Metabolic Side Effects from Antipsychotic Treatment with Clozapine Linked to Aryl Hydrocarbon Receptor (AhR) Activation DOI Creative Commons
Karin Fehsel

Biomedicines, Journal Year: 2024, Volume and Issue: 12(10), P. 2294 - 2294

Published: Oct. 10, 2024

Metabolic syndrome (MetS) is the most common adverse drug reaction from psychiatric pharmacotherapy. Neuroreceptor blockade by antipsychotic clozapine induces MetS in about 30% of patients. Similar to insulin resistance, impedes Akt kinase activation, leading intracellular glucose and glutathione depletion. Additional cystine shortage triggers tryptophan degradation kynurenine, which a well-known AhR ligand. Ligand-bound downregulates iron pool, thereby increasing risk mitochondrial dysfunction. Scavenging stabilizes transcription factor HIF-1, shifts metabolism toward transient glycolysis. Furthermore, inhibits AMPK obesity liver steatosis. Increasing uptake activation prevents dyslipidemia damage and, therefore, reduces MetS. In line with vitro results, feeding experiments rats revealed disturbed glucose-/lipid-/iron-metabolism treatment hyperglycemia hepatic deposits female steatosis anemia male animals. Decreased energy expenditure seems be cause fast weight gain first weeks treatment. patients, this due neuroleptic correlates an improvement psychotic syndromes can even used anticipate therapeutic effect

Language: Английский

O-GlcNAcylation: A Major Nutrient/Stress Sensor that Regulates Cellular Physiology DOI Creative Commons
Lance Wells, Gerald W. Hart

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(9), P. 107635 - 107635

Published: Aug. 5, 2024

Language: Английский

Citations

4
Evidence for Functional Regulation of the KLHL3/WNK Pathway by O-GlcNAcylation DOI Creative Commons

Jimin Hu,

Duc T. Huynh,

Denise E. Dunn

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

The 42-member Kelch-like (KLHL) protein family are adaptors for ubiquitin E3 ligase complexes, governing the stability of a wide range substrates. KLHL proteins critical maintaining proteostasis in variety tissues and mutated human diseases, including cancer, neurodegeneration, familial hyperkalemic hypertension. However, regulation remains incompletely understood. Previously, we reported that two members, KEAP1 gigaxonin, regulated by O-linked β- N -acetylglucosamine (O-GlcNAc), an intracellular form glycosylation. Interestingly, some ubiquitination targets gigaxonin themselves also O-GlcNAcylated, suggesting multi-level control this post-translational modification may influence many pathways. To test hypothesis, examined KLHL3, which ubiquitinates with-no-lysine (WNK) kinases to modulate downstream ion channel activity. Our biochemical glycoproteomic data demonstrate KLHL3 all four WNK (WNK1-4) O-GlcNAcylated. Moreover, our results suggest O-GlcNAcylation affects WNK4 function both osmolarity ferroptosis, with potential implications ranging from blood pressure neuronal health survival. This work demonstrates functional KLHL3/WNK axis supports broader model O-GlcNAc serving as general regulator signaling proteostasis.

Language: Английский

Citations

0
O-GlcNAc informatics: advances and trends DOI
Chunyan Hou, Weiyu Li, Yaoxiang Li

et al.

Analytical and Bioanalytical Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 18, 2024

Language: Английский

Citations

2
Changes in transcriptomic landscape with macronutrients intake switch are independent from O-GlcNAcylation levels in heart throughout postnatal development in rats DOI Creative Commons
Antoine Persello, Thomas Dupas,

Amandine Vergnaud

et al.

Heliyon, Journal Year: 2024, Volume and Issue: 10(9), P. e30526 - e30526

Published: April 30, 2024

Language: Английский

Citations

1
Opportunities for Therapeutic Modulation of O-GlcNAc DOI

Steven S. Cheng,

Alison Mody,

Christina M. Woo

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(22), P. 12918 - 13019

Published: Nov. 7, 2024

O-Linked β-N-acetylglucosamine (O-GlcNAc) is an essential, dynamic monosaccharide post-translational modification (PTM) found on serine and threonine residues of thousands nucleocytoplasmic proteins. The installation removal O-GlcNAc controlled by a single pair enzymes, transferase (OGT) O-GlcNAcase (OGA), respectively. Since its discovery four decades ago, has been diverse classes proteins, playing important functional roles in many cellular processes. Dysregulation homeostasis implicated the pathogenesis disease, including neurodegeneration, X-linked intellectual disability (XLID), cancer, diabetes, immunological disorders. These foundational studies disease biology have motivated efforts to target therapeutically, with multiple clinical candidates under evaluation. In this review, we describe characterization biochemistry OGT OGA, regulation, development OGA inhibitors, pathophysiology, progress modulators, emerging opportunities for targeting O-GlcNAc. This comprehensive resource should motivate further study into function inspire strategies therapeutic modulation

Language: Английский

Citations

1
The role of protein O-GlcNAcylation in diabetic cardiomyopathy DOI
John C. Chatham, Adam R. Wende

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 27, 2024

It is well established that diabetes markedly increases the risk of multiple types heart disease including failure. However, despite substantial improvements in treatment failure recent decades relative increased associated with remains unchanged. There increasing appreciation importance post translational modification by O-linked-N-acetylglucosamine (O-GlcNAc) serine and threonine residues on proteins regulating cardiomyocyte function mediating stress responses. In response to there a sustained increase cardiac O-GlcNAc levels, which has been attributed many adverse effects heart. Here we provide an overview potential mechanisms O-GlcNAcylation contributes highlight some key gaps our knowledge.

Language: Английский

Citations

1
Pancreatic islets undergo functional and morphological adaptation during development of Barth Syndrome DOI
Christopher Carlein, Markus D. A. Hoffmann, Andressa G. Amaral

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 2, 2024

Abstract Barth syndrome is a multisystem genetic disorder caused by mutation in TAFAZZIN , gene that encodes phospholipid:lysophospholipid transacylase important for cardiolipin remodeling. Syndrome patients suffer from number of symptoms including early heart failure, fatigue, and systemic metabolic alterations, hypoglycemia. The endocrine pancreas central to glucose homeostasis, however, the impact defective remodeling on pancreatic islet function consequences metabolism unclear. Surprisingly, mouse model with global knockdown, we observed improved tolerance compared wildtype littermates. We show secretory are robustly maintained through various compensatory mechanisms increased uptake mitochondrial volume. Transcriptomics analyses revealed expression genes encoding proteins involved N-acetylglucosamine synthesis protein O -linked N-acetylglucosaminylation. These pathways might provide molecular mechanism coupling changes volume regulation.

Language: Английский

Citations

0
Metabolic Side Effects from Antipsychotic Treatment with Clozapine Linked to Aryl Hydrocarbon Receptor (AhR) Activation DOI Creative Commons
Karin Fehsel

Biomedicines, Journal Year: 2024, Volume and Issue: 12(10), P. 2294 - 2294

Published: Oct. 10, 2024

Metabolic syndrome (MetS) is the most common adverse drug reaction from psychiatric pharmacotherapy. Neuroreceptor blockade by antipsychotic clozapine induces MetS in about 30% of patients. Similar to insulin resistance, impedes Akt kinase activation, leading intracellular glucose and glutathione depletion. Additional cystine shortage triggers tryptophan degradation kynurenine, which a well-known AhR ligand. Ligand-bound downregulates iron pool, thereby increasing risk mitochondrial dysfunction. Scavenging stabilizes transcription factor HIF-1, shifts metabolism toward transient glycolysis. Furthermore, inhibits AMPK obesity liver steatosis. Increasing uptake activation prevents dyslipidemia damage and, therefore, reduces MetS. In line with vitro results, feeding experiments rats revealed disturbed glucose-/lipid-/iron-metabolism treatment hyperglycemia hepatic deposits female steatosis anemia male animals. Decreased energy expenditure seems be cause fast weight gain first weeks treatment. patients, this due neuroleptic correlates an improvement psychotic syndromes can even used anticipate therapeutic effect

Language: Английский

Citations

0