Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids

Papsdorf, Katharina; Miklas, Jason W.; Hosseini, Amir; Cabruja, Matías; Morrow, Christopher S.; Savini, Marzia; Yu, Yong Ming; Silva-García, Carlos Giovanni; Haseley, Nicole; Murphy, Luke; Yao, Pallas; Launoit, Elisa de; Dixon, Scott J.; Snyder, M; Wang, Meng C.; Mair, William; Brunet, Anne

doi:10.1038/s41556-023-01136-6

Cited by 42 publications

(13 citation statements)

References 158 publications

(185 reference statements)

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“…2C) and examined the number of lipid droplets (LDs) in the mutant fly brain. The fly LDs, primarily consisting of triacylglycerols (TAGs) and sterol esters, serve as a major source of fatty acid storage and protect against oxidative damage during larval development (Kis et al, 2015; Papsdorf et al, 2023; Welte, 2015). Using the Nile red staining (Yin et al, 2021), we detected a 47% of decrease in the numbers of lipid droplets in the larval brain of Obp44a knockout flies (Fig.…”

Section: Resultsmentioning

confidence: 99%

Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developingDrosophilabrain

Yin,

Chen,

Grigsby-Brown

et al. 2024

Preprint

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Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of the central nervous system (CNS). Through transcriptomics and imaging analyses, we have identified Obp44a as one of the most abundantly produced secretory proteins fromDrosophilaCNS glia. Protein structure homology modeling and Nuclear Magnetic Resonance (NMR) experiments reveal Obp44a as a fatty acid binding protein (FABP) with a high affinity towards long-chain fatty acids in both native and oxidized forms. Further analyses demonstrate that Obp44a effectively infiltrates the neuropil, traffics between neuron and glia, and is secreted into hemolymph, acting as a lipid chaperone and scavenger to regulate lipid and redox homeostasis in the developing brain. In agreement with this essential role, deficiency of Obp44a leads to anatomical and behavioral deficits in adult animals and elevated oxidized lipid levels. Collectively, our findings unveil the crucial involvement of a noncanonical lipid chaperone to shuttle fatty acids within and outside the brain, as needed to maintain a healthy brain lipid environment. These findings could inspire the design of novel approaches to restore lipid homeostasis that is dysregulated in CNS diseases.

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Section: Resultsmentioning

confidence: 99%

Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developingDrosophilabrain

Yin,

Chen,

Grigsby-Brown

et al. 2024

Preprint

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“…In addition to induction of lipid catabolism pathways, Kombucha-associated microbes may impair TAG accumulation or LD expansion. To investigate this further using our mRNA-Seq data, we compared the expression levels of genes that are known to function in LD synthesis or expansion for animals fed E. coli OP50, KTMs, or the KTM-M [69,79]. Although levels of seipin ( seip-1 ), lipin ( lpin-1 ), and acs- 22/FATP4 (a long-chain fatty acid transporter and acyl-CoA synthetase enzyme) were not altered in response to KTM feeding, the dgat-2/DGAT2 gene was dramatically and specifically down-regulated upon KTM consumption (Figures 6H-K), suggesting that TAG synthesis may be impaired in these animals.…”

Section: Resultsmentioning

confidence: 99%

Kombucha Tea-associated Microbes Remodel Host Metabolic Pathways to Suppress Lipid Accumulation

DuMez-Kornegay,

Morris,

Dowen

2023

Preprint

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The popularity of the ancient, probiotic-rich beverage Kombucha Tea (KT) has surged in part due to its purported health benefits, which include protection against metabolic diseases; however, these claims have not been rigorously tested and the mechanisms underlying host response to the probiotics in KT are unknown. Here, we establish a reproducible method to maintainC. eleganson a diet exclusively consisting of Kombucha Tea-associated microbes (KTM), which mirrors the microbial community found in the fermenting culture. KT microbes robustly colonize the gut of KTM-fed animals and confer normal development and fecundity. Intriguingly, animals consuming KTMs display a marked reduction in total lipid stores and lipid droplet size. We find that the reduced fat accumulation phenotype is not due to impaired nutrient absorption, but rather it is sustained by a programed metabolic response in the intestine of the host. KTM consumption triggers widespread transcriptional changes within core lipid metabolism pathways, including upregulation of a suite of lysosomal lipase genes that are induced during lipophagy. The elevated lysosomal lipase activity, coupled with a decrease in lipid droplet biogenesis, is partially required for the reduction in host lipid content. We propose that KTM consumption stimulates a fasting- like response in theC. elegansintestine by rewiring transcriptional programs to promote lipid utilization. Our results provide mechanistic insight into how the probiotics in Kombucha Tea reshape host metabolism and how this popular beverage may impact human metabolism.

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“…Plin-1 is the only known perilipin in C. elegans [146,147], whereas Fitm-2 is essential for the budding of LDs from the ER [148]. Another publication also confirmed the life-prolonging effect of monounsaturated fatty acids such as oleate [149].…”

Section: Significance Of Lipid Droplet Accumulation To C Elegans Life...mentioning

confidence: 91%

The Janus-Faced Role of Lipid Droplets in Aging: Insights from the Cellular Perspective

et al. 2023

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It is widely accepted that nine hallmarks—including mitochondrial dysfunction, epigenetic alterations, and loss of proteostasis—exist that describe the cellular aging process. Adding to this, a well-described cell organelle in the metabolic context, namely, lipid droplets, also accumulates with increasing age, which can be regarded as a further aging-associated process. Independently of their essential role as fat stores, lipid droplets are also able to control cell integrity by mitigating lipotoxic and proteotoxic insults. As we will show in this review, numerous longevity interventions (such as mTOR inhibition) also lead to strong accumulation of lipid droplets in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and mammalian cells, just to name a few examples. In mammals, due to the variety of different cell types and tissues, the role of lipid droplets during the aging process is much more complex. Using selected diseases associated with aging, such as Alzheimer’s disease, Parkinson’s disease, type II diabetes, and cardiovascular disease, we show that lipid droplets are “Janus”-faced. In an early phase of the disease, lipid droplets mitigate the toxicity of lipid peroxidation and protein aggregates, but in a later phase of the disease, a strong accumulation of lipid droplets can cause problems for cells and tissues.

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Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids

Cited by 42 publications

References 158 publications

Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developingDrosophilabrain

Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developingDrosophilabrain

Kombucha Tea-associated Microbes Remodel Host Metabolic Pathways to Suppress Lipid Accumulation

The Janus-Faced Role of Lipid Droplets in Aging: Insights from the Cellular Perspective

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