Removing a Double Bond from Ceramides Ameliorates Insulin Resistance and Hepatic Steatosis
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ABSTRACT:
PROVIDER: PRJNA545734 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9172050_1.fastq.gz | Fastqsanger.gz | |||
| SRR9172050_2.fastq.gz | Fastqsanger.gz | |||
| SRR9172060_1.fastq.gz | Fastqsanger.gz | |||
| SRR9172060_2.fastq.gz | Fastqsanger.gz | |||
| SRR9172051_1.fastq.gz | Fastqsanger.gz |
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Project description:Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase-1 (DES1) which inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals, or tissue-specific deletion in the liver, and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed new ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and cardiometabolic disorders.
2020-01-30 | GSE132056 | GEO
Project description:Alcohol’s impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid-ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and lipid droplet compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol’s inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri-lipid droplet ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.
2020-07-08 | GSE139015 | GEO
Project description:Perturbations in proximal tubule mitochondrial function and lipid metabolism potentiate kidney dysfunction in acute kidney injury (AKI). We identified the bioactive lipid ceramides as drivers of proximal tubule pathology in AKI. Ceramide synthesis was upregulated in humans and mice with AKI. We utilized a proteome-wide thermal shift assay to observe that ceramides interact with proximal tubule proteins involved in lipid and mitochondrial metabolism. Mechanistic studies revealed that ceramides altered assembly of the inner mitochondrial membrane MICOS complex and respiratory supercomplexes in proximal tubule cells leading to acute impacts on mitochondrial respiration, cristae architecture, and mitochondrial morphology. Effects of ceramides on complex assembly and mitochondrial function were dependent on the presence of the 4-5 trans double bond incorporated by dihydroceramide desaturase 1 (DES1). Blunting ceramide synthesis, via genetic or pharmacologic inhibition of DES1, prevented kidney injury in mice following renal ischemia reperfusion injury. Ceramides may be a novel therapeutic target to combat mitochondrial disruption during AKI.
2025-12-17 | GSE284451 | GEO
Project description:Lipids are bioactive signaling molecules implicated in tissue-specific and whole-body insulin resistance, with ceramides and diacylglycerols (DAGs) as prominent species. Their precise roles remain unclear. Here, we leverage natural genetic variation in 399 male Diversity Outbred Australia (DOz) mice fed chow or a high-fat diet to examine the relationship between muscle lipids and insulin sensitivity. Fat mass was significantly associated with 55% of muscle lipid features and whole-body insulin sensitivity, with DAGs enriched in this association. To disentangle adiposity and muscle lipid contributions, we used: (1) linear models correcting lipid features for fat mass, and (2) insulin sensitivity quartiles within adiposity bins. Both approaches identified very long-chain ceramides, not DAGs, as linked to insulin resistance. RNA sequencing and proteomics from the same muscles associated these ceramides with cellular stress, mitochondrial dysfunction, and protein synthesis regulation. Meanwhile, DAGs correlated with leptin gene expression, suggesting an adipocyte, rather than myocyte, origin. These findings highlight very long-chain ceramides as key muscle lipids associated with insulin resistance, independent of adiposity.
2025-08-06 | GSE290031 | GEO
Project description:Lipid remodeling is crucial for hypoxic tolerance in animals, whilst little is known about the hypoxia-induced lipid dynamics in plant cells. Here we performed a mass spectrometry-based analysis to survey the lipid profiles of Arabidopsis rosettes under various hypoxic conditions. We observed that hypoxia caused a significant increase in total amounts of phosphatidylserine, phosphatidic acid and oxylipins, but a decrease in phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Particularly, significant gains in the polyunsaturated species of PC, PE and phosphatidylinositol, and losses in their saturated and mono-unsaturated species were evident during hypoxia. Moreover, hypoxia led to a remarkable elevation of ceramides and hydroxyceramides. Depletion of ceramide synthases LOH1, LOH2, and LOH3 enhanced plant sensitivity to dark submergence (DS), but displayed more resistance to submergence under light than wild type. Consistently, levels of unsaturated ceramide species (22:1, 24:1, and 26:1) predominantly declined in the loh1, loh2, and loh3 mutants under DS. Evidence that C24:1-ceramide interacted with recombinant CTR1 protein in vitro, enhanced ER-to-nucleus translocation of EIN2-GFP and stabilization of EIN3-GFP in vivo, suggests a role of ceramides in modulating ethylene signaling. The DS-sensitive phenotypes of loh mutants were rescued by a ctr1-1 mutation. Thus, our findings demonstrate that unsaturation of very-long-chain ceramides is a protective strategy for hypoxic tolerance in Arabidopsis. Arabidopsis Affymetrix GeneChip arrays were probed with RNAs isolated from leaves of untreated plants (controls) and plants upon hypoxia under light submergence for 48 h.
2016-07-24 | E-GEOD-59719 | biostudies-arrayexpress
Project description:Background: As a worldwide threat to mental health, depression affects about 322 million people globally. Recently, the role of gut microbiota dysbiosis on the pathogenesis of depression has received widespread attention, but the underlying mechanism remains elusive.Results: Corticosterone (CORT)-treated mice showed depressive-like behaviors, a reduction in hippocampal neurogenesis, and an altered composition of gut microbiota (GM). Fecal microbial transplantation (FMT) from CORT-treated mice transferred depressive-like phenotypes and their dominant GM, especially bifidobacterium and lactobacillus, to the recipients. Fecal metabolic profiling showed that the relative abundances of fecal ceramides were significantly increased in CORT-treated and the recipient mice. Metagenomic sequencing exposed that bifidobacterium and lactobacillus might be responsible for gut ceramides production in CORT-treated mice. We then found that treatment with ceramides via oral gavage was sufficient to recapitulate the depressive-like phenotypes in wild -type mice. Finally, RNA-sequencing data exposed that most of the differentially expressed genes (DEGs) between ceramides-treated mice and the control group were enriched in oxidative phosphorylation (OXPHOS) pathway. Conclusion: We conclude that chronic exposure to CORT leads to an altered GM composition and consequent ceramides production, thus leading to subtle mitochondrial OXPHOS dysfunction in hippocampus, which may contribute to the development of depressive disorders.
2024-04-01 | GSE229237 | GEO
Project description:CPEB4 prevents hepatic steatosis
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Project description:Background: Ginseng flower bud (GFB) is a part of ginseng with high content of ginsenosides, the known active components of ginseng. While the scientific data for the pharmacological activity of ginseng roots are accumulating, the therapeutic potential of GFB have been neglected. The current study aimed to examine the therapeutic effect of GFB on hepatic steatosis and to elucidate the underlying mechanisms. Methods: HepG2 cells treated with free fatty acids mixture and hepatocytes isolated from rats after 3 weeks of HFD feeding were used as in vitro models of hepatic steatosis for evaluation of anti-steatotic effect of GFB. The effect of GFB was further investigated in pathological conditions of hepatic steatosis induced by 12 weeks of HFD feeding in C57BL/6J mice. We performed systematical analyses on hepatic gene expression profiles in GFB treated mice. The effect of GFB on the expression profile of selected genes was validated by quantitative PCR. Results: GFB treatment markedly reduced oil red O stained lipid droplets and intracellular triglyceride levels in HepG2 cells and rat hepatocytes. In HFD-fed mice, GFB (500 mg/kg) treatment markedly reduced histological signs of hepatic steatosis and decreased hepatic triglyceride content by 34.1% compared to those of HFD. These changes by GFB treatment were accompanied by improved insulin signaling. Global gene expression analysis revealed that hepatic gene expression in the steatotic liver was reversed by GFB treatment, and the GFB-regulated genes are involved in immune process, insulin response and lipid storage. Conclusion: These findings provide a substantial evidence for the medicinal use of GFB in prevention or treatment of NAFLD through suppression of hepatic inflammation and fatty acid uptake while sensitizing hepatic insulin signaling
2021-01-01 | GSE142059 | GEO
Project description:Lipid remodeling is crucial for hypoxic tolerance in animals, whilst little is known about the hypoxia-induced lipid dynamics in plant cells. Here we performed a mass spectrometry-based analysis to survey the lipid profiles of Arabidopsis rosettes under various hypoxic conditions. We observed that hypoxia caused a significant increase in total amounts of phosphatidylserine, phosphatidic acid and oxylipins, but a decrease in phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Particularly, significant gains in the polyunsaturated species of PC, PE and phosphatidylinositol, and losses in their saturated and mono-unsaturated species were evident during hypoxia. Moreover, hypoxia led to a remarkable elevation of ceramides and hydroxyceramides. Depletion of ceramide synthases LOH1, LOH2, and LOH3 enhanced plant sensitivity to dark submergence (DS), but displayed more resistance to submergence under light than wild type. Consistently, levels of unsaturated ceramide species (22:1, 24:1, and 26:1) predominantly declined in the loh1, loh2, and loh3 mutants under DS. Evidence that C24:1-ceramide interacted with recombinant CTR1 protein in vitro, enhanced ER-to-nucleus translocation of EIN2-GFP and stabilization of EIN3-GFP in vivo, suggests a role of ceramides in modulating ethylene signaling. The DS-sensitive phenotypes of loh mutants were rescued by a ctr1-1 mutation. Thus, our findings demonstrate that unsaturation of very-long-chain ceramides is a protective strategy for hypoxic tolerance in Arabidopsis.
2016-07-24 | GSE59719 | GEO
Project description:Ceramides Drive Mitochondrial Dysfunction and Tubular Injury in AKI
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