Reducing ether lipids improves Drosophila overnutrition-associated pathophysiology phenotypes via a switch from lipid storage to beta-oxidation

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: July 29, 2022

Abstract High-calorie diets increase the risk of developing obesity, cardiovascular disease, type-two diabetes (T2D), and other comorbidities. These “overnutrition” also promote accumulation a variety harmful lipids in heart peripheral organs, known as lipotoxicity. However, mechanisms underlying lipotoxicity its influence on pathophysiology remain unknown. Our study uses genetics to identify role ether lipids, class potential lipotoxins, Drosophila model overnutrition. A high-sugar diet (HSD) increases produces T2D-like phenotypes, including insulin resistance, cardiac failure. Therefore, we targeted lipid biosynthesis through enzyme dihydroxyacetonephosphate acyltransferase (encoded by gene DHAPAT ). We found that reducing fat body improved TAG glucose homeostasis, function, respiration, signaling flies fed HSD. The reduction may cause switch molecular from lipogenesis fatty acid oxidation via activation PPARα-like receptor, bezafibrate produced similar improvements HS-fed flies. Taken together, our findings suggest be lipotoxins reduce fitness during

Language: Английский

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Peroxisome import stress impairs ribosome biogenesis and induces integrative stress response through eIF2α phosphorylation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2020, Volume and Issue: unknown

Published: Nov. 20, 2020

Abstract Peroxisome biogenesis diseases (PBDs) are characterized by global defects in peroxisomal function and can result severe brain, liver, kidney, bone malfunctions. PBDs due to mutations peroxisome factors (PEX genes) that responsible for assembly function. Increasing evidence suggests import functions decline during aging. However, the transcriptome profiling of how they affect disease development still lacking. PEX5 encodes cytoplasmic receptors peroxisome-targeting signal types 1. We generate knock-in human HEK293 cells mutant using CRISPR transiently express cysteine 11 alanine (PEX5 C11A ), which blocks recycling exerts dominant negative effect on mediated import. To identify conserved responses, we perform transcriptomic analysis Drosophila oenocyte-specific Pex1, Pex12 Pex5 knockdowns with impaired siRNA respectively). induction triggers vast changes, including decreased oxidative phosphorylation, increased MAPK signaling HIPPO signaling. specifically decreases spliceosome activity increases cholesterol metabolism. Using gene set enrichment (GSEA), protein processing endoplasmic reticulum pathway, ER-associated degradation (ERAD) pathway is induced all PEX . dysfunction elevates eIF2α phosphorylation both cell culture independent XBP1 activation, suggesting integrative stress response (ISR). Moreover, ribosome genes impairs flies cells. Specifically, 5’-ETS cleavage dampens 40S small ribosomal export human. Our results suggest reduced elevated ISR could be cellular stress.

Language: Английский

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Varroa destructor parasitism and Deformed wing virus infection in honey bees are linked to peroxisome‐induced pathways

PROTEOMICS, Journal Year: 2024, Volume and Issue: 24(9)

Published: March 6, 2024

The ectoparasitic mite Varroa destructor transmits and triggers viral infections that have deleterious effects on honey bee colonies worldwide. We performed a manipulative experiment in which worker bees collected at emergence were exposed to for 72 h, their proteomes compared with those of untreated control bees. Label-free quantitative proteomics identified 77 differentially expressed A. mellifera proteins (DEPs). In addition, by orthogonal analysis, most importantly, Deformed wing virus (DWV) was found high levels/intensity Varroa-exposed Pathway enrichment analysis suggested the main pathways affected included peroxisomal metabolism, cyto-/exoskeleton reorganization, cuticular proteins. Detailed examination individual DEPs revealed additional changes associated function. proteome data support importance TGF-β signaling Varroa-DWV interaction involvement mTORC1 Hippo pathways. These results suggest effect DWV feeding aberrant autophagy. particular, autophagy is selectively modulated peroxisomes, observed strongly corresponded. This study complements previous research different designs suggests peroxisome, plays key role infections.

Language: Английский

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A Structural Proteome Screen Identifies Protein Mimicry in Host-Microbe Systems

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 13, 2024

Summary Host-microbe systems are evolutionary niches that produce coevolved biological interactions and a key component of global health. However, these have historically been difficult field research due to their experimental intractability. Impactful advances in health will be obtained by leveraging silico screens identify genes involved mediating interspecific interactions. These predictions progress our understanding lay the groundwork for future vitro vivo experiments bioengineering projects. A driver host-manipulation intracellular survival utilized host-associated microbes is molecular mimicry, critical mechanism can occur at any level from DNA protein structures. We applied structure prediction alignment tools explore bacterial structural proteomes examples mimicry. By Legionella pneumophila proteome its many known mimics, we developed validated screen virtually host-microbe system uncover signals mimics represent candidate proteins mediate host microbial proteomes. successfully this other with demonstrated effects on health, Helicobacter pylori Wolbachia , identifying mimic candidates each proteome. discuss roles may play important -induced phenotypes show Wobachia infection partially rescue loss one factors. This work demonstrates how genome-wide offers an opportunity functionally systems.

Language: Английский

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New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 22, 2024

Abstract Acyl-CoA binding domain-containing proteins (ACBDs) perform diverse but often uncharacterised functions linked to cellular lipid metabolism. Human ACBD4 and ACBD5 are closely related peroxisomal membrane proteins, involved in tethering of peroxisomes the ER capturing fatty acids for β-oxidation. deficiency causes neurological abnormalities including ataxia white matter disease. Peroxisome-ER contacts depend on an ACBD4/5-FFAT motif, which interacts with ER-resident VAP proteins. As ACBD4/5-like present most fungi all animals, we combined phylogenetic analyses experimental approaches improve understanding their evolution functions. Notably, vertebrates exhibit gene sequences both ACBD5, while invertebrates possess only a single protein. Our revealed alterations domain structure FFAT sequences, help functional diversification We show that Drosophila melanogaster protein possesses motif tether via Dm_Vap33. Depletion Dm_Acbd4/5 caused peroxisome redistribution wing neurons reduced life expectancy. In contrast, filamentous fungus Ustilago maydis lacks does not interact Um_Vap33. Loss Um_Acbd4/5 resulted accumulation early endosomes at hyphal tip. Moreover, droplet numbers increased mitochondrial potential declined, implying altered homeostasis. findings reveal differences between metabolic across evolution, improving our ACBD4/5 function health The need unifying nomenclature ACBD is discussed.

Language: Английский

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Insulin/insulin-like growth factor signaling pathway promotes higher fat storage inDrosophilafemales

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

Summary In Drosophila , adult females store more fat than males. While the mechanisms that restrict body in males are becoming clearer, less is known about how achieve higher storage. Here, we perform a detailed investigation of promote storage females. We show greater intake dietary sugar supports due to female-biased remodeling lipidome. Dietary stimulates female-specific increase insulin-like peptide 3 (Dilp3), which acts together with peripheral insulin sensitivity augment insulin/insulin-like growth factor signaling pathway (IIS) activity Indeed, Dilp3 overexpression prevented decrease after removal sugar. Given adult-specific IIS inhibition caused fat, our data reveal as key determinant female

Language: Английский

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Insulin/Insulin-Like Growth Factor Signaling Pathway Promotes Higher Fat Storage in Drosophila Females

Published: Jan. 1, 2024

Language: Английский

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Dietary cysteine and methionine promote peroxisome elevation and fat loss by induction of CG33474 expression in Drosophila adipose tissue

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: April 22, 2024

Abstract The high-protein diet (HPD) has emerged as a potent dietary approach to curb obesity. Peroxisome, highly malleable organelle, adapts nutritional changes maintain homeostasis by remodeling its structure, composition, and quantity. However, the impact of HPD on peroxisomes underlying mechanism remains elusive. Using Drosophila melanogaster model system, we discovered that specifically increases peroxisome levels within adipose tissues. This HPD-induced elevation is attributed cysteine methionine triggering expression CG33474 , fly homolog mammalian PEX11G . Both overexpression human result in increased size. In addition, diets both reduce lipid contents, process depends presence Furthermore, stimulates breakdown neutral lipids cell-autonomous manner. Moreover, triggered requires TOR signaling. Finally, found promotes inter-organelle contacts between droplets (LDs), which might be potential for -induced fat loss. summary, our findings demonstrate CG33474/PEX11G may serve an essential molecular bridge linking dynamics metabolism. Graphical abstract HPD, with serving key amino acids, elevates tissues inducing expression. / performs two biological roles evolutionarily conserved manner: firstly, leads size; secondly, LDs manner (by strengthening peroxisome-LD interaction). signaling required cysteine- methionine-induced

Language: Английский

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Manipulation and Visualization of Peroxisomes in Drosophila

Methods in molecular biology, Journal Year: 2023, Volume and Issue: unknown, P. 455 - 467

Published: Jan. 1, 2023

Language: Английский

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Hepatic peroxisome and its implications on cardiac function, inflammation and aging

Published: Jan. 1, 2020

Aging is characterized by a chronic, low-grade inflammation, which major risk factor for cardiovascular diseases.As one of the important metabolic centers, liver shows agerelated dysregulation lipid metabolism, increased and oxidative stress response.It remains poorly understood whether pro-inflammatory factors released from contribute to non-autonomous regulation age-related cardiac dysfunction.We showed that Drosophila oenocytes share molecular similarities changes with mammalian livers.We perform translatomic profiling on understand age-and stress-regulated gene expression changes.We show aging downregulates phosphorylation, ribosome, proteasome peroxisomal biogenesis in oenocytes, whereas innate immune response Ras/MAPK signaling pathways are induced.Next, we identify age-dependent induction cytokine unpaired 3 (upd3) primary mechanism aging.Oenocytespecific knockdown upd3 sufficient block aging-induced arrhythmia.We further triggered impaired import elevated JNK aged oenocytes.Intriguingly, oenocyte-specific overexpression Pex5, key receptor, blocks alleviates arrhythmicity.Our previous studies prompt us transcriptomic responses under peroxisome dysfunction.Thus, performed RNA-seq analysis cellular caused defects human cells.Intriguingly, endoplasmic reticulum genes induced, ribosome vii defects.Altogether, these demonstrate role hepatic maintaining homeostasis whole organismal health. CHAPTER 1. GENERAL INTRODUCTIONAging dysfunction.Peroxisomes organelles regulate aging, metabolism.Liver highly enriched peroxisomes.However, little known about how peroxisomes other organs non-autonomously.In this thesis, I first summarize current knowledge liver-heart communications, inflammation aging.In following chapter, present (hepatocyte-like cells) or stress.In study, discover compromised during aging.Next, genetic evidence showing dysfunction can induce arrhythmia non-autonomously through proinflammatory factor, (homologous interleukin 6).We also liver-aging induced production arrhythmia.Lastly, conduct fly dysfunction, aiming defects.We stress.These will provide new insights treat related disease diseases.

Language: Английский

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