Liver X receptor controls a bifurcated transcriptional program where lipogenesis genes overshoot upon refeeding while cholesterol biosynthesis genes return to pre-fasting levels
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE243057 | GEO | 2024/07/10
REPOSITORIES: GEO
Similar Datasets
Project description:Transitions from a fed to a fasted state are common in mammals. The liver orchestrates adaptive responses to feeding/fasting by transcriptionally regulating metabolic pathways of energy usage and storage. Transcriptional and enhancer dynamics following cessation of fasting (refeeding) were never explored. We aimed to inspect the transcriptional and chromatin events occurring upon refeeding, their kinetic behavior and their molecular drivers. We found that the refeeding response is temporally-organized with an early response focused on ramping up protein translation while later stages of refeeding drive a bifurcated lipid synthesis program. While both lipid synthesis pathways were inhibited during fasting, cholesterol biosynthesis genes returned to their basal levels upon refeeding while lipogenesis genes significantly overshoot above pre-fasting levels. Lipogenic gene overshoot is dictated by Liver X Receptor alpha (LXRα) which directly binds and activates lipogenic enhancers. These findings unravel the mechanism behind the long-known phenomenon of refeeding fat overshoot.
2024-07-10 | GSE243050 | GEO
Project description:Transitions from a fed to a fasted state are common in mammals. The liver orchestrates adaptive responses to feeding/fasting by transcriptionally regulating metabolic pathways of energy usage and storage. Transcriptional and enhancer dynamics following cessation of fasting (refeeding) were never explored. We aimed to inspect the transcriptional and chromatin events occurring upon refeeding, their kinetic behavior and their molecular drivers. We found that the refeeding response is temporally-organized with an early response focused on ramping up protein translation while later stages of refeeding drive a bifurcated lipid synthesis program. While both lipid synthesis pathways were inhibited during fasting, cholesterol biosynthesis genes returned to their basal levels upon refeeding while lipogenesis genes significantly overshoot above pre-fasting levels. Lipogenic gene overshoot is dictated by Liver X Receptor alpha (LXRα) which directly binds and activates lipogenic enhancers. These findings unravel the mechanism behind the long-known phenomenon of refeeding fat overshoot.
2024-07-10 | GSE243054 | GEO
Project description:Transitions from a fed to a fasted state are common in mammals. The liver orchestrates adaptive responses to feeding/fasting by transcriptionally regulating metabolic pathways of energy usage and storage. Transcriptional and enhancer dynamics following cessation of fasting (refeeding) were never explored. We aimed to inspect the transcriptional and chromatin events occurring upon refeeding, their kinetic behavior and their molecular drivers. We found that the refeeding response is temporally-organized with an early response focused on ramping up protein translation while later stages of refeeding drive a bifurcated lipid synthesis program. While both lipid synthesis pathways were inhibited during fasting, cholesterol biosynthesis genes returned to their basal levels upon refeeding while lipogenesis genes significantly overshoot above pre-fasting levels. Lipogenic gene overshoot is dictated by Liver X Receptor alpha (LXRα) which directly binds and activates lipogenic enhancers. These findings unravel the mechanism behind the long-known phenomenon of refeeding fat overshoot.
2024-07-10 | GSE243051 | GEO
Project description:Transitions from a fed to a fasted state are common in mammals. The liver orchestrates adaptive responses to feeding/fasting by transcriptionally regulating metabolic pathways of energy usage and storage. Transcriptional and enhancer dynamics following cessation of fasting (refeeding) were never explored. We aimed to inspect the transcriptional and chromatin events occurring upon refeeding, their kinetic behavior and their molecular drivers. We found that the refeeding response is temporally-organized with an early response focused on ramping up protein translation while later stages of refeeding drive a bifurcated lipid synthesis program. While both lipid synthesis pathways were inhibited during fasting, cholesterol biosynthesis genes returned to their basal levels upon refeeding while lipogenesis genes significantly overshoot above pre-fasting levels. Lipogenic gene overshoot is dictated by Liver X Receptor alpha (LXRα) which directly binds and activates lipogenic enhancers. These findings unravel the mechanism behind the long-known phenomenon of refeeding fat overshoot.
2024-07-10 | GSE243049 | GEO
Project description:Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity.We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation.In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting.Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3-mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease.ClinicalTrials.gov NCT02122575 and NCT00442195.Division of Intramural Research, NHLBI of the NIH.
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Project description:Animals acquire nutrients and energy through feeding to achieve a balance between growth and organismal health. When there is a change in nutrient acquisition, the state of growth changes and may also cause changes in the intrinsic immune system. Compensatory growth (CG), a specific growth phenomenon, involves the question of whether changes in growth can be accompanied by changes in innate immunity. The zebrafish (Danio rerio), a well-known fish model organism, can serve as a suitable model. In this study, the zebrafish underwent 3 weeks of fasting and refeeding for 3 to 7 day periods. It was found that CG could be achieved in zebrafish. Zebrafish susceptibility to Streptococcus agalactiae increased after starvation. In addition, the amount of melano-macrophage centers increased after fasting and the proportion of injured tubules increased after refeeding for 3 and 5 days, respectively. Furthermore, the kidneys of zebrafish suffering from starvation were under oxidative stress, and the activity of several antioxidant enzymes increased after starvation, including catalase, glutathione peroxidases and superoxide dismutase. Innate immune parameters were influenced by starvation. Additionally, the activity of alkaline phosphatase and lysozyme increased after starvation. The mRNA expression of immune-related genes like il-1β was elevated to a different extent after fasting with or without lipopolysaccharides (LPS) challenge. This study showed that the function of the innate immune system in zebrafish could be influenced by nutrition status.
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Project description:Nutrition and energy are essential for poultry growth and production performance. Fasting and refeeding have been widely used to study the effects of nutrition, energy, and related mechanisms in chicken. Previous studies have shown that geese have a strong capacity for fat synthesis and storage; thus, changes in the goose liver transcriptome may be different from those in chicken assessed with a model of fasting and refeeding. However, the responses of the goose liver transcriptome to fasting and refeeding have not yet been addressed. In this study, 36 70-day-old Si Ji geese with similar body weight were randomly assigned to three groups: control (ad libitum feeding), fasting (fasted for 24 h), and refeeding (fast for 24 h followed by 2-h feeding) groups. After treatment, eight geese per group were sacrificed for sample collection. Liver samples from four geese in each group were subjected to transcriptome analysis, followed by validation of differentially expressed genes (DEGs) using quantitative polymerase chain reaction with the remaining samples. As a result, 155 DEGs (73 up-regulated) were identified between the control and fasting groups, and 651 DEGs (321 up-regulated) were identified between the fasting and refeeding groups. The enrichment analyses of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed that fasting mainly influenced material metabolism in the liver, especially lipid metabolism; in contrast, refeeding affected not only lipid metabolism but also glucose and amino acid metabolism. In addition, the peroxisome proliferator-activated receptor (PPAR) signaling pathway may play an important role in lipid metabolism. In conclusion, fasting and refeeding have a strong effect on lipid metabolism in the goose liver; specifically, fasting promotes fatty acid oxidation and inhibits fatty acid synthesis, and refeeding has the opposite effect. The model of fasting and refeeding is suitable for goose nutrition studies.
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Project description:Hepatic lipogenesis is nutritionally regulated (i.e., downregulated during fasting and upregulated during the postprandial state) as an adaptation to the nutritional environment. While alterations in the expression level of the transcription factor SREBP-1c are known to be critical for nutritionally regulated lipogenesis, upstream mechanisms governing Srebf1 expression remain unclear. Here, we show that the fasting-induced transcription factor KLF15, a key regulator of gluconeogenesis, forms a complex with LXR/RXR, specifically on the Srebf1 promoter. This complex recruits the corepressor RIP140 instead of the coactivator SRC1, resulting in reduced Srebf1 and thus downstream lipogenic enzyme expression during the early and euglycemic period of fasting prior to hypoglycemia and PKA activation. Through this mechanism, KLF15 overexpression specifically ameliorates hypertriglyceridemia without affecting LXR-mediated cholesterol metabolism. These findings reveal a key molecular link between glucose and lipid metabolism and have therapeutic implications for the treatment of hyperlipidemia.
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Project description:The freshwater clam (Corbicula spp.) is a popular edible bivalve and has been used as a folk remedy for liver disease in Asia. As a Chinese traditional medicine, it is said that freshwater clam ameliorates alcoholic intoxication and cholestasis. In this study, to estimate the practical benefit of freshwater clam extract (FCE), we compared the effects of FCE and soy protein isolate (SPI) on triglyceride and cholesterol metabolism in rats. FCE and SPI lowered serum cholesterol, and FCE tended to reduce serum triglycerides. FCE enhanced fecal sterol excretion and hepatic mRNA levels of CYP7A1 and ABCG5 more substantially than SPI; however, both diets reduced hepatic cholesterol. Both of the diets similarly suppressed liver lipids improved ?9-desaturated fatty acid profile, and FCE was associated with a reduction in FAS and SCD1 mRNA levels. Hepatic transcriptome analysis revealed that inhibition of lipogenesis-related gene expression may contribute to downregulation of hepatic triglycerides by FCE. FCE would have better potential benefits for preventing metabolic disorders, through greater improvement of metabolism of triglycerides and cholesterol, likely through a mechanism similar to SPI.
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Project description:BackgroundDiets that include some aspect of fasting have dramatically increased in popularity. In addition, fasting reduces inflammasome activity in the brain while improving learning. Here, we examine the impact of refeeding a low-fat diet (LFD) or high-fat diet (HFD) after fasting.MethodsMale wildtype (WT), caspase-1 knockout (KO) and/or IL-1 receptor 1 (IL-1R1) KO mice were fasted for 24 h or allowed ad libitum access to food (chow). Immediately after fasting, mice were allowed to refeed for 2 h in the presence of LFD, HFD or chow. Mouse learning was examined using novel object recognition (NOR) and novel location recognition (NLR). Caspase-1 activity was quantified in the brain using histochemistry (HC) and image analysis.ResultsRefeeding with a HFD but not a LFD or chow fully impaired both NOR and NLR. Likewise, HFD when compared to LFD refeeding increased caspase-1 activity in the whole amygdala and, particularly, in the posterior basolateral nuclei (BLp) by 2.5-fold and 4.6-fold, respectively. When caspase-1 KO or IL-1R1 KO mice were examined, learning impairment secondary to HFD refeeding did not occur. Equally, administration of n-acetylcysteine to fasted WT mice prevented HFD-dependent learning impairment and caspase-1 activation in the BLp. Finally, the free-fatty acid receptor 1 (FFAR1) antagonist, DC260126, mitigated learning impairment associated with HFD refeeding while blocking caspase-1 activation in the BLp.ConclusionsConsumption of a HFD after fasting impairs learning by a mechanism that is dependent on caspase-1 and the IL-1R1 receptor. These consequences of a HFD refeeding on the BLP of the amygdala appear linked to oxidative stress and FFAR1.
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