its benefit when combined with retinol.Following treatment with hydroxystearic acids peroxisomal proliferator-activated receptor alpha (PPARα) activity was determined in a luciferase reporter gene assay, collagen type I was assessed in primary human dermal fibroblasts by immunohistochemistry, modification of the intracellular fibroblast collagen proteome was studied by mass-spectrometry-based proteomics and collagen type III was assessed by immunohistochemistry on human ex vivo skin.10-HSA was the most effective PPARα agonist (15.7× induction; p 0.001), followed by 9-HSA (10.1× induction) and then 12-HSA (4.9× induction) with 17-HSA (1.7× induction) being similar to the effects of stearic acid (1.8× induction). Collagen type I levels were increased in primary human fibroblasts by 2.12× and 1.56× for 10-HSA and 9-HSA, respectively, in vitro with the10-HSA being significant (p 0.05), whereas 12-HSA and SA had no statistical effect over the untreated control. 10-HSA and 12-HSA modified the intracellular fibroblast collagen proteome slightly with significant increases in collagen alpha-1 (VI) and alpha-3 (VI) proteins but only 10-HSA increased levels of collagen alpha-2 (V), alpha-1 (III), alpha-1 (I) and alpha-2 (I) (all p 0.05) with the increases being significantly different between 10-HSA and 12-HSA for collagen alpha-1 (I), collagen-3 (VI) and collagen alpha-2 (I) (p 0.01). Collagen type III in ex vivo skin was increased +47% (p 0.05) by 0.05% (1.7 mM) retinol, +70% (p 0.01) by 0.01% (0.33 mM) 10-HSA and the combination increased levels by +240% (p 0.01 for either ingredient).Chiral (R)-10-HSA has been shown to be superior to 9, 12 and 17-HSA as a PPARα agonist. Moreover, 10-HSA stimulated collagen synthesis in monolayer fibroblast culture as assessed by proteomics and immunohistochemically. Furthermore, we also show the synergistic effects of 10-HSA with retinol on collagen III synthesis in skin explants. These results further highlight the efficacy of 10-HSA as a cosmetically acceptable PPARα agonist and anti-ageing ingredient.Nous rapportons les effets in vitro et ex vivo de l'acide chiral (R)-10-hydroxystéarique (10-HSA) par rapport à d'autres régioisomères d'acide mono-hydroxystéarique et à l'acide stéarique (SA) ainsi que ses avantages lorsqu'il est associé au rétinol. MÉTHODES: Après un traitement avec des acides hydroxystéariques, l'activité du récepteur alpha activé par les proliférateurs peroxysomaux (PPARα) a été déterminée dans un test du gène rapporteur de la luciférase, le collagène de type I a été évalué dans les fibroblastes dermiques humains primaires par immunohistochimie, la modification du protéome du collagène des fibroblastes intracellulaires a été étudiée par spectrométrie de masse. La protéomique et le collagène de type III ont été évalués par immunohistochimie sur la peau humaine ex vivo. RÉSULTATS: la 10-HSA était l'agoniste PPARα le plus efficace (induction 15,7X ; p0,001), suivi de la 9-HSA (induction 10,1X) puis de la 12-HSA (induction 4,9X) avec la 17-HSA (induction 1,7X) étant similaire aux effets de l'acide stéarique (induction 1,8X). Les niveaux de collagène de type I ont été augmentés dans les fibroblastes humains primaires de 2,12X et 1,56X pour la 10-HSA et la 9-HSA respectivement in vitro, la 10-HSA étant significative (p0,05) : alors que la 12-HSA et la SA n'ont eu aucun effet statistique sur le témoin non traité. La 10-HSA et la 12-HSA ont légèrement modifié le protéome du collagène des fibroblastes intracellulaires avec des augmentations significatives des protéines de collagène alpha-1 (VI) et alpha-3 (VI), mais seule la 10-HSA a augmenté les niveaux de collagène alpha-2 (V), alpha -1 (III), alpha-1 (I) et alpha-2 (I) (tous p0,05) avec des augmentations significativement différentes entre 10-HSA et 12-HSA pour le collagène alpha-1 (I), le collagène- 3 (VI) et Collagène alpha-2 (I) (p0,01). Le collagène de type III dans la peau ex vivo a augmenté de +47 % (p0,05) de 0,05 % (1,7 mM) de rétinol, de +70 % (p0,01) de 0,01 % (0,33 mM) de 10-HSA et la combinaison a augmenté les niveaux de +240 % (p0,01 pour chaque ingrédient).La chiral (R)-10-HSA s'est avérée supérieure à 9, 12 et 17-HSA en tant qu'agoniste de PPARα. De plus, la 10-HSA a stimulé la synthèse de collagène dans la culture de fibroblastes monocouche telle qu'évaluée par protéomique et immunohistochimique. De plus, nous montrons également les effets synergiques de la 10-HSA avec le rétinol sur la synthèse du collagène III dans les explants de peau. Ces résultats soulignent en outre l'efficacité de la 10-HSA en tant qu'agoniste de PPARα et ingrédient anti-âge cosmétiquement acceptable.

Peroxisomes are single membrane-bound organelles important for the optimum functioning of eukaryotic cells. Seminal discoveries in the field of peroxisomes are made using yeast as a model. Several proteins required for the biogenesis and function of peroxisomes are identified to date. As with proteins involved in other major cellular pathways, peroxisomal proteins are also subjected to regulatory post-translational modifications. Identification, characterization and mapping of these modifications to specific amino acid residues on proteins are critical toward understanding their functional significance. Several studies have tried to identify post-translational modifications of peroxisomal proteins and determine their impact on peroxisome structure and function. In this manuscript, we provide an overview of the various post-translational modifications that govern the peroxisome dynamics in yeast.

Background Proximal tubular (PT) cells are enriched in mitochondria and peroxisomes. Whereas mitochondrial fatty acid oxidation (FAO) plays an important role in kidney function by supporting the high-energy requirements of PT cells, the role of peroxisomal metabolism remains largely unknown. EHHADH, also known as L-bifunctional protein, catalyzes the second and third step of peroxisomal FAO. Methods We studied kidneys of WT and Ehhadh KO mice on a C57BL/6N background using histology, immunohistochemistry, immunofluorescence, immunoblot, RNA-sequencing, and metabolomics. To assess the role of androgens in the kidney phenotype of Ehhadh KO mice, mice underwent orchiectomy. Results We observed male-specific kidney hypertrophy and glomerular filtration rate reduction in adult Ehhadh KO mice. Transcriptome analysis unveiled a gene expression signature similar to PT injury in acute kidney injury mouse models. This was further illustrated by the presence of KIM-1 (kidney injury molecule-1), SOX-9, and Ki67-positive cells in the PT of male Ehhadh KO kidneys. Male Ehhadh KO kidneys had metabolite changes consistent with peroxisomal dysfunction as well as an elevation in glycosphingolipid levels. Orchiectomy of Ehhadh KO mice decreased the number of KIM-1 positive cells to WT levels. We revealed a pronounced sexual dimorphism in the expression of peroxisomal FAO proteins in mouse kidney, underlining a role of androgens in the kidney phenotype of Ehhadh KO mice. Conclusions Our data highlight the importance of EHHADH and peroxisomal metabolism in male kidney physiology and reveal peroxisomal FAO as a sexual dimorphic metabolic pathway in mouse kidneys.

The utility of CRISPR-Cas9 to repair or reverse diseased states that arise from recent genetic mutations in the human genome is now widely appreciated. The use of CRISPR to “design” the outcomes of biology is challenged by both specialized ethicists and the general public. Less of a focus, however, is the ability of CRISPR to provide metabolic supplements or prophylactic molecules that improve long-term human health by overwriting ancient evolutionary events. Here, we use CRISPR to genomically integrate a functional uricase gene that encodes an enzymatically active protein into the human genome. These uricase-producing cells are able to reduce or even eliminate high concentrations of exogenous uric acid despite the enzyme being localized to peroxisomes. Our evolutionary engineered cells represent the first instance of the primate ape lineage expressing a functional uricase encoded in the genome within the last 20 million years. We anticipate that human cells expressing uricase will help prevent hyperuricemia (including gout) as well as hypertension and will help protect against fatty liver disease in the future., Graphical abstract, Humans are uniquely susceptible to the buildup of uric acid because our ancestors lost the ability to express an active uricase enzyme 20 million years ago. We have now used CRISPR technology to genomically integrate a functional ancestral uricase, and we demonstrate that these cells are protective against acute hyperuricemia.

Different organelles function coordinately in numerous intracellular processes. Photorespiration incidental to photosynthetic carbon fixation is organized across three subcellular compartments: chloroplasts, peroxisomes, and mitochondria. Under light conditions, these three organelles often form a ternary organellar complex in close proximity, suggesting a connection with metabolism during photorespiration. However, due to the heterogeneity of intercellular organelle localization and morphology, organelles' responses to changes in the external environment remain poorly understood. Here we used array tomography by field emission scanning electron microscopy to image organelles inside the whole plant cell at nanometer resolution, generating a three-dimensional (3D) spatial map of the light-dependent positioning of chloroplasts, peroxisomes, nuclei, and vacuoles. Our results show, in light-treated cells, the volume of peroxisomes increased, and mitochondria were simplified. In addition, the population of free organelles decreased, and the ternary complex centered on chloroplasts increased. Moreover, our results emphasized the expansion of the proximity area rather than the increase in the number of proximity sites inter-organelles. All of these phenomena were quantified for the first time on the basis of nanoscale spatial maps. In summary, we provide the first 3D reconstruction of Arabidopsis mesophyll cells, together with nanoscale quantified organelle morphology and their positioning via proximity areas, and then evidence of their light-dependent changes., 一つの植物細胞を丸ごと3次元で再現 --光依存的なオルガネラの変化をナノスケールで探る--. 京都大学プレスリリース. 2022-10-19.

Mapping the network of proteins provides a powerful means to investigate the function of disease genes and to unravel the molecular basis of phenotypes. We present an automated informatics-aided and bioluminescence resonance energy transfer-based approach (iBRET) enabling high-confidence detection of protein-protein interactions in living mammalian cells. A screen of the ABCD1 protein, which is affected in X-linked adrenoleukodystrophy (X-ALD), against an organelle library of peroxisomal proteins demonstrated applicability of iBRET for large-scale experiments. We identified novel protein-protein interactions for ABCD1 (with ALDH3A2, DAO, ECI2, FAR1, PEX10, PEX13, PEX5, PXMP2, and PIPOX), mapped its position within the peroxisomal protein-protein interaction network, and determined that pathogenic missense variants in ABCD1 alter the interaction with selected binding partners. These findings provide mechanistic insights into pathophysiology of X-ALD and may foster the identification of new disease modifiers.

To investigate the value of very long chain acylcarnitine (VLCAC) and lysophosphatidylcholine (LPC) in screening of peroxisomal disease in children. Eighteen children with peroxisomal disease, including 14 cases of X-linked adrenoleukodystrophy (X-ALD group) and 4 cases of Zellweger syndrome (ZS group) diagnosed based on clinical symptoms, MRI and genetic tests were enrolled in the study; and 200 healthy children were selected as control group. Samples of dried blood spots were collected from all subjects, VLCAC and LPC in dried blood spots were extracted by solvent containing internal isotopic standards hexacosanoylcarnitine (H-C26) and C26:0 lysophosphatidylcholine (H-C26:0-LPC). The eicosanoylcarnitine (C20), docosanoylcarnitine (C22), tetracosanoylcarnitine (C24), hexacosanoylcarnitine (C26), C20:0 lysophosphatidylcholine (C20:0-LPC), C22:0 lysophosphatidylcholine (C22:0-LPC), C24:0 lysophosphatidylcholine (C24:0-LPC) and C26:0 lysophosphatidylcholine (C26:0-LPC) were detected by tandem mass spectrometry (MS/MS). The above 8 indicators and the ratios were compared among the groups using Kruskal-Wallis test and Mann-Whitney test; the contribution of each index to the disease were analyzed by partial least square method. Except C24:0-LPC/C20:0-LPC, there were significant differences in all indicators and ratios among all groups (

The Tibetan chicken (Gallus gallus) provides high quality protein and iron for humans, which shows many phenotypic adaptations to the low oxygen. Study of the genetic mechanisms of circular RNAs (circRNAs) in hypoxia adaptation has not been reported. Four embryonic heart tissue samples from Tibetan chickens and Daheng broilers were collected. Differentially expressed circRNAs (DEcircRNAs) were identified via high-throughput sequencing. Bioinformatic analysis was used to indicate the functions and pathways of the DEcircRNAs. A total of 29 DEcircRNAs were identified between 4 Tibetan chickens and 4 Daheng broilers, including 15 upregulated and 14 downregulated DEcircRNAs in Tibetan chickens. GO analysis revealed that the DEcircRNAs were mainly involved in lung development or oxygen metabolism, such as ubiqunegative regulation of mesenchymal cell proliferation involved in lung development, oxidoreductase activity, and peroxisome. Pathway analysis showed that DEcircRNAs were mainly enriched in oxidative phosphorylation, tight junction, VEGF/MAPK/PPAR/Ras/PI3K-Akt signaling pathway. We also constructed a circRNA-miRNA-mRNA-pathway network to visualize the regulatory relationship associated with hypoxia adaptation of the tight junction pathways. The circRNA expression profile was obtained to complement the current Tibetan chicken circRNA database and provides new information for future studies into biological adaptation to hypoxic stress in the Tibetan chicken.

Mitochondria and peroxisomes are metabolically interconnected and functionally active subcellular organelles. These two dynamic organelles, share a number of common biochemical functions such as β-oxidation of fatty acids and detoxification of peroxides. The biogenesis and morphology of both these organelles in the mammalian cells is controlled by common transcription factors like PGC1α, and by a common fission machinery comprising of fission proteins like DRP1, Mff, and hFis1, respectively. In addition, the outer membrane mitochondria-anchored protein ligase (MAPL), the first mitochondrial SUMO E3 ligase with a RING-finger domain, also regulates mitochondrial morphology inducing mitochondrial fragmentation upon its overexpression. This fragmentation is dependent on both the RING domain of MAPL and the presence of the mitochondrial fission GTPase dynamin-related protein-1 (DRP1). Earlier studies have demonstrated that mitochondrial-derived vesicles are formed independently of the known mitochondrial fission GTPase, DRP1 are enriched for MAPL and are targeted to peroxisomes. The current study shows that MAPL regulates morphology of peroxisomes in a cell-type specific manner. Fascinatingly, the peroxisome elongation caused either due to silencing of DRP1 or by addition of polyunsaturated fatty acid, docosahexaenoic acid was blocked by overexpressing MAPL in mammalian cell lines. Furthermore, the transfection and colocalisation studies of MAPL with peroxisome membrane marker, PMP70, in different cell lines clearly revealed a cell-type specificity of transport of MAPL to peroxisomes. Previous work has placed the Vps35 (retromer component) as vital for delivery of MAPL to peroxisomes, placing the retromer as critical for the formation of MAPL-positive mitochondrial-derived vesicles. The results of polyethylene glycol-based cell-cell fusion assay signified that the enrichment of MAPL in peroxisomes is through vesicles and a retromer dependent phenomenon. Thus, a novel function for MAPL in peroxisomes is established to regulate peroxisome elongation and morphology under growth conditions and thus possibly modulate peroxisome fission.

On the basis of rational drug design fourteen novel compounds having benzoic acid as acidic head, hydrazone as linker and substituted diaryl sulfanyl/aryl-cyclohexylsulfanyl as a hydrophobic tail were synthesized and characterized by physicochemical and spectrophotometric (FTIR, Mass, 1HNMR and 13CNMR) analysis. The spectral data were satisfactory with their structures. The designed compounds were docked against peroxisome proliferated activated receptors (PPARγ) and further evaluated for in vitro PPARγ agonist activity and in vivo hypoglycemic activity in wistar strain of albino rats. Compound 3k and 3m exhibited potent anti-diabetic activity without ulcerogenic toxicity and minimum side effects as weight gain. Therefore these compounds would be considered as promising agents for the development of novel antidiabetic agents.

Reportedly, decreases in fatty acid (FA) chain length of ceramide (CER) are associated with interferon-γ (IFN-γ), which shows increased expression in psoriasis. However, the underlying mechanism of this association remains unclear. Therefore, in this study, we aimed to clarify this association between FA chain length of CER, IFN-γ, and the major transcriptional factors involving psoriasis. CER profiling according to FA chain length and class was performed in murine epidermis (n = 10 BALB/c mice topically treated with imiquimod, n = 10 controls) and human stratum corneum (SC) (n = 12 psoriasis, n = 11 controls). The expression of lipid synthetic enzymes, including elongases (ELOVLs), in murine epidermis was also measured using RT-PCR. Furthermore, the association of IFN-γ with various enzymes and transcription factors involved in the generation of long-chain CERs was also investigated using in vitro keratinocyte. A significant decrease in the percentage of long-chain CERs was observed in psoriasis-like murine epidermis and human psoriatic SC. Additionally, the expression levels of ELOVL1, ELOVL4, and ceramide synthase3 (CerS3) were significantly decreased in psoriasis-like murine epidermis and IFN-γ-treated keratinocyte. There was also a significant decrease in the expression of transcriptional factors, including peroxisome proliferator-activated receptor (PPAR), in IFN-γ treated keratinocyte. Thus, it could be suggested that IFN-γ may regulate ELOVL and CerS levels by down-regulating the transcriptional factors. Additionally, given the possible involvement of PPARs or liver X receptor agonist in the CER elongation process, they may serve as potential therapeutic agents for lengthening the CER FAs in psoriasis.

It has been reported that H. mollendorffii roots (HMR) have various pharmacological activities such as anti‐inflammatory activity and immunostimulatory activity. However, the anti‐obesity activity of HMR has not been studied. Thus, we evaluated in vitro anti‐obesity of HMR in mouse preadipocytes, 3T3‐L1 cells. HMR reduced the lipid accumulation and triglyceride (TG) contents in 3T3‐L1 cells. HMR inhibited the protein expressions such as CCAAT/enhancer‐binding protein alpha (CEBPα), peroxisome proliferator‐activated receptor gamma (PPARγ), perilipin‐1, adiponectin, fatty acid‐binding protein 4 (FABP4), fatty acid synthase (FAS), and acetyl‐CoA carboxylase (ACC) related to the lipid accumulation of the mature adipocytes. In addition, HMR induced the proteasomal degradation of CEBPα related to the differentiation of the preadipocytes into the mature adipocytes by activating c‐Jun N‐terminal kinases (JNK) and glycogen synthase kinase 3 beta (GSK3β). Based on the results of this study, HMR inhibited the differentiation of preadipocytes into mature adipocytes through the CEBPα degradation via JNK and GSK3β activation and subsequently blocked lipid accumulation of mature adipocytes through inhibiting lipid accumulation‐related proteins such as CEBPα, PPARγ, perilipin‐1, adiponectin, FABP4, FAS, and ACC., Blurb For EtocHMR inhibited the accumulation of lipid and triglyceride in the mature adipocytes.

Fusarium wilt is one of the major biotic factors limiting cucumber (Cucumis sativus L.) growth and yield. The outcomes of cucumber-Fusarium interactions can be influenced by the form of nitrogen nutrition (nitrate [NO3 - ] or ammonium [NH4 + ]); however, the physiological mechanisms of N-regulated cucumber disease resistance are still largely unclear. Here, we investigated the relationship between nitrogen forms and cucumber resistance to Fusarium infection. Our results showed that on Fusarium infection, NO3 - feeding decreased the levels of the fungal toxin, fusaric acid, leaf membrane oxidative, organelle damage and disease-associated loss in photosynthesis. Metabolomic analysis and gas-exchange measurements linked NO3 - mediated plant defence with enhanced leaf photorespiration rates. Cucumber plants sprayed with the photorespiration inhibitor isoniazid were more susceptible to Fusarium and there was a negative correlation between photorespiration rate and leaf membrane injury. However, there were positive correlations between photorespiration rate, NO3 - assimilation and the tricarboxylic acid (TCA) cycle. This provides a potential electron sink or the peroxisomal H2 O2 catalysed by glycolate oxidase. We suggest that the NO3 - nutrition enhanced cucumber resistance against Fusarium infection was associated with photorespiration. Our findings provide a novel insight into a mechanism involving the interaction of photorespiration with nitrogen forms to drive wider defence.

The loach is one of the most important fish species in aquaculture in China. The study of peroxisome proliferator-activated receptors (PPARs) will be essential for the determination of the functional role of the PPARα and PPARγ in loach fish. We used immunohistochemistry for PPARα and PPARγ at some stages of development beginning from the age of 1 month till the age of 15 months. Our result indicated that the expression of PPARα and PPARγ was found in; columnar cells lining intestinal folds, hepatocytes, blood sinusoids in the liver, pancreatic islets, pancreatic acini, the whole spleen and epithelial cells lining renal tubules of the kidney. The expression pattern of both PPARα and PPARγ was low at the age of one month, then reach its highest level at the age of 2 months. Then it declines at the age of 5 months. Then it re-increase at the age of 7 months and became low in older ages. The expression of PPARα was higher in comparison with PPARγ.

Peroxisomes are ubiquitous organelles in eukaryotes that fulfill various important metabolic functions. In this study, we investigated the role of docking/translocation module (DTM) peroxins, mainly FvPex8, FvPex13, FvPex14, and FvPex33, in Fusarium verticillioides development, virulence, and fumonisin B1 (FB1) biosynthesis. Protein interaction experiments suggested that FvPex13 serves as the central DTM subunit in F. verticillioides. Notably, FvPex8 and FvPex14 did not show direct interaction in our experiments. We generated gene-deletion mutants (ΔFvpex8, ΔFvpex13, ΔFvpex14, ΔFvpex33, ΔFvpex33/14) and further examined the functional role of these peroxins. Deletion mutants exhibited disparity in carbon nutrient utilization and defect in cell-wall integrity when stress agents were applied. Under nutrient starvation, mutants also showed higher levels of lipid droplet accumulation. Particularly, ΔFvpex8 mutant showed significant FB1 reduction and altered expression of key FB1 biosynthesis genes. However, FvPex13 was primarily responsible for asexual conidia reproduction and virulence, while the ΔFvpex33/14 double mutant also showed a virulence defect. In summary, our study suggests that FvPex13 is the central component of DTM, with direct physical interaction with other DTM peroxins, and regulates peroxisome membrane biogenesis as well as PTS1- and PTS2-mediated transmembrane cargo transportation. Importantly, we also characterized FvPex8 as a key component in F. verticillioides DTM that affects peroxisome function and FB1 biosynthesis. [Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

In Zellweger syndrome (ZS), lack of peroxisome function causes physiological and developmental abnormalities in many organs such as the brain, liver, muscles, and kidneys, but little is known about the exact pathogenic mechanism. By disrupting the zebrafish pex2 gene, we established a disease model for ZS and found that it exhibits pathological features and metabolic changes similar to those observed in human patients. By comprehensive analysis of the fatty acid profile, we found organ-specific accumulation and reduction of distinct fatty acid species, such as an accumulation of ultra-very-long-chain polyunsaturated fatty acids (ultra-VLC-PUFAs) in the brains of pex2 mutant fish. Transcriptome analysis using microarray also revealed mutant-specific gene expression changes that might lead to the symptoms, including reduction of crystallin, troponin, parvalbumin, and fatty acid metabolic genes. Our data indicated that the loss of peroxisomes results in widespread metabolic and gene expression changes beyond the causative peroxisomal function. These results suggest the genetic and metabolic basis of the pathology of this devastating human disease.

Iris bungei Maxim. (IB), which is native to China and Mongolia, is used as a traditional medicine for conditions such as inflammation, cancer, and bacterial infections. However, the effects of Iris bungei Maxim. on adipocyte differentiation have not been studied. In the present study, we first demonstrated the molecular mechanisms underlying the adipogenic activity of the methanol extract of Mongolian I. bungei Maxim. (IB). IB significantly enhanced intracellular lipid accumulation and adipocyte differentiation in 3T3-L1 preadipocytes in a concentration-dependent manner. Moreover, IB markedly stimulated the expression of genes related to adipogenesis such as peroxisome proliferator-activated receptor γ, adiponectin, and aP2. In addition, we also observed that IB induces lipogenic genes such as fatty acid synthase, sterol regulatory element binding protein 1c, stearoyl-CoA desaturase, and acetyl-CoA carboxylase. Interestingly IB regulated adipocyte differentiation in both the early and middle stages. Taken together, these adipogenic and lipogenic effects of IB suggest its efficacy for the prevention and/or treatment of type 2 diabetes.

Silent information-regulated transcription factor 1 (SIRT1) is the most prominent and widely studied member of the sirtuins (a family of mammalian class III histone deacetylases). It is a nuclear protein, and the deacetylation of the peroxisome proliferator-activated receptor coactivator-1 has been extensively implicated in metabolic control and mitochondrial biogenesis and is the basis for studies into its involvement in caloric restriction and its effects on lifespan. The present study discusses the potentially protective mechanism of SIRT1 in the regulation of the mitochondrial biogenesis and autophagy involved in the modulation of Alzheimer’s disease, which may be correlated with the role of SIRT1 in affecting neuronal morphology, learning, and memory during development; regulating metabolism; counteracting stress responses; and maintaining genomic stability. Drugs that activate SIRT1 may offer a promising approach to treating Alzheimer’s disease.

This study aimed to investigate the effect of the supplementation of branched-chain amino acids (BCAAs) at different ratios in protein restriction diets on lipid metabolism in a finishing pig model. The BCAA supplementation (leucine/isoleucine/valine = 2:1:1 and 2:1:2) ameliorated the poor growth performance and carcass characteristics, particularly high fat mass caused by a protein-restricted diet. Serum adiponectin increased while leptin decreased in BCAA diets in comparison to the 12% CP group. BCAA supplementation also increased the low-protein expression of AMPK and SIRT1 caused by protein restriction. The mRNA and protein levels of peroxisome proliferation-activated receptor-γ (PPARγ) and acetyl-CoA carboxylase (ACC) were highest in the protein-restricted group and lowered in the 2:1:1 or 2:1:2 group. In conclusion, BCAAs supplemented in an adequate ratio range of 2:1:1 to 2:1:2 (2:1:2 is recommended) in reduced protein diets could modulate lipid metabolism by accelerating the secretion of adipokines and fatty acid oxidation.

Microbial production of α-farnesene from renewable raw materials is a feasible alternative to traditional petroleum craft. Recently, the research on improving α-farnesene production in Pichia pastoris mainly focused on cytoplasmic engineering, while comprehensive engineering of multiple subcellular compartments is rarely reported. Here, we first sought to confirm that the isopentenol utilization pathway (IUP) could act as a two-step shortcut for IPP synthesis in P. pastoris peroxisomes. In addition, we proposed dual regulation of cytoplasm and peroxisomes to boost α-farnesene synthesis in P. pastoris X33, thus the resultant strain produced 2.18 ± 0.04 g/L, which was 1.3 times and 2.1 times than that of the strain only with peroxisomal or cytoplasmic engineering, respectively. The α-farnesene production achieved 2.56 ± 0.04 g/L in shake flasks after carbon source cofeeding, which was the highest reported production in worldwide literatures to the best of my knowledge. Therefore, we propose these strategies as efficient approaches to enhancing α-farnesene production in P. pastoris, which might bring new ideas for the biosynthesis of high-value compounds.

Insulin-producing pancreatic β-cells are central to glucose homeostasis, and their failure is a principal driver of diabetes development. To preserve optimal health β-cells must withstand both intrinsic and extrinsic stressors, ranging from inflammation to increased peripheral insulin demand, in addition to maintaining insulin biosynthesis and secretory machinery. Autophagy is increasingly being appreciated as a critical β-cell quality control system vital for glycemic control. Here we focus on the underappreciated, yet crucial, roles for selective and organelle-specific forms of autophagy as mediators of β-cell health. We examine the unique molecular players underlying each distinct form of autophagy in β-cells, including selective autophagy of mitochondria, insulin granules, lipid, intracellular amyloid aggregates, endoplasmic reticulum, and peroxisomes. We also describe how defects in selective autophagy pathways contribute to the development of diabetes. As all forms of autophagy are not the same, a refined view of β-cell selective autophagy may inform new approaches to defend against the various insults leading to β-cell failure in diabetes.

This repository contains renal cortical RNA-seq (ZDF and ZDSD rat models) and urinary 1H-NMR data (ZDSD rat model) following a diet-induced weight loss plus medical therapy intervention in rat models of diabetic kidney disease.

This repository contains renal cortical RNA-seq and urinary 1H-NMR data for the research manuscript entitled “Medications Activating Tubular Fatty Acid Oxidation Enhance the Protective Effects of Roux-en-Y Gastric Bypass Surgery in a Rat Model of Early Diabetic Kidney Disease”.

Seventy years following the discovery of peroxisomes, their complete proteome, the peroxi-ome, remains undefined. Uncovering the peroxi-ome is crucial for understanding peroxisomal activities and cellular metabolism. We used high-content microscopy to uncover peroxisomal proteins in the model eukaryote – Saccharomyces cerevisiae. This strategy enabled us to expand the known peroxi-ome by ~40% and paved the way for performing systematic, whole-organellar proteome assays. By characterizing the sub-organellar localization and protein targeting dependencies into the organelle, we unveiled non-canonical targeting routes. Metabolomic analysis of the peroxi-ome revealed the role of several newly identified resident enzymes. Importantly, we found a regulatory role of peroxisomes during gluconeogenesis, which is fundamental for understanding cellular metabolism. With the current recognition that peroxisomes play a crucial part in organismal physiology, our approach lays the foundation for deep characterization of peroxisome function in health and disease., Molecular Systems Biology, 18 (9), ISSN:1744-4292

In the yeast Hansenula polymorpha, the ER protein Pex32 is required for associating peroxisomes to the ER. Here, we report on a structure–function analysis of Pex32. Localization studies of various Pex32 truncations showed that the N-terminal transmembrane domain of Pex32 is responsible for sorting. Moreover, this part of the protein is sufficient for the function of Pex32 in peroxisome biogenesis. The C-terminal DysF domain is required for concentrating Pex32 at ER-peroxisome contact sites and has the ability to bind to peroxisomes. In order to better understand the role of Pex32 in peroxisome biogenesis, we analyzed various peroxisomal proteins in pex32 cells. This revealed that Pex11 levels are strongly reduced in pex32 cells. This may explain the strong reduction in peroxisome numbers in pex32 cells, which also occurs in cells lacking Pex11.