Fatty Acid Β-oxidation Research Articles

Unveiling the crucial role of peroxisomal acyl-CoA metabolism in muscle atrophy: Insights from genetic models and therapeutic interventions

In this study, we report the rejuvenation of aged muscle fibers facilitated by heterochronic parabiosis, underscored by a notable upregulation in peroxisomal gene expression. Our findings highlight the pivotal role of dysregulation in peroxisomal biogenesis and consequential impairment of fatty acid β-oxidation in myoblast differentiation and muscle regeneration. Notably, we demonstrate the novel therapeutic strategy that involves the administration of peroxisome-COS-FITC complexes and nanozymes that mimic peroxisomal function, effectively rejuvenating aged muscle tissues. This innovative approach paves the way for new methods to mitigate or reverse sarcopenia, offering new avenues of the treatment of age-related muscle atrophy and a significant advancement in our understanding for the molecular underpinnings in muscle aging.

Abstract Tu119: The exocyst trafficking complex mediates fuel transporter membrane delivery in cardiomyocytes.

Introduction: To maintain homeostasis, cardiomyocytes (CMs) primarily rely on fatty acid β-oxidation for ATP production facilitated by substrate uptake via fuel transporters. The glucose transporter, GLUT4, and fatty acid translocase, CD36, are directed to the cardiomyocyte sarcolemma in response to insulin signaling and AMP-activated protein kinase (AMPK) signaling. In adverse conditions like acute hypoxia and ischemia, these cells undergo a metabolic shift to favor glycolysis. Previous reports showed that under these conditions, CD36 moved away from the sarcolemma as GLUT4 was delivered to the cell membrane, contributing to a shift from fatty acid oxidation to glycolysis. Investigating CD36 and GLUT4 membrane delivery in cardiomyocytes is key to better understanding cardiac energy metabolism under normal and disease conditions. Prior work in adipocytes, and our own studies in skeletal muscle showed that the exocyst trafficking complex is critical for membrane delivery of GLUT4 and CD36 in response to insulin and AMPK. Our objective was to determine if in cardiomyocytes GLUT4 and CD36 trafficking, and subsequent fuel uptake is dependent on the exocyst. Methods and Results: We demonstrate that the exocyst is recruited to GLUT4 and CD36-vesicles in cultured H9C2 cells in response to stimuli with proximity ligation assays. Using on-cell Western analysis and fuel uptake assays we also show that the exocyst is essential for induced GLUT4 and CD36 cell surface delivery and subsequent energy substrate uptake, as inhibition of the exocyst attenuates stimulated surface translocation of both fuel transporters and subsequent fluorescent fuel analog uptake. Our earlier work revealed that protein levels of exocyst subunits are increased in murine heart tissue following myocardial infarction. To examine the role of the exocyst in fuel uptake under ischemic conditions, we used an in vitro model of simulated ischemia, and found similar alterations in exocyst subunit expression in this model at both mRNA and protein levels. This suggests an increased demand for exocyst activity. Conclusion: Further research will explore how ischemia impacts exocyst-mediated trafficking and if the exocyst contributes to the glycolytic shift under ischemia in cardiomyocytes.

Engineering the TetR-family transcriptional regulator XNR_0706 to enhance heterologous spinosad production in Streptomyces albus B4 chassis

The TetR family of regulators are an important group of transcription regulators that regulate diverse cellular processes in prokaryotes. In this study, we found that XNR_0706, a TetR family regulator, controlled the expression of XNR_0345, XNR_0454, XNR_0513 and XNR_1438 putatively involved in fatty acid β-oxidation by interacting with the promoter regions in Streptomyces albus B4. The transcription level of these four genes was downregulated in XNR_0706 deletion strain (ΔXNR_0706) and restored by XNR_0706 complementation in Δ0706/pIB-0706, demonstrating that XNR_0706 was a positive transcriptional regulator of the genes. With toxic long-chain fatty acids addition in TSB media, deletion of XNR_0706 caused significantly poor growth, whereas XNR_0706 complementation increased the utilization of additional fatty acids, resulting in restored growth. Fatty acid β-oxidation is one source of acetyl- and malonyl-CoA precursors for polyketides biosynthesis in actinobacteria. Overexpression of XNR_0706 in B4/spnNEW, a spinosad heterologous expression strain derived from S. albus B4, increased spinosad yield by 20.6%. Additionally, supplement of 0.3 g/L fatty acids resulted in a further 42.4% increase in spinosad yield. Our study reveals a regulatory mechanism in long-chain fatty acids metabolism in S. albus and these insights into the molecular regulation of β-oxidation by XNR_0706 are instrumental for increasing secondary metabolites in actinobacteria.

Endogenous activation of peroxisome proliferator-activated receptor-α in proximal tubule cells in counteracting phosphate toxicity.

Increased dietary phosphate consumption intensifies renal phosphate burden. Several mechanisms for phosphate-induced renal tubulointerstitial fibrosis have been reported. Considering the dual nature of phosphate as both a potential renal toxin and an essential nutrient for the body, kidneys may possess inherent protective mechanisms against phosphate overload, rather than succumbing solely to injury. However, there is limited understanding of such mechanisms. To identify these mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) analysis of the kidneys of control and dietary phosphate-loaded (Phos) mice at a time point when the Phos group had not yet developed tubulointerstitial fibrosis. scRNA-seq analysis identified the highest number of differentially expressed genes in the clusters belonging to proximal tubular epithelial cells (PTECs). Based on these differentially expressed genes, in silico analyses suggested that the Phos group activated peroxisome proliferator-activated receptor-α (PPAR-α) and fatty acid β-oxidation (FAO) in the PTECs. This activation was further substantiated through various experiments, including the use of an FAO activity visualization probe. Compared with wild-type mice, Ppara knockout mice exhibited exacerbated tubulointerstitial fibrosis in response to phosphate overload. Experiments conducted with cultured PTECs demonstrated that activation of the PPAR-α/FAO pathway leads to improved cellular viability under high-phosphate conditions. The Phos group mice showed a decreased serum concentration of free fatty acids, which are endogenous PPAR-α agonists. Instead, experiments using cultured PTECs revealed that phosphate directly activates the PPAR-α/FAO pathway. These findings indicate that noncanonical metabolic reprogramming via endogenous activation of the PPAR-α/FAO pathway in PTECs is essential to counteract phosphate toxicity.NEW & NOTEWORTHY This study revealed the activation of peroxisome proliferator-activated receptor-α and fatty acid β-oxidation in proximal tubular epithelial cells as an endogenous mechanism to protect the kidney from phosphate toxicity. These findings highlight noncanonical metabolic reprogramming as a potential target for suppressing phosphate toxicity in the kidneys.

Protein-sparing effects of lipids in the diet of golden pompano (Trachinotus ovatus): evaluation of growth, feed utilization, and lipid metabolism.

To investigate the influences of dietary protein and lipid levels on the growth, feed utilization, morphometric parameters, body composition, serum biochemical parameters, and lipid metabolism of golden pompano (Trachinotus ovatus), nine test diets containing three protein levels (35%, 40%, and 45%) and three lipid levels (8%, 13%, and 18%) were designed in the present study. Each diet (named D1-D9) was randomly assigned to feed triplicate groups of golden pompano juvenile (initial weight ~ 70 g) for 50 days. The results showed that the dietary lipid levels positively correlated with weight gain, specific growth rate, and protein efficiency ratio (PER), suggesting that the high lipid diets (18%) can be efficiently utilized in this fish species. The dietary protein levels have no significant influences on the growth and feed utilization except for the PER. Increasing dietary protein levels resulted in a decrease in hepatosomatic index (HSI), viscerosomatic index (VSI), and intestinal somatic index (ISI), while the dietary lipid level did not have a significant impact on morphological indices except for ISI. The dietary protein and lipid levels had no significant influences on the contents of crude lipid, crude ash, and moisture of whole body, while the crude protein contents was significantly affected by the dietary protein levels. Serum biochemical indexes, including cholesterol (CHO), triglycerides (TG), high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL), as well as HDL/LDL ratio were significantly affected by the dietary lipid levels, but not by the dietary protein levels. The expression levels of genes and their associated proteins involved in hepatic lipogenesis (Srebp-1c and Fas) and fatty acids β-oxidation (Pparα and Cpt-1) were up-regulated with increasing dietary lipid levels, while the former was up-regulated, and the latter was down-regulated with increasing dietary protein levels. Considering the present results in terms of growth performance, feed utilization, morphometric parameters, and lipid metabolism, the recommended dietary protein and lipid levels for golden pompano are 40% and 18%, respectively. The findings suggested that this species exhibits a significant protein-sparing effect on lipid utilization.

Fucoxanthin Mitigates High-Fat-Induced Lipid Deposition and Insulin Resistance in Skeletal Muscle through Inhibiting PKM1 Activity.

Glucose and lipid metabolism dysregulation in skeletal muscle contributes to the development of metabolic disorders. The efficacy of fucoxanthin in alleviating lipid metabolic disorders in skeletal muscle remains poorly understood. In this study, we systematically investigated the impact of fucoxanthin on mitigating lipid deposition and insulin resistance in skeletal muscle employing palmitic acid-induced lipid deposition in C2C12 cells and ob/ob mice. Fucoxanthin significantly alleviated PA-induced skeletal muscle lipid deposition and insulin resistance. In addition, fucoxanthin prominently upregulated the expression of lipid metabolism-related genes (Pparα and Cpt-1), promoting fatty acid β-oxidation metabolism. Additionally, fucoxanthin significantly increased the expression of Pgc-1α and Tfam, elevated the mtDNA/nDNA ratio, and reduced ROS levels. Further, we identified pyruvate kinase muscle isozyme 1 (PKM1) as a high-affinity protein for fucoxanthin by drug affinity-responsive target stability and LC-MS and confirmed their robust interaction by CETSA, microscale thermophoresis, and circular dichroism. Supplementation with pyruvate, the product of PKM1, significantly attenuated the beneficial effects of fucoxanthin on lipid deposition and insulin resistance. Mechanistically, fucoxanthin reduced glucose glycolysis rate and enhanced mitochondrial biosynthesis and fatty acid β-oxidation through inhibiting PKM1 activity, thereby alleviating lipid metabolic stress. These findings present a novel clinical strategy for treating metabolic diseases using fucoxanthin.

Etomoxir-carnitine, a novel pharmaco-metabolite of etomoxir, inhibits phospholipases A2 and mitochondrial respiration

Mitochondrial fatty acid oxidation serves as an essential process for cellular survival, differentiation, proliferation, and energy metabolism. Numerous studies have utilized etomoxir (ETO) for the irreversible inhibition of carnitine palmitoylcarnitine transferase 1 (CPT1), which catalyzes the rate-limiting step for mitochondrial long-chain fatty acid β-oxidation to examine the bioenergetic roles of mitochondrial fatty acid metabolism in many tissues in multiple diverse disease states. Herein, we demonstrate that intact mitochondria robustly metabolize ETO to etomoxir-carnitine (ETO-carnitine) prior to nearly complete ETO-mediated inhibition of CPT1. The novel pharmaco-metabolite, ETO-carnitine, was conclusively identified by accurate mass, fragmentation patterns, and isotopic fine structure. On the basis of these data, ETO-carnitine was successfully differentiated from isobaric structures (e.g., 3-hydroxy-C18:0 carnitine and 3-hydroxy-C18:1 carnitine). Mechanistically, generation of ETO-carnitine from mitochondria required exogenous Mg2+, ATP or ADP, CoASH, and L-carnitine, indicating that thioesterification by long-chain acyl-CoA synthetase to form ETO-CoA precedes its conversion to ETO-carnitine by CPT1. CPT1-dependent generation of ETO-carnitine was substantiated by an orthogonal approach using ST1326 (a CPT1 inhibitor), which effectively inhibits mitochondrial ETO-carnitine production. Surprisingly, purified ETO-carnitine potently inhibited calcium-independent PLA2γ and PLA2β as well as mitochondrial respiration independent of CPT1. Robust production and release of ETO-carnitine from HepG2 cells incubated in the presence of ETO was also demonstrated. Collectively, this study identifies the chemical mechanism for the biosynthesis of a novel pharmaco-metabolite of ETO, ETO-carnitine, that is generated by CPT1 in mitochondria and likely impacts multiple downstream (non-CPT1 related) enzymes and processes in multiple subcellular compartments.

Systemic inhibition of mitochondrial fatty acid β-oxidation impedes zebrafish ventricle regeneration

Unlike humans and other mammals, zebrafish demonstrate a remarkable capacity to regenerate their injured hearts throughout life. Mitochondrial fatty acid β-oxidation (FAO) contributes to major energy demands of the adult hearts under physiological conditions; however, its functions in regulating cardiac regeneration and the underlying mechanisms are not completely understood. Different strategies targeting FAO have yield mixed outcomes. Here, we demonstrated that pharmacological inhibition of mitochondrial FAO with mildronate (MD) caused lipid accumulation in zebrafish larvae and suppressed ventricle regeneration. MD treatment impeded cardiogenic factor reactivation and cardiomyocyte (CM) proliferation, and impaired ventricle regeneration could be rescued by exogenous l-carnitine supplementation. Moreover, compared with the ablated hearts of wild-type fish, ventricle regeneration, cardiogenic factor reactivation and CM proliferation were significantly blocked in the ablated hearts of carnitine palmitoyltransferase-1b (cpt1b) knockout zebrafish. Further experiments suggested that NF-κB signaling and increased inflammation may be involved in the impediment of ventricle regeneration caused by systemic mitochondrial FAO inhibition. Overall, our study demonstrates the essential roles of mitochondrial FAO in zebrafish ventricle regeneration and reaffirms the sophisticated and multifaceted roles of FAO in heart regeneration with regard to different injury models and means of FAO inhibition.

Shallow water seeding cultivation enhances cold tolerance in tobacco seedlings

Cold stress can impact plant biology at both the molecular and morphological levels. We cultivated two different types of tobacco seedlings using distinct seeding methods, observing significant differences in their cold tolerance at 4 °C. After 12 h cold stress, shallow water seeding cultivation treatment demonstrates a relatively good growth state with slight wilting of the leaves. Tobacco grown using the float system exhibited short, thick roots, while those cultivated through shallow water seeding had elongated roots with more tips and forks. After cold stress, the shallow water seeding cultivation treatment demonstrated higher antioxidant enzyme activity, and lower malondialdehyde (MDA) content.Transcriptome analysis was performed on the leaves of these tobacco seedlings at three stages of cold treatment (before cold stress, after cold stress, and after 3 days of recovery). Upon analyzing the raw data, we found that the shallow water seeding cultivation treatment was associated with significant functional enrichment of nicotinamide adenine dinucleotide (NAD) biosynthesis and NAD metabolism before cold stress, enrichment of functions related to the maintenance of cellular structure after cold stress, and substantial functional enrichment related to photosynthesis during the recovery period. Weighted gene co-expression network analysis (WGCNA) was conducted, identifying several hub genes that may contribute to the differences in cold tolerance between the two tobacco seedlings. Hub genes related to energy conversion were predominantly identified in shallow water seeding cultivation treatment during our analysis, surpassing findings in other areas. These include the AS gene, which controls the synthesis of NAD precursors, the PED1 gene, closely associated with fatty acid β-oxidation, and the RROP1 gene, related to ATP production.Overall, our study provides a valuable theoretical basis for exploring improved methods of cultivating tobacco seedlings. Through transcriptome sequencing technology, we have elucidated the differences in gene expression in different tobacco seedlings at three time points, identifying key genes affecting cold tolerance in tobacco and providing possibilities for future gene editing.

Jujuboside A through YY1/CYP2E1 signaling alleviated type 2 diabetes-associated fatty liver disease by ameliorating hepatic lipid accumulation, inflammation, and oxidative stress

Non-alcoholic fatty liver disease (NAFLD) was a chronic complication of type 2 diabetes mellitus (T2DM), and this comorbid disease lacked therapeutic drugs. Semen Ziziphi Spinosae (SZS) was the seed of Ziziphus jujuba var. Spinosa (Bunge) Hu ex H.F. Chow, and it could alleviate the symptoms of T2DM patients. As a triterpene saponin, Jujuboside A (Ju A) was the main active substance isolated from SZS and could improve hyperglycemia of diabetic mice. However, it was still unknown whether Ju A has protective effects on T2DM-associated NAFLD. Our study showed that Ju A attenuated T2DM-associated liver damage by alleviating hepatic lipid accumulation, inflammatory response, and oxidative stress in the liver of db/db mice, and high glucose (HG) and free fatty acid (FFA) co-stimulated human hepatocellular carcinomas (HepG2) cells. Along with the improved hyperglycemia and liver injury, Ju A restrained Yin Yang 1 (YY1)/cytochrome P450 2E1 (CYP2E1) signaling in vivo and in vitro. YY1 overexpression intercepted the protective effects of Ju A on T2DM-induced liver injury via promoting hepatic lipid accumulation, inflammatory response, and oxidative stress. While, the blocking effect of YY1 overexpression on Ju A's hepatoprotective effect was counteracted by further treatment of CYP2E1 specific inhibitor diethyldithiocarbamate (DDC) in vitro. In-depth mechanism research showed that Ju A through YY1/CYP2E1 signaling promoted hepatic fatty acid β-oxidation, and inhibited inflammatory response and oxidative stress by activating peroxisome proliferator-activated receptor alpha (PPARα), leading to the improvement of T2DM-associated NAFLD. Ju A might be a potential agent in the treatment and health care of T2DM-associated liver disease, especially NAFLD.

Mitochondria to plasma membrane redox signaling is essential for fatty acid β-oxidation-driven insulin secretion

We asked whether acute redox signaling from mitochondria exists concomitantly to fatty acid- (FA-) stimulated insulin secretion (FASIS) at low glucose by pancreatic β-cells. We show that FA β-oxidation produces superoxide/H2O2, providing: i) mitochondria-to-plasma-membrane redox signaling, closing KATP-channels synergically with elevated ATP (substituting NADPH-oxidase-4-mediated H2O2-signaling upon glucose-stimulated insulin secretion); ii) activation of redox-sensitive phospholipase iPLA2γ/PNPLA8, cleaving mitochondrial FAs, enabling metabotropic GPR40 receptors to amplify insulin secretion (IS). At fasting glucose, palmitic acid stimulated IS in wt mice; palmitic, stearic, lauric, oleic, linoleic, and hexanoic acids also in perifused pancreatic islets (PIs), with suppressed 1st phases in iPLA2γ/PNPLA8-knockout mice/PIs. Extracellular/cytosolic H2O2-monitoring indicated knockout-independent redox signals, blocked by mitochondrial antioxidant SkQ1, etomoxir, CPT1 silencing, and catalase overexpression, all inhibiting FASIS, keeping ATP-sensitive K+-channels open, and diminishing cytosolic [Ca2+]-oscillations. FASIS in mice was a postprandially delayed physiological event. Redox signals of FA β-oxidation are thus documented, reaching the plasma membrane, essentially co-stimulating IS.

Cellular Senescence and Extracellular Vesicles in the Pathogenesis and Treatment of Obesity-A Narrative Review.

This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction and generate reactive oxygen species with DNA damage. This triggers adipocyte hypertrophy and hypoxia, inhibition of adiponectin secretion and adipogenesis, increased endoplasmic reticulum stress and maladaptive unfolded protein response, metaflammation, and polarization of macrophages. Such feed-forward cycles are not resolved by antioxidant systems, heat shock response pathways, or DNA repair mechanisms, resulting in transmissible cellular senescence via autocrine, paracrine, and endocrine signaling. Senescence can thus affect preadipocytes, mature adipocytes, tissue macrophages and lymphocytes, hepatocytes, vascular endothelium, pancreatic β cells, myocytes, hypothalamic nuclei, and renal podocytes. The senescence-associated secretory phenotype is closely related to visceral adipose tissue expansion and metaflammation; inhibition of SIRT-1, adiponectin, and autophagy; and increased release of exosomes, exosomal micro-RNAs, pro-inflammatory adipokines, and saturated free fatty acids. The resulting hypernefemia, insulin resistance, and diminished fatty acid β-oxidation lead to lipotoxicity and progressive obesity, metabolic syndrome, and physical and cognitive functional decline. Weight cycling is related to continuing immunosenescence and exposure to palmitate. Cellular senescence, exosome release, and the transmissible senescence-associated secretory phenotype contribute to obesity and metabolic syndrome. Targeted therapies have interrelated and synergistic effects on cellular senescence, obesity, and premature aging.

Macauba (Acrocomia aculeata) pulp oil reduces fat accumulation and enhances the lifespan of Caenorhabditis elegans at low temperatures via fat-1- and fat-7-dependent pathway.

Macauba (Acrocomia aculeata) is a Brazilian palm tree whose oil in the pulp is rich in oleic acid and carotenoids. However, its physiological function remains unknown. This study aimed to investigate the effects of macauba pulp oil (MPO) on the metabolic link between lipid metabolism and lifespan using Caenorhabditis elegans (C. elegans). C. elegans were treated with 5.0mg/mL of MPO for analyzing triglyceride and glycerol accumulation, fatty acid profile, gene expression of lipid and oxidative metabolism proteins under cold (4°C) stress conditions, and lifespan analysis under stress conditions such as cold (4°C), heat (37°C), and oxidative (paraquat) stress. MPO significantly suppressed fat accumulation and increased glycerol (a lipolysis index) and the lifespan of C. elegans at low temperature (4°C). This was accompanied by decreased mRNA levels of the genes involved in lipogenesis (spb-1 and pod-2) and increased levels of the genes involved in fatty acid β-oxidation (acs-2 and nhr-49) and fat mobilization genes (hosl-1 and aak-2). Additionally, MPO treatment modulated fatty acid pools in C. elegans at low temperatures in that MPO treatment decreased saturated fatty acid levels and shifted the fatty acid profile to long-chain fatty acids. Moreover, the effect of MPO on fat accumulation at low temperatures was abolished in fat-7 mutants, whereas both fat-1 and fat-7 contribute, at least in part, to MPO-elevated survival of C. elegans under cold conditions. PRACTICAL APPLICATION: The results obtained in the present study may contribute to the understanding of the health benefits of consuming macauba pulp oil and consequently stimulate economic growth and the industrial application of this new type of oil, which may result in the creation of new jobs and increased value of small producers.

ACADM inhibits AMPK activation to modulate PEDV-induced lipophagy and β-oxidation for impairing viral replication

Porcine epidemic diarrhea virus (PEDV) belongs to the Alphacoronavirus genus within the Coronavirus family, causing severe watery diarrhea in piglets and resulting in significant economic losses. Medium-chain acyl-CoA dehydrogenase (ACADM) is an enzyme participating in lipid metabolism associated with metabolic diseases and pathogen infections. Nonetheless, the precise role of ACADM in regulating PEDV replication remains uncertain. In this study, we identified ACADM as the host binding partner of NSP4 via immunoprecipitation-mass spectrometry analysis. The interaction between ACADM and NSP4 was subsequently corroborated through coimmunoprecipitation and laser confocal microscopy. Following this, a notable upsurge in ACADM expression was observed during PEDV infection. ACADM overexpression effectively inhibited virus replication, whereas ACADM knockdown facilitated virus replication, suggesting ACADM has negative regulation effect on PEDV infection. Furthermore, we demonstrated fatty acid β-oxidation affected PEDV replication for the first time, inhibition of fatty acid β-oxidation reduced PEDV replication. ACADM decreased PEDV-induced β-oxidation to suppress PEDV replication. Mechanistically, ACADM reduced cellular free fatty acid levels and subsequent β-oxidation by hindering AMPK-mediated lipophagy. In summary, our results reveal that ACADM plays a negative regulatory role in PEDV replication by regulating lipid metabolism. The present study introduces a novel approach for the prevention and control of PEDV infection.

Characterization of aroma dynamic changes during six developing stages of yellow cultivar Flammulina filiformis based on E-Nose, GC×GC-TOF MS, GC-IMS, and GC-O-MS

The aroma volatiles of Flammulina filiformis (F. filiformis) had notably dynamic changes during various developing stages. However, the dynamic fingerprints of the overall aroma volatiles during mushroom development remained largely unknown in F. filiformis. The purpose of this study was to characterize the dynamic changes in the aroma volatiles of yellow cultivar F. filiformis using E-Nose, GC-MS/O, GC-IMS, and GC × GC-TOF MS. A total of 140 volatiles were characterized (about 59% by GC × GC-TOF MS). Phenylacetaldehyde, 2-octenal, hexanal, nonanal, 2,4-decadienal, β-citronellol, 3-octanone, 1-octen-3-one, 2-methylpropyl butanoate, limonene, and 2-pentyl-furan were identified as key aroma compounds. The richness of odorants (numbers and concentrations) was most abundant during the initial stage of fruiting (with a fruity note). The concentrations of C8 volatiles and ketones gradually decreased before the mature stage, followed by a slight increase (with mushroom and sweet notes). An excellent correlation was observed between the changes in aroma attributes corresponding to odorants. Furthermore, the correlation between the volatile contents could be well explained by metabolic pathways (unsaturated fatty acids, β-oxidation of saturated fatty acids, and Ehrlich pathways for amino acids). Overall, this study provides insights into the metabolic pathways of volatiles potential for aroma quality enhancement in F. filiformis.

A single gene mutation underpins metabolic adaptation and acquisition of filamentous competence in the emerging fungal pathogen Candida auris.

Filamentous cell growth is a vital property of fungal pathogens. The mechanisms of filamentation in the emerging multidrug-resistant fungal pathogen Candida auris are poorly understood. Here, we show that exposure of C. auris to glycerol triggers a rod-like filamentation-competent (RL-FC) phenotype, which forms elongated filamentous cells after a prolonged culture period. Whole-genome sequencing analysis reveals that all RL-FC isolates harbor a mutation in the C2H2 zinc finger transcription factor-encoding gene GFC1 (Gfc1 variants). Deletion of GFC1 leads to an RL-FC phenotype similar to that observed in Gfc1 variants. We further demonstrate that GFC1 mutation causes enhanced fatty acid β-oxidation metabolism and thereby promotes RL-FC/filamentous growth. This regulation is achieved through a Multiple Carbon source Utilizer (Mcu1)-dependent mechanism. Interestingly, both the evolved RL-FC isolates and the gfc1Δ mutant exhibit an enhanced ability to colonize the skin. Our results reveal that glycerol-mediated GFC1 mutations are beneficial during C. auris skin colonization and infection.

Nicotinamide mitigates visceral leishmaniasis by regulating inflammatory response and enhancing lipid metabolism

BackgroundCurrently, treatment regimens for visceral leishmaniasis (VL) are limited because of the presence of numerous adverse effects. Nicotinamide, a readily available and cost-effective vitamin, has been widely acknowledged for its safety profile. Several studies have demonstrated the anti-leishmanial effects of nicotinamide in vitro. However, the potential role of nicotinamide in Leishmania infection in vivo remains elusive.MethodsIn this study, we assessed the efficacy of nicotinamide as a therapeutic intervention for VL caused by Leishmania infantum in an experimental mouse model and investigated its underlying molecular mechanisms. The potential molecular mechanism was explored through cytokine analysis, examination of spleen lymphocyte subsets, liver RNA-seq analysis, and pathway validation.ResultsCompared to the infection group, the group treated with nicotinamide demonstrated significant amelioration of hepatosplenomegaly and recovery from liver pathological damage. The NAM group exhibited parasite reduction rates of 79.7% in the liver and 86.7% in the spleen, respectively. Nicotinamide treatment significantly reduced the activation of excessive immune response in infected mice, thereby mitigating hepatosplenomegaly and injury. Furthermore, nicotinamide treatment enhanced fatty acid β-oxidation by upregulating key enzymes to maintain lipid homeostasis.ConclusionsOur findings provide initial evidence supporting the safety and therapeutic efficacy of nicotinamide in the treatment of Leishmania infection in BALB/c mice, suggesting its potential as a viable drug for VL.Graphical

Wnt/Wingless signaling promotes lipid mobilization through signal-induced transcriptional repression

The Wnt/Wingless signaling pathway plays critical roles in metazoan development and energy metabolism, but its role in regulating lipid homeostasis remains not fully understood. Here, we report that the activation of canonical Wnt/Wg signaling promotes lipolysis while concurrently inhibiting lipogenesis and fatty acid β-oxidation in both larval and adult adipocytes, as well as cultured S2R+ cells, in Drosophila. Using RNA-sequencing and CUT&RUN (Cleavage Under Targets & Release Using Nuclease) assays, we identified a set of Wnt target genes responsible for intracellular lipid homeostasis. Notably, active Wnt signaling directly represses the transcription of these genes, resulting in decreased de novo lipogenesis and fatty acid β-oxidation, but increased lipolysis. These changes lead to elevated free fatty acids and reduced triglyceride (TG) accumulation in adipocytes with active Wnt signaling. Conversely, downregulation of Wnt signaling in the fat body promotes TG accumulation in both larval and adult adipocytes. The attenuation of Wnt signaling also increases the expression of specific lipid metabolism-related genes in larval adipocytes, wing discs, and adult intestines. Taken together, these findings suggest that Wnt signaling-induced transcriptional repression plays an important role in regulating lipid homeostasis by enhancing lipolysis while simultaneously suppressing lipogenesis and fatty acid β-oxidation.

2,3,5,4′-tetrahydroxy-stilbene-2-O-β-D-glucoside promotes liver regeneration after partial hepatectomy in mice: The potential involvement of PPARα-mediated fatty acid metabolism

Ethnopharmacological relevance2,3,5,4′-tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG) is the principal bioactive compound contained in Polygonum multiflorum Thunb. (PMT), which is traditionally recorded to possess tonic and anti-aging efficacy. Aim of the studyTo identify the TSG-provided promotion on liver regeneration (LR) following partial hepatectomy (PHx) in mice and to explicate its involved mechanism. Materials and methodsThe promotion of TSG on LR was evaluated by hematoxylin and eosin (H&E), 5-bromodeoxyuridinc (BrdU) and Ki-67 staining, and measuring the level of proliferating cell nuclear antigen (PCNA) and Cyclin D1 in mice with PHx at different time points. Gene Expression Omnibus (GEO, GSE15239) database and the label-free quantitative proteomics from liver of mice at 24 h after PHx were integrated to identify potential involved critical proteins, which were verified by Western-blot, Real-time polymerase chain reaction (RT-PCR), molecular docking and luciferase activity assay. Primary hepatocytes isolated from mice were used to investigate the TSG-provided promotion on proliferation in vitro. ResultsTSG (20 mg/kg) promoted LR in mice after PHx. Results from RNA expression data from clinical samples and proteomic analysis from liver tissues indicated that peroxisome proliferator-activated receptor α (PPARα)-mediated fatty acid metabolism pathway were crucially associated with the TSG-provided promotion on LR. TSG enhanced the nuclear translocation of PPARα and the mRNA expression of a series of PPARα-regulated downstream genes. In addition, TSG lowered hepatic triglyceride (TG) and non-esterified fatty acid (NEFA) amounts and increased hepatic adenosine triphosphate (ATP) level in mice after PHx. TSG up-regulated the transcriptional activity of PPARα in vitro. Next results displayed that TSG promoted cell proliferation as well as ATP level in mice primary hepatocytes, which were abolished when PPARα was suppressed. Meanwhile, the cell viability was also elevated in mice primary hepatocytes treated with ATP. ConclusionActivating PPARα-mediated fatty acid β-oxidation (FAO) pathway led to the production of ATP, which contributed to the TSG-provided promotion on LR after PHx in mice.

Do low skeletal muscle bulk and disturbed body fat mass impact tumor recurrence in stage I/II HCC undergoing surgery? An observational cohort study.

The influence of deranged body composition on stage I/II HCC after surgery remains undetermined. The current study aimed to investigate the impact of low skeletal muscle bulk and disturbed body fat mass on the recurrence outcome of stage I/II HCC patients undergoing liver resection. The associated metabolomic alterations were also assessed. From 2012 to 2021, stage I and II HCC patients who underwent liver resection at our institute were retrospectively reviewed. Their preoperative body composition including skeletal muscle mass and body fat volume was measured by computed tomography (CT). The recurrence outcome was recorded and analyzed. The preoperative serum was collected and subjected to metabolomic analysis. A total of 450 stage I and II HCC patients were included in the current study. Among them, 76% were male and around 60% had HBV infection. After stratified by normal cutoff values obtained from a healthy cohort, 6.4% of stage I/II HCC patients were found to have a low psoas muscle index (PMI), 17.8% a high subcutaneous adipose tissue (SAT) index, and 27.8% a high visceral adipose tissue (VAT) index. Cox regression multivariate analysis further demonstrated that low PMI and high SAT index were independent prognostic factors for time-to-recurrence (TTR) after surgery. Metabolomic analysis discovered that free fatty acid β-oxidation was enhanced in with low PMI or high SAT index. The current study demonstrated that reduced psoas muscle mass may impair while elevated SAT may prolong the TTR of stage I/II HCC patients undergoing liver resections. VAT, on the other hand, was not associated with recurrence outcome after surgery. Further studies are warranted to validate our findings.