Background: This study aims to investigate the role of endoplasmic reticulum stress (ER stress) in human dermal lymphatic endothelial cells (HDLECs) and lymphatic malformations (LMs) and its relationship with aerobic glycolysis and inflammation.
Methods: The proliferation and apoptosis of HDLECs were examined with lipopolysaccharide (LPS) treatment. ER stress-associated proteins and glycolysis-related markers were detected by western blot. Glycolysis indexes were detected by seahorse analysis and lactic acid production assay kits. Immunohistochemistry was used to reveal the ER stress state of lymphatic endothelial cells (LECs) in LMs.
Results: LPS induced ER stress in HDLECs but did not trigger detectable apoptosis. Intriguingly, LPS-treated HDLECs also showed increased glycolysis flux. Knockdown of Hexokinase 2, a key enzyme for aerobic glycolysis, significantly inhibited the ability of HDLECs to resist ER stress-induced apoptosis. Moreover, compared to normal skin, glucose-regulated protein 78 (GRP78/BIP), and phosphorylation protein kinase R-like kinase (p-PERK), two key ER stress-associated markers, were upregulated in LECs of LMs, which was correlated with the inflected state. In addition, excessively activated ER stress inhibited the progression of LMs in rat models.
Conclusions: These data indicate that glycolysis could rescue activated ER stress in HDLECs, which is required for the accelerated development of LMs.
Impact: Inflammation enhances both ER stress and glycolysis in LECs while glycolysis is required to attenuate the pro-apoptotic effect of ER stress. Endoplasmic reticulum (ER) stress is activated in lymphatic endothelial cells (LECs) of LMs, especially in inflammatory condition. The expression of ER stress-related proteins is increased in LMs and correlated with Hexokinase 2 expression. Pharmacological activation of ER stress suppresses the formation of LM lesions in the rat model. ER stress may be a promising and effective therapeutic target for the treatment of LMs.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/s41390-024-03181-9 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Bile acid synthesis impedes tumor-specific T cell responses during liver cancer.
Science
January 2025
NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.
The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid -acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy.
View Article and Find Full Text PDFDeveloping Topics.
Alzheimers Dement
December 2024
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
Background: Autophagy-lysosomal pathway (ALP) efficiency declines Alzheimer's disease (AD). In AD mouse models expressing a fluorescent autophagy and pH probe, autolysosomes pH elevation, resulting from deficient v-ATPase activity, causes autophagy substrates, including Aβ and APP-βCTF, to build up selectively within autolysosomes before extracellular amyloid deposits. In the most compromised but still intact neurons, massive numbers of Aβ-positive autolysosomes pack into huge petal-like blebs bulging out from the perikaryal membrane (PANTHOS).
View Article and Find Full Text PDFBackground: G protein-coupled receptors (GPCRs) are associated with multiple stages of the pathophysiology of Alzheimer's disease (AD). Biased GPCR signaling preferentially activates G protein- or β-arrestin-mediated signaling pathways and presents opportunities to develop more selective and safer therapeutics but remains largely unexplored in AD. Recently, we developed a G protein-biased GPR3 AD mouse model, which does not recruit β-arrestin 2, that displays reduced amyloid-β (Aβ) pathology without adverse cognitive effects associated with elimination of both G protein and β-arrestin signaling.
View Article and Find Full Text PDFDeveloping Topics.
Alzheimers Dement
December 2024
University of Pennsylvania, Philadelphia, PA, USA.
Background: Epidemiological studies indicate that chronic short sleep and/or disrupted sleep are all associated with metabolic dysfunction, cardiovascular risk, cognitive impairments, and increased risk for Alzheimer's disease. We have shown that acute sleep deprivation disrupts proteostasis, leading to the activation of an adaptive endoplasmic reticulum (ER) stress response known as the unfolded protein response (UPR). However, prolonged ER stress triggers the integrated stress response, which has been implicated in memory impairments.
View Article and Find Full Text PDFCaveolin-1 mitigates the advancement of metabolic dysfunction-associated steatotic liver disease by reducing endoplasmic reticulum stress and pyroptosis through the restoration of cholesterol homeostasis.
Int J Biol Sci
January 2025
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, which has the potential to advance to fibrosis. CAV1 has the effects of improving liver lipid deposition in MASLD, however, the potential mechanism is largely unknown. Here, we establish a MASLD mouse model in CAV1 knockout (KO) mice and perform transcriptome analysis on livers from mice to investigate the effects of CAV1 in MASLD progression.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!