Starvation resistant cavefish reveal conserved mechanisms of starvation-induced hepatic lipotoxicity
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PROVIDER: PRJNA1023959 | ENA |
REPOSITORIES: ENA
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Project description:Starvation is a severe form of malnutrition that occurs when an individual's intake of food is inadequate to meet their body's energy requirements. Prolonged starvation can cause permanent organ damage, stunted growth in children, and death if left untreated. It is estimated that approximately 45% of deaths among children under the age of 5 years are linked to undernutrition. Notably, the liver’s health is compromised during starvation. More than 60 years ago, it was recognized that chronic severe malnutrition in children, such as kwashiorkor, leads to fatty liver. Subsequently, starvation has been shown to induce accumulation of liver fat (steatosis) in drosophila, zebrafish, and humans. To uncover potential strategies for protecting the liver, we turned to adaptation strategies present in a genetically tractable and naturally occurring model of starvation resistance - the Astyanax mexicanus model system. Cave populations of this species have adapted to survive in conditions of extreme starvation, while the surface populations of the same species display relatively normal vertebrate physiology. We took advantage of this unique system to study the response of the liver to starvation and identified reduced expression of the fatty acid uptake gene slc27a2a/fatp2 allowing cavefish to prevent liver damage under starvation. Targeting this pathway in both fish and flies mitigates starvation-induced hepatic steatosis and protects the liver from lipotoxicity in zebrafish. This demonstrates that the identified pathway is evolutionary conserved for over 400 million years, highlighting its potential as a druggable target.
2024-01-11 | GSE244648 | GEO
Project description:Starvation causes the accumulation of lipid droplets in the liver, a somewhat counterintuitive phenomenon that is nevertheless conserved from flies to humans. Much like fatty liver resulting from overfeeding, hepatic lipid accumulation (steatosis) during undernourishment can lead to lipotoxicity and atrophy of the liver. Here, we found that while surface populations of Astyanax mexicanus undergo this evolutionarily conserved response to starvation, the starvation-resistant cavefish larvae of the same species do not display an accumulation of lipid droplets upon starvation. Moreover, cavefish are resistant to liver atrophy during starvation, providing a unique system to explore strategies for liver protection. Using comparative transcriptomics between zebrafish, surface fish, and cavefish, we identified the fatty acid transporter slc27a2a/fatp2 to be correlated with the development of fatty liver. Pharmacological inhibition of slc27a2a in zebrafish rescues steatosis and atrophy of the liver upon starvation. Further, down-regulation of FATP2 in drosophila larvae inhibits the development of starvation-induced steatosis, suggesting the evolutionary conserved importance of the gene in regulating fatty liver upon nutrition deprivation. Overall, our study identifies a conserved, druggable target to protect the liver from atrophy during starvation.
| S-EPMC10802416 | biostudies-literature
Project description:Starvation causes the accumulation of lipid droplets in the liver, a somewhat counterintuitive phenomenon that is nevertheless conserved from flies to humans. Much like fatty liver resulting from overfeeding, hepatic lipid accumulation (steatosis) during undernourishment can lead to lipotoxicity and atrophy of the liver. Here, we found that although surface populations of Astyanax mexicanus undergo this evolutionarily conserved response to starvation, the starvation-resistant cavefish larvae of the same species do not display an accumulation of lipid droplets upon starvation. Moreover, cavefish are resistant to liver atrophy during starvation, providing a unique system to explore strategies for liver protection. Using comparative transcriptomics between zebrafish, surface fish, and cavefish, we identified the fatty acid transporter slc27a2a/fatp2 to be correlated with the development of fatty liver. Pharmacological inhibition of slc27a2a in zebrafish rescues steatosis and atrophy of the liver upon starvation. Furthermore, down-regulation of FATP2 in Drosophila larvae inhibits the development of starvation-induced steatosis, suggesting the evolutionarily conserved importance of the gene in regulating fatty liver upon nutrition deprivation. Overall, our study identifies a conserved, druggable target to protect the liver from atrophy during starvation.
| S-EPMC10927358 | biostudies-literature
Project description:Starvation causes the accumulation of lipid droplets in the liver, a somewhat counterintuitive phenomenon that is nevertheless conserved from flies to humans. Much like fatty liver resulting from overfeeding, hepatic lipid accumulation (steatosis) during undernourishment can lead to lipotoxicity and atrophy of the liver. Here, we found that while surface populations of Astyanax mexicanus undergo this evolutionarily conserved response to starvation, the starvation-resistant cavefish larvae of the same species do not display an accumulation of lipid droplets upon starvation. Moreover, cavefish are resistant to liver atrophy during starvation, providing a unique system to explore strategies for liver protection. Using comparative transcriptomics between zebrafish, surface fish, and cavefish, we identified the fatty acid transporter slc27a2a/fatp2 to be correlated with the development of fatty liver. Pharmacological inhibition of slc27a2a in zebrafish rescues steatosis and atrophy of the liver upon starvation. Further, down-regulation of FATP2 in drosophila larvae inhibits the development of starvation-induced steatosis, suggesting the evolutionary conserved importance of the gene in regulating fatty liver upon nutrition deprivation. Overall, our study identifies a conserved, druggable target to protect the liver from atrophy during starvation.
2024-01-11 | GSE252997 | GEO
Project description:We found higher substitution rates in cavefish compared with surface fish, in accordance with a smaller cavefish population size which has allowed more rapid fixation of derived alleles present in the ancestral population. This result also implies that the Pachn cave population is much younger than previously estimated. The comparison of these data with simulations suggests that the Pachn cavefish population has probably been underground less than 30,000 years. This new time frame, together with other evidence, indicate that the evolution of cave phenotypes mainly involves the fixation of cryptic genetic variants present in surface fish populations within a short period of time.
2016-06-27 | E-MTAB-5142 | biostudies-arrayexpress
Project description:To test wheather cavefish have higher lipogenesis capability than surface fish, we used liver sample from fasted and refed fish to do RNA-seq to compare their transcriptome responding to feeding in surface fish and Pachón cavefish. Moreover, we did the Pparγ ChIP-seq with liver from fed surface fish and Pachón cavefish. We amied to test whether Pparγ in Pachón cavefish have more biding sites and higher binding peaks than surface fish.
2022-02-10 | GSE173494 | GEO
Project description:Reduced parasitic infection rates in the developed world are suspected to underlie the rising prevalence of autoimmune disorders. However, the long-term evolutionary consequences of decreased parasite exposure on an immune system are not well understood. We used the Mexican tetra Astyanax mexicanus to understand how loss of parasite diversity influences the evolutionary trajectory of the vertebrate immune system, by comparing river with cave morphotypes. Here, we present field data affirming a strong reduction in parasite diversity in the cave ecosystem, and show that cavefish immune cells display a more sensitive pro-inflammatory response towards bacterial endotoxins. Surprisingly, other innate cellular immune responses, such as phagocytosis, are drastically decreased in cavefish. Using two independent single-cell approaches, we identified a shift in the overall immune cell composition in cavefish as the underlying cellular mechanism, indicating strong differences in the immune investment strategy. While surface fish invest evenly into the innate and adaptive immune systems, cavefish shifted immune investment to the adaptive immune system, and here, mainly towards specific T-cell populations that promote homeostasis. Additionally, inflammatory responses and immunopathological phenotypes in visceral adipose tissue are drastically reduced in cavefish. Our data indicate that long-term adaptation to low parasite diversity coincides with a more sensitive immune system in cavefish, which is accompanied by a reduction in the immune cells that play a role in mediating the pro-inflammatory response.
2020-07-20 | GSE128306 | GEO
Project description:Dysregulation of sleep has widespread health consequences and represents an enormous health burden. Short-sleeping individuals are predisposed to the effects of neurodegeneration, suggesting a critical role for sleep in the maintenance of neuronal health. While the effects of sleep on cellular function are not completely understood, growing evidence has identified an association between sleep loss and DNA damage, raising the possibility that sleep facilitates efficient DNA repair. The Mexican tetra fish,Astyanax mexicanusprovides a model to investigate the evolutionary basis for changes in sleep and the consequences of sleep loss. Multiple cave-adapted populations of these fish have evolved to sleep for substantially less time compared to surface populations of the same species without identifiable impacts on healthspan or longevity. To investigate whether the evolved sleep loss is associated with DNA damage and cellular stress, we compared the DNA Damage Response (DDR) and oxidative stress levels betweenA. mexicanuspopulations. We measured markers of chronic sleep loss and discovered elevated levels of the DNA damage marker γH2AX in the brain, and increased oxidative stress in the gut of cavefish, consistent with chronic sleep deprivation. Notably, we found that acute UV-induced DNA damage elicited an increase in sleep in surface fish but not in cavefish. On a transcriptional level, only the surface fish activated the photoreactivation repair pathway following UV damage. These findings suggest a reduction of the DDR in cavefish compared to surface fish that coincides with elevated DNA damage in cavefish. To examine DDR pathways at a cellular level, we created an embryonic fibroblast cell line from the two populations ofA. mexicanus. We observed that both the DDR and DNA repair were diminished in the cavefish cells, corroborating thein vivofindings and suggesting that the acute response to DNA damage is lost in cavefish. To investigate the long-term impact of these changes, we compared the transcriptome in the brain and gut of aged surface fish and cavefish. Strikingly, many genes that are differentially expressed between young and old surface fish do not transcriptionally vary by age in cavefish. Taken together, these findings suggest that have developed resilience to sleep loss, despite possessing cellular hallmarks of chronic sleep deprivation.
2024-10-13 | GSE272696 | GEO
Project description:We report the shift in skeletal muscle investment strategies of the Mexican cavefish following cave colonization
2022-12-31 | GSE196531 | GEO