Cystathionine γ-lyase downregulation contributes to hepatocyte injury and dysfunction via multiple signaling pathways by regulation of histone lysine methylation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE279401 | GEO | 2024/10/17
REPOSITORIES: GEO
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Project description:In the present study, we explored whether skeletal muscle cystathionine γ-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout (CthΔskm) mice. Metabolomics coupled with transcriptome showed that CthΔskm mice displayed impaired energy metabolism and some signaling pathways linked to insulin resistance (IR) in skeletal muscle although the mice had normal insulin sensitivity. HFD led to reduced CTH expression and impaired energy metabolism in skeletal muscle in Cth-floxed mice (Cthf/f) mice. CTH deficiency and HFD had some common pathways enriched in the aspects of amino acid metabolism, carbon metabolism, and fatty acid metabolism. CthΔskm+HFD mice exhibited increased body weight gain, fasting blood glucose, plasma insulin, and IR, and reduced glucose transporter 4 and CD36 expression in skeletal muscle compared to Cthf/f+HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in CthΔskm+HFD mice. Omics analysis showed differential pathways enriched between CthΔskm mice and Cthf/f mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in CthΔskm+HFD mice compared to Cthf/f+HFD mice. Our data indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD.
2024-05-11 | GSE254704 | GEO
Project description:Neurovascular dysfunction in penis is a fundamental reason of erectile dysfunction. Diabetes mellitus is one of the major causes of erectile dysfunction and leads to a poor response to oral phosphodiesterase-5 inhibitors. Heat shock protein 70 (Hsp70), a ubiquitous molecular chaperone exist in all living organisms, is known to play a role in cell survival and neuroprotection. Here, we report an effectiveness of Hsp70 in mediating neurovascular regeneration in diabetic conditions. Using Hsp70-Tg mice or Hsp70 protein administration, we demonstrate that overexpression of Hsp70 in diabetic mice restores erectile function through enhanced penile angiogenesis and neural regeneration. We found that cystathionine gamma-lyase (Cse) is a novel target of Hsp70-driven penile angiogenesis and neural regeneration. Hsp70-Cse triggered SDF1/HO-1/PI3K/Akt/eNOS/NF-κB p65 pathways involved in angiogenesis and neural regeneration. Coimmunoprecipitation and His-Tag pull down assay using mouse cavernous endothelial cells treated with Hsp70 showed the physical interaction between Hsp70 and Cse, and solid-phase binding assay revealed a high-affinity Hsp70-Cse binding with an apparent dissociation constant of 1.8 nmol/L. We provide a novel and solid evidence for Cse-dependent mechanism of Hsp70, which mediates Hsp70-induced neurovascular regeneration and the restoration of erectile function under diabetic conditions.
2022-05-11 | GSE180916 | GEO
Project description:Ischemia/reperfusion injury (IRI) occurs in liver transplantations and major resections and can lead to liver dysfunction. HMGB1 locates in nucleus of normal hepatocytes, but translocates to cytoplasm and the extracellular space during IRI. Although the functions of nuclear and extracellular HMGB1 are well explored, the role cytoplasmic HMGB1 plays in hepatic IRI is still unknown. We hypothesize cytoplasmic HMGB1 interacts with binding proteins involved in the hepatocellular response to IRI. In this study binding proteins of cytoplasmic HMGB1 during hepatic IRI were identified. Normal and warm ischemia reperfusion (WI/R) liver tissues were used for cytoplasmic protein extraction. The protein extracts were subjected to co-immunoprecipitation to enrich HMGB1-protein complexes. To identify the immunoprecipitated proteins in eluates, 2DE and subsequent MS detection were performed. Three identified proteins were verified using western blotting: betaine--homocysteine S-methyltransferase 1 (BHMT), cystathionine gamma-lyase (CTH) and ATP synthase beta subunit (ATP5B). All three identified proteins have a role in metabolic pathways and autophagy. Our results demonstrate cytoplasmic HMGB1 binds to BHMT, CTH and ATP5B during hepatic WI/R. Since both, cytoplasmic HMGB1 and binding proteins, are involved in autophagy, we speculate this protein complex may be involved in the hepatocellular response to IRI via the autophagy pathway.
2017-03-10 | PXD003538 | Pride
Project description:Background/Aims: Cholestatic liver diseases (CLD) are the leading indication for pediatric liver transplantation. Increased intrahepatic bile acid concentrations cause endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) is activated to maintain homeostasis. UPR dysregulation, including the inositol-requiring enzyme 1α/X-box protein 1 (IRE1α/XBP1) pathway, is associated with several adult liver diseases. We evaluated hepatic UPR expression in pediatric patients with end-stage CLD and hypothesize that an inability to appropriately activate the hepatic IRE1α/XBP1 pathway is associated with the pathogenesis of CLD. Methods: We evaluated 34 human liver explants. Cohorts included: pediatric CLD (Alagille, ALGS, and progressive familial intrahepatic cholestasis, PFIC), pediatric non-cholestatic liver disease controls (autoimmune hepatitis, AIH), adult CLD, and normal controls. We performed RNA-seq, quantitative PCR, and western blotting to measure expression differences of the hepatic UPR and other signaling pathways. Results: Metascape pathway analysis demonstrated that the KEGG ‘protein processing in ER’ pathway was downregulated in pediatric CLD compared to normal controls. Pediatric CLD had decreased hepatic IRE1α/XBP1 pathway gene expression and decreased protein expression of p-IRE1α compared to normal controls. These CLD changes were not disease-specific to ALGS or PFIC. IRE1α/XBP1 pathway gene expression was decreased in pediatric CLD compared to AIH disease controls. Conclusion: Pediatric CLD explants have decreased gene and protein expression of the protective IRE1α/XBP1 pathway and down-regulated KEGG protein processing in the ER pathways. IRE1α/XBP1 pathway expression differences occur when compared to both normal and non-cholestatic disease controls. Attenuated expression of the IRE1α/XBP1 pathway is associated with cholestatic diseases and could be targeted to treat pediatric CLD.
2022-06-23 | GSE206364 | GEO
Project description:<p>The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathogenic bacteria through signaling involving phosphatidylinositol 3-kinase (PI3K)/MTOR and the transcription factor SP1. This results in the synthesis of cystathionine, which facilitates the survival of pathogens within myeloid cells. Our data demonstrate that the expression of CTH leads to defective macrophage activation by (i) dysregulation of polyamine metabolism by depletion of S-adenosylmethionine, resulting in immunosuppressive putrescine accumulation and inhibition of spermidine and spermine synthesis, and (ii) increased histone H3K9, H3K27, and H3K36 di/trimethylation, which is associated with gene expression silencing. Thus, CTH is a pivotal enzyme of the innate immune response that disrupts host defense. The induction of the reverse transsulfuration pathway by bacterial pathogens can be considered an unrecognized mechanism for immune escape.</p><p><strong>IMPORTANCE:</strong> Macrophages are professional immune cells that ingest and kill microbes. In this study, we show that different pathogenic bacteria induce the expression of cystathionine γ-lyase (CTH) in macrophages. This enzyme is involved in a metabolic pathway called the reverse transsulfuration pathway, which leads to the production of numerous metabolites, including cystathionine. Phagocytized bacteria use cystathionine to better survive in macrophages. In addition, the induction of CTH results in dysregulation of the metabolism of polyamines, which in turn dampens the proinflammatory response of macrophages. In conclusion, pathogenic bacteria can evade the host immune response by inducing CTH in macrophages.</p>
2020-05-15 | MTBLS696 | MetaboLights
Project description:Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation on relatively few identified proteins, tissue-specific sulfhydrome profiles and their associated functions are not well characterized, specifically under conditions known to modulate H2S production. We hypothesized that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific sulfhydromes. Here, we found protein persulfidation was enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking H2S producing enzyme cystathionine γ-lyase (CGL) had overall decreased tissue protein persulfidation and failed to functionally augment sulfhydromes in response to DR. Overall, we defined tissue- and CGL-dependent sulfhydromes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.
2021-01-25 | PXD022954 | Pride
Project description:Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation on relatively few identified proteins, tissue-specific sulfhydrome profiles and their associated functions are not well characterized, specifically under conditions known to modulate H2S production. We hypothesized that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific sulfhydromes. Here, we found protein persulfidation was enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking H2S producing enzyme cystathionine γ-lyase (CGL) had overall decreased tissue protein persulfidation and failed to functionally augment sulfhydromes in response to DR. Overall, we defined tissue- and CGL-dependent sulfhydromes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.
2021-01-25 | PXD022888 | Pride
Project description:Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation on relatively few identified proteins, tissue-specific sulfhydrome profiles and their associated functions are not well characterized, specifically under conditions known to modulate H2S production. We hypothesized that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific sulfhydromes. Here, we found protein persulfidation was enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking H2S producing enzyme cystathionine γ-lyase (CGL) had overall decreased tissue protein persulfidation and failed to functionally augment sulfhydromes in response to DR. Overall, we defined tissue- and CGL-dependent sulfhydromes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.
2021-01-25 | PXD022956 | Pride
Project description:Objective- Flow patterns differentially regulate endothelial cell phenotype, with laminar flow promoting vasodilation and disturbed flow promoting endothelial proinflammatory activation. CSE (cystathionine ?-lyase), a major source of hydrogen sulfide (H2S) in endothelial cells, critically regulates cardiovascular function, by both promoting vasodilation and reducing endothelial activation. Therefore, we sought to investigate the role of CSE in the endothelial response to flow. Approach and Results- Wild-type C57Bl/6J and CSE knockout ( CSE-/-) mice underwent partial carotid ligation to induce disturbed flow in the left carotid. In addition, endothelial cells isolated from wild-type and CSE -/- mice were exposed to either laminar or oscillatory flow, an in vitro model of disturbed flow. Interestingly, laminar flow significantly reduced CSE expression in vitro, and only disturbed flow regions show discernable CSE protein expression in vivo, correlating with enhanced H2S production in wild-type C57BL/6J but not CSE-/- mice. Lack of CSE limited disturbed flow-induced proinflammatory gene expression (ICAM-1[intercellular adhesion molecule 1], VCAM-1 [vascular cell adhesion molecular 1]) and monocyte infiltration and CSE-/- endothelial cells showed reduced NF-?B (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and proinflammatory gene expression in response to oscillatory flow in vitro. In addition, CSE-/- mice showed reduced inward remodeling after partial carotid ligation. CSE-/- mice showed elevated vascular nitrite levels (measure of nitric oxide [NO]) in the unligated carotids, suggesting an elevation in baseline NO production, and the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide normalized the reduced inward remodeling, but not inflammation, of ligated carotids in CSE-/- mice. Conclusions- CSE expression in disturbed flow regions critically regulates both endothelial activation and flow-dependent vascular remodeling, in part through altered NO availability.
| S-EPMC6662734 | biostudies-literature
Project description:We report studies of six individuals with marked elevations of cystathionine in plasma and/or urine. Studies of CTH, the gene that encodes cystathionine gamma-lyase, revealed the presence among these individuals of either homozygous or compound heterozygous forms of a novel large deletion, p.Gly57_Gln196del, two novel missense mutations, c.589C>T (p.Arg197Cys) and c.932C>T (p.Thr311Ile), and one previously reported alteration, c.200C>T (p.Thr67Ile). Another novel missense mutation, c.185G>T (p.Arg62His), was found in heterozygous form in three mildly hypercystathioninemic members of a Taiwanese family. In one severely hypercystathioninemic individual no CTH mutation was found. Brief clinical histories of the cystathioninemic/cystathioninuric patients are presented. Most of the novel mutations were expressed and the CTH activities of the mutant proteins determined. The crystal structure of the human enzyme, hCTH, and the evidence available as to the effects of the mutations in question, as well as those of the previously reported p.Gln240Glu, on protein structure, enzymatic activity, and responsiveness to vitamin B(6) administration are discussed. Among healthy Czech controls, 9.3% were homozygous for CTH c.1208G>T (p.Ser403Ile), previously found homozygously in 7.5% of Canadians for whom plasma total homocysteine (tHcy) had been measured. Compared to wild-type homozygotes, among the 55 Czech c.1208G>T (p.Ser403Ile) homozygotes a greater level of plasma cystathionine was found only after methionine loading. Three of the four individuals homozygous or compound heterozygous for inactivating CTH mutations had mild plasma tHcy elevations, perhaps indicating a cause-and-effect relationship. The experience with the present patients provides no evidence that severe loss of CTH activity is accompanied by adverse clinical effects.
| S-EPMC2752209 | biostudies-literature