HFD-inducued metabolic syndrome is promoted by JNK7b isoform [Liver_RNAseq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE278155 | GEO | 2026/02/27
REPOSITORIES: GEO
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Project description:The JUN NH2-terminal kinase (JNK) signal transduction pathway is activated during the hepatic metabolic stress response. The pre-mRNAs expressed by the Mapk8 and Mapk9 genes (encode JNK1 and JNK2) in hepatocytes exhibit mutually exclusive inclusion exons 7a or 7b that encode a segment of the substrate binding site that is required for selective protein phosphorylation. We established mice with conditional inclusion of exons 7a / 7b to test the function of JNK spliceoforms. We report that the JNK27b spliceoform plays a key role in the hepatic metabolic stress response by suppressing signaling by the nuclear hormone receptor PPARa. This function of JNK27b is mediated by an integrated mechanism involving circadian dysfunction and the phosphorylation of the PPARa partner protein RXRa on Ser265. Our analysis identifies a key role for a specific JNK spliceoform in the hepatic adaptive response to metabolic stress.
2026-02-27 | GSE277336 | GEO
Project description:The JUN NH2-terminal kinase (JNK) signal transduction pathway is activated during the hepatic metabolic stress response. The pre-mRNAs expressed by the Mapk8 and Mapk9 genes (encode JNK1 and JNK2) in hepatocytes exhibit mutually exclusive inclusion exons 7a or 7b that encode a segment of the substrate binding site that is required for selective protein phosphorylation. We established mice with conditional inclusion of exons 7a / 7b to test the function of JNK spliceoforms. We report that the JNK27b spliceoform plays a key role in the hepatic metabolic stress response by suppressing signaling by the nuclear hormone receptor PPARa. This function of JNK27b is mediated by an integrated mechanism involving circadian dysfunction and the phosphorylation of the PPARa partner protein RXRa on Ser265. Our analysis identifies a key role for a specific JNK spliceoform in the hepatic adaptive response to metabolic stress.
2026-02-27 | GSE281332 | GEO
Project description:The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating PPARa-dependent expression of the hepatokine FGF21. Hepatocyte-specific gene ablation studies demonstrated that the Mapk9 gene (encodes JNK2) plays a key mechanistic role. Mutually exclusive inclusion of exons 7a and 7b yields expression of the isoforms JNK2a and JNK2b. Here we demonstrate that Fgf21 gene expression and metabolic regulation is primarily regulated by the JNK2a isoform. To identify relevant substrates of JNK2a, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK-deficiency in hepatocytes, and mice that express only JNK2a or JNK2b in hepatocytes. We identified the JNK substrate RXRa as a protein that exhibited JNK2a-promoted phosphorylation in vivo. RXRa functions as a heterodimeric partner of PPARa and may therefore mediate the effects of JNK2a signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXRa proteins. We found that the RXRa phosphorylation site Ser260 was required for suppression of Fgf21 gene expression. Collectively, these data establish a JNK-mediated signaling pathway that regulates hepatic Fgf21 expression.
2022-10-12 | PXD034183 | Pride
Project description:Chronic stress disorders lead to metabolic complications, including hepatic lipid accumulation. Here we address the role of FGF21 in the hepatic metabolic regulation in a mouse model for chronic variable stress (Cvs). Global FGF21KO and WT mice show an intact stress response with short-term Cvs induced alterations in hepatic lipid metabolism, mitochondrial function and gene expression. Hepatic steatosis is found with the highest significance in enrichment analyses of hepatic transcriptome data, with PPARa and SREBP-1 as main upstream regulatory molecules, which are directly associated to FGF21. After 3 months recovery, stress-related metabolic improvements are not visible in FGF21KO mice in contrast to WT mice, indicating the crucial role of FGF21 in the post-stress metabolic adaptations. Overall, we suggest that Cvs-induced gene regulation determines the metabolic late effects after stress. Furthermore, FGF21 is a key player in the protection from stress-induced hepatic lipid accumulation.
2021-10-13 | GSE158653 | GEO
Project description:Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease, however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARa is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARa in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARa levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARa agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARa function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point towards new therapeutic leads in sepsis.
2019-11-23 | GSE139484 | GEO
Project description:Gene expression in livers of wild type adult male mice and in lncRNA 3930402G23Rik ("G23Rik") knockdown adult male mouse liver was assayed by RNA-seq, as part of a study of liver transcriptomic changes in response to activation of PPARA by WY-14,643, published in Molecular and Cellular Endocrinology (2022). These studies found that G23Rik-null mice were more susceptible to hepatic lipid accumulation in response to acute fasting. Histological analysis further revealed a pronounced buildup of lipid droplets and a significant increase in neutral triglycerides and lipids as indicated by enhanced oil red O staining of liver sections. Hepatic cholesterol, non-esterified fatty acid, and triglyceride levels were significantly elevated in G23Rik-null mice and associated with induction of the lipid-metabolism related gene Cd36. These findings provide evidence for a lncRNA dependent mechanism by which PPARA attenuates hepatic lipid accumulation in response to metabolic stress through lncRNA G23Rik induction.
2022-07-31 | GSE197885 | GEO
Project description:Flavin adenine dinucleotide (FAD) mediates oxidation-reduction reactions required for cellular energy demands. Fatty acid oxidation (FAO) disorders caused by flavoprotein mutations and FAD depletion disrupt energy balance and glucose production during fasting. These FAO disorders are difficult to manage clinically, and their biochemical pathogenesis is poorly understood. Here, we identify a mechanistic connection between FAD levels and hepatic glucose production. Depleting the FAD pool in mice with a vitamin B2 deficient diet (B2D) resulted in phenotypes associated with organic acidemia phenotypes, including reduced body weight and whole-body fat oxidation rates coupled with hypoglycemia. Integrated discovery approaches revealed that B2D broadly tempered fasting activation of target genes for the nuclear receptor PPARa, including those required for gluconeogenesis. Consistent with this, Ppara knockout depleted liver FAD levels and worsened B2D hepatic glucose production. Treatment with the PPARa agonist fenofibrate overcame B2D phenotypes and rescued glucose availability and fatty liver signatures through activation of the integrated stress response and refilling anaplerotic amino acid substrates for glucose production. We conclude that PPARa governs metabolic responses to FAD availability and suggest pharmacologic activation as a strategy for treating disorders of riboflavin and FAD deficiency.
2022-06-18 | GSE206200 | GEO
Project description:Chronic stress leads post-traumatic stress disorder (PTSD) and to metabolic complications, including fatty liver. It is feasible, that stress immediately initiates molecular mechanisms to alter energy metabolism and glucose homeostasis which interfere with hepatic lipid accumulation after stress recovery. We aim to elucidate these molecular mechanisms of long term stress effects on metabolism and focus on physiological adaptation and the role of FGF21, which is protective in hepatic lipid accumulation. Methods FGF21 knockout and control mice were exposed to chronic variable stress (Cvs) and recovered for 3 months to simulate PTSD. We determined in vivo and ex vivo energy metabolism, mitochondrial function by extracellular flux analysis, alterations in DNA modifying enzymes and gene regulation immediately after stress and after the recovery period to determine long term alterations. Results Chronic stress leads to reduced insulin sensitivity and hepatic lipid accumulation with increased fatty acid uptake (FAU), stress-induced lipolysis, and reduction in NAD+/NAD ratio and Sirt activity. Immediately after stress, PPARa and SREBP-1 target genes are differentially regulated and are involved in the development of stress-induced fatty liver. After recovery, insulin sensitivity increases but insulin-induced de novo lipogenesis (DNL) is reduced and FAU is increased. HDAC and MT activity are suppressed, whereas HAT activity increases, linking metabolic adjustments to transcriptional regulators. Thus, key metabolic genes are differentially regulated and secreted proteins indicate the activation of liver disease by Cvs only in FGF21WT. GR binding to the Cd36 promoter is altered. After stress recovery, serum FGF21 is increased and protects against lipid accumulation. FGF21 interacts by attenuating DNL, increasing FAU and HAT activity, and balancing mitochondrial activity. Higher long-term stress-induced activation and binding of GR to the FGF21 promoter may contribute to the prolonged FGF21 release. Conclusions We show that previous stress exposure determines predisposition to fatty liver disease is regulated by FGF21. Immediately after Cvs, altered gene regulation and activity of DNA-modifying enzymes determine the metabolic late effects seen in PTSD. FGF21 functions after chronic stress exposure i) to protect against hepatic lipid accumulation, ii) to maintain mitochondrial capacity, and iii) to mediate in the modulation of DNA-modifying enzymes. These findings highlight the protective role of FGF21 even in stress-induced hepatic lipid accumulation.
2022-03-10 | PXD025268 | Pride
Project description:Let-7 microRNAs (miRNAs) are a family of highly conserved well-established promoters of terminal differentiation that are expressed in all healthy adult tissues and frequently repressed in cancer cells. The tumour suppressive role of let-7 in a variety of cancers in vitro and in vivo has been widely documented and prompted these miRNAs to be candidate genes for miRNA replacement therapy. Reprogrammed metabolism, recently identified as a new hallmark of cancer, contributes to cancer cell growth, proliferation, invasiveness and drug resistance. In this study we identified a new metabolic role of let-7a in triple-negative breast cancer and metastatic melanoma cell lines. We show that let-7a down-regulates key anabolic enzymes, promotes oxidative phosphorylation and mitochondrial ROS formation accompanied by the up-regulation of the oxidative stress responsive genes. To assess if we could exploit these increased ROS levels for therapeutic purposes, we combined let-7a transfection with the antitumor drug doxorubicin. In both cancer types we observed a stronger response to the doxorubicin treatment in let-7a transfected cells. Pre-treatment with an antioxidant N-acetyl cysteine totally abolished this difference, indicating that the increased doxorubicin sensitivity of let-7a cells depends on the redox pathway. We demonstrated that let-7a plays a prominent role in regulating energy metabolism in cancer cells. We propose that a benefit from let-7 miRNA replacement therapy could come not only from the repression of oncogenic pathways targeted directly by let-7, but also by increased sensitivity to chemotherapeutic agents through indirect metabolic changes caused by let-7. Investigation of let-7a metabolic role in breast cancer and melanoma cells.
2015-12-31 | E-GEOD-60326 | biostudies-arrayexpress
Project description:Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis, with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics analysis and pharmacological intervention showed that loss of FBXW7 function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRa and PPARa, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression. These results provide the foundation for developing alternative strategies co-targeting ERRa and PPARa for the treatment of NASH.
2023-08-18 | GSE205845 | GEO