FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity

Wieder, Nicolas; Fried, Juliana Coraor; Kim, Choah; Sidhom, Eriene-Heidi; Brown, Matthew; Marshall, Jamie L.; Arevalo, Carlos; Dvela‐Levitt, Moran; Kost‐Alimova, Maria; Sieber, Jonas; Gabriel, Katlyn R.; Pacheco, Julian Avila; Clish, Clary B.; Abbasi, Hamdah Shafqat; Singh, Shantanu; Rutter, Justine C.; Therrien, Martine; Yoon, Haejin; Lai, Zon Weng; Baublis, Aaron; Subramanian, Renuka; Devkota, Ranjan; Small, Jonnell; Sreekanth, Vedagopuram; Han, Myeonghoon; Lim, Donghyun; Carpenter, Anne E.; Flannick, Jason; Finucane, Hilary; Haigis, Marcia C.; Claussnitzer, Melina; Sheu, Eric G.; Stevens, Beth; Wagner, Bridget K.; Choudhary, Amit; Shaw, Jillian L.; Pablo, Juan Lorenzo; Greka, Anna

doi:10.1016/j.cmet.2023.03.018

Cited by 14 publications

(2 citation statements)

References 142 publications

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“…It is, therefore, not surprising that the degree of severity of lipid-associated metabolic disorders has been associated with the abundance of specific TAG species [63]. Understanding how different TAG species can alter specific cellular functions and cause lipotoxic damage to organelles is still an open question [64]. Lipids other than FAs also induce cellular damage when they accumulate beyond a certain threshold, namely DAG and ceramides.…”

Section: Discussionmentioning

confidence: 99%

Lipid droplets and fatty acid‐induced lipotoxicity: in a nutshell

Obaseki,

Adebayo,

Bandyopadhyay

et al. 2024

FEBS Letters

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Lipid droplets (LDs) are fat storage organelles that are conserved from bacteria to humans. LDs are broken down to supply cells with fatty acids (FAs) that can be used as an energy source or membrane synthesis. An overload of FAs disrupts cellular functions and causes lipotoxicity. Thus, by acting as hubs for storing excess fat, LDs prevent lipotoxicity and preserve cellular homeostasis. LD synthesis and turnover have to be precisely regulated to maintain a balanced lipid distribution and allow for cellular adaptation during stress. Here, we discuss how prolonged exposure to excess lipids affects cellular functions, and the roles of LDs in buffering cellular stress focusing on lipotoxicity.

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Section: Discussionmentioning

confidence: 99%

Lipid droplets and fatty acid‐induced lipotoxicity: in a nutshell

Obaseki,

Adebayo,

Bandyopadhyay

et al. 2024

FEBS Letters

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“…CTL EV), it may be plausible that these sEV expose PS on the outer leaflet thus enhancing β-cell susceptibility to immune cell attack. Further investigation will go into understanding these lipid alterations due to PAL exposure and in addition, the contribution of other pathologically relevant FFAs that have been implicated in T2D 48 .…”

Section: Discussionmentioning

confidence: 99%

Lipotoxicity Induces Beta Cell Small Extracellular Vesicle-mediated β-cell Dysfunction

Roy,

Hoff,

Her

et al. 2024

Preprint

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Chronically elevated circulating excess free fatty acids (i.e.lipotoxicity) is a pathological process implicated in several metabolic disorders, including obesity-driven Type 2 diabetes (T2D). Lipotoxicity exerts detrimental effects on pancreatic islet β-cells by reducing glucose-stimulated insulin secretion (GSIS), altering β-cell transcriptional identity, and promoting apoptosis. While β-cell-derived small extracellular vesicles (sEV) have been shown to contribute to β-cell failure in T2D, their specific role in lipotoxicity-mediated β-cell failure remains to be elucidated. In this work, we demonstrate that lipotoxicity enhances the release of sEVs from β-cells, which exhibit altered proteomic and lipidomic profiles. These lipotoxic sEV induce β-cell dysfunction in healthy mouse and human islets and trigger significant islet transcriptional changes, including the upregulation of genes associated with the TGFβ/Smad3 pathway, as noted by RNA sequencing. Importantly, pharmacological inhibition of the TGFβI/II receptor improved lipotoxic sEV-induced β-cell dysfunction, underscoring their involvement in activating the TGFβ/Smad3 pathway during this process. We have comprehensively characterized lipotoxic β-cell sEVs and implicated their role in inducing β-cell functional failure in T2D. These findings highlight potential avenues for therapeutic interventions targeting sEV-mediated pathways to preserve β-cell health in metabolic disorders.Article HighlightsDiabetogenic lipotoxic conditions enhance β-cell sEV release and induce alterations in both protein and lipid content.Global islet transcriptional changes and alterations in β-cell function were noted upon exposure to lipotoxic sEV.Lipotoxic sEV were shown to activate the TGFβ/Smad3 pathway and blockade of this pathway improved β-cell function.

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PAQR proteins and the evolution of a superpower: Eating all kinds of fats

Pilon

Ruiz

2023

BioEssays

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Recently published work showed that members of the PAQR protein family are activated by cell membrane rigidity and contribute to our ability to eat a wide variety of diets. Cell membranes are primarily composed of phospholipids containing dietarily obtained fatty acids, which poses a challenge to membrane properties because diets can vary greatly in their fatty acid composition and could impart opposite properties to the cellular membranes. In particular, saturated fatty acids (SFAs) can pack tightly and form rigid membranes (like butter at room temperature) while unsaturated fatty acids (UFAs) form more fluid membranes (like vegetable oils). Proteins of the PAQR protein family, characterized by the presence of seven transmembrane domains and a cytosolic N‐terminus, contribute to membrane homeostasis in bacteria, yeasts, and animals. These proteins respond to membrane rigidity by stimulating fatty acid desaturation and incorporation of UFAs into phospholipids and explain the ability of animals to thrive on diets with widely varied fat composition.

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FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity

Cited by 14 publications

References 142 publications

Lipid droplets and fatty acid‐induced lipotoxicity: in a nutshell

Lipid droplets and fatty acid‐induced lipotoxicity: in a nutshell

Lipotoxicity Induces Beta Cell Small Extracellular Vesicle-mediated β-cell Dysfunction

PAQR proteins and the evolution of a superpower: Eating all kinds of fats

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